Page 62 – Practical Gastro

Patrick C Bonasso,Jared Feyko,Nezar Jrebi

We report the case of a 70 year-old female with a palpable abdominal mass and anemia. After colonoscopy was inconclusive for diagnosis, resection via laparoscopic right hemicolectomy revealed malignant fibrous histiocytoma of the cecum. This case discusses the pathology and treatment of this rare disease.

Patrick C Bonasso, MD; Jared Feyko, DO; Nezar Jrebi, MD Department of Surgery, Ruby Memorial Hospital, West Virginia University; Division of Surgical Oncology, West Virginia School of Medicine

CASE PRESENTATION

A 70-year-old female presented with abdominal pain, fatigue, anorexia and weight loss. On exam, she had a palpable abdominal mass in the right lower quadrant. Her initial laboratory values revealed severe microcytic, hypochromic anemia with a hemoglobin of 7.6 g/dL. Her white blood cell count (WBC) was 5.4 thou/mcL, platelets 350 thou/mcL, creatinine 0.5 mg/ dL and carcinoembryonic antigen (CEA) less than 0.2 ng/mL. Computed tomography (CT) of the abdomen and pelvis showed a mixed density lobular cecal mass measuring 7.5 x 10.2 x 7.9 cm with several enlarged lower right mesenteric lymph nodes (Figure 1).

The patient was admitted and underwent colonoscopy with biopsy (Figure 2). Pathology showed ulceration with inflammation and scattered atypical cells suspicious for malignancy. She was taken to the operating room and underwent laparoscopic right hemicoloectomy (Figure 3). She progressed through hospitalization without any complications. She tolerated a regular diet and was discharged on postoperative day three.

Final pathology revealed a neoplasm composed of large, pleomorphic giant cells and spindle cells, arranged in fascicular and storiform pattern mixed with inflammatory cells infiltration, including lymphocytes, plasma cells, polymorphonuclear leukoocytes (PMNs) and multinucleated giant cells. Immunohistochemical (IHC) staining showed positive reaction of tumor cells with a1 antitrypsin, Vimentin and focal smooth muscle actin (SMA). The tumor was Grade III with 9 out of 21 lymph nodes positive for malignant disease.

Discussion

Malignant fibrous histiocytoma (MFH) is the most common soft tissue sarcoma in adults.¹ Common locations of this sarcoma include the lower and upper extremities (most common, 46%), retroperitoneum, abdominal cavity, head and neck.

Primary MFH in the alimentary tract is rare. There have only been 25 reported cases in the colorectal literature,² most commonly in the right colon. Often these tumors are large with an average size of 8.1 cm and a range of 2-19 cm. Review of previously reported cases show a male to female ratio of 2.3:1 with an average age of 55.7 years. Most of the tumors were solitary, but some were multiple.

Common presenting symptoms include abdominal pain, fever, palpable mass, bloody stools, diarrhea and anorexia secondary to compression from the large mass. Laboratory values commonly include leukocytosis, elevated erythrocyte sedimentation rate (ESR) and elevated C-reactive protein (CRP). Predisposing factors include genetics, exposure to radiation or chemotherapy, chemical carcinogens, chronic irritation and lymphedema.

Treatment options include radical surgical resection, chemotherapy with cyclophosphamide, vincristine, adriamycin, dimethyl triazenoinidazole carboxamide (CYVADIC) or radiotherapy (5000 to 5400 cGy). The prognosis is unclear with most reports suggesting that outcomes are poor. The overall survival at two and five years is 60% and 47%, respectively.²

The tumor arises from primitive mesenchymal cells that retain histiocytic and fibroblastic potential. Pathology of the sarcoma shows both histiocytic and fibrous elements accompanied by pleomorphic giant cells, xanthoma cells and inflammatory cells. Pleomorphic fibroblastic cells are commonly arranged in a storiform pattern and positive for vimentin and a 1-antichymotrypsin. MFH is further classified into four types: storiform-pleomorphic, inflammatory, myxoid and giant cell. The most common type is storiform- pleomorphic.³

CONCLUSION

We report a rare case of malignant fibrous histiocytoma (undifferentiated pleomorphic sarcoma) of the alimentary tract treated with colon resection.

FRONTIERS IN ENDOSCOPY, SERIES #32

Introducing POEM in Your Institution: The Blueprint for Launching a New Program in the Endoscopy Suite

Dennis Yang,

Peter V. Draganov

Per-oral endoscopic myotomy (POEM) is a prime example of a hybrid technique derived from NOTES and endoscopic submucosal dissection (ESD). POEM is an endoscopic therapeutic procedure aimed at treating achalasia and spastic esophageal disorders. While POEM was introduced and traditionally performed in the operating room (OR) setting, its well-documented safety and efficacy over the past 8 years has led to its natural acceptance by therapeutic endoscopists worldwide and consequently a growing interest in performing this procedure in the endoscopy suite. This review aims to provide a practical guide of introducing POEM in the endoscopy suite from a gastroenterologist’s perspective.

Dennis Yang, MD Peter V. Draganov, MD Division of Gastroenterology and Hepatology, Department of Medicine, University of Florida College of Medicine, Gainesville, FL

The birth of natural orifice transluminal endoscopic surgery (NOTES) in the early 2000s introduced the revolutionary concept of endoscopy beyond the restrictive walls of the gastrointestinal tract. The initial impetus was subsequently met with skepticism as these novel ideas were crippled by the rudimentary instruments and accessories available on the flexible endoscopic platforms. With advances in technology over recent years, there has been a resurgence of NOTES, as witnessed by the increasing number of interventional endoscopists expanding endoluminal applications outside the confines of the gastrointestinal tract.

Per-oral endoscopic myotomy (POEM) is a prime example of a hybrid technique derived from NOTES and endoscopic submucosal dissection (ESD). Initially introduced as a concept by Pasricha and colleagues in 2007 and translated into clinical application by Inoue et al. in 2008, POEM is an endoscopic therapeutic procedure aimed at treating achalasia and spastic esophageal disorders.^1,2 While POEM was introduced and traditionally performed in the operating room (OR) setting, its well-documented safety and efficacy over the past 8 years has led to its natural acceptance by therapeutic endoscopists worldwide and consequently a growing interest in performing this procedure in the endoscopy suite.³ This review aims to provide a practical guide of introducing POEM in the endoscopy suite from a gastroenterologist’s perspective.

There are tangible and intangible benefits of adopting complex procedures such as POEM in the endoscopy unit. Advantages of the endoscopy unit over OR include: (1) better ergonomics for endoscopic procedures, (2) readily available endoscopic equipment and accessories and (3) familiarity of the surrounding environment by the endoscopist and the assisting team. We had previously demonstrated that POEM can be safely and efficiently done in the endoscopy suite based on the experience of our first 52 consecutive patients.⁴ Since then we have performed an additional 100 cases with excellent clinical response rates to further corroborate our initial results. The POEM program at our institution has become a crucial arm within the spectrum of a comprehensive motility program. That being said, starting a POEM program can be a challenging endeavor and careful planning is essential in order to ensure long-term success and stability. There are several key components that must be addressed prior to launching a POEM program in the endoscopy unit: (1) institutional support, (2) training, and (3) establishing a multi-disciplinary team.^5,6

Institutional Support

Institutional endorsement on various fronts should be obtained prior to starting a POEM program. The potential advantage of a POEM program should be discussed, with an emphasis on its role in the establishment of a comprehensive motility program at your institution. While the approach may differ at every institution, one should actively seek and contact all stakeholders, which may include the department chair and division chief, the director of the endoscopy unit and other institutional administrators.

Institutional support in terms of protected time to train in an animal laboratory is highly desirable. In our institution, POEM trainees have full access to a well- equipped animal laboratory which facilitates hands- on experience prior to any attempts in humans. This approach permits a realistic exposure to the procedure while removing the high stakes of a clinical setting. Indeed, the international POEM survey on practice patterns demonstrated that most POEM practitioners underwent preclinical training in animal models before human cases.⁷

Institutional support must also be obtained to make infrastructural adjustments in the endoscopy unit to facilitate the introduction of POEM. As noted earlier, POEM has been traditionally performed in the OR, an environment conventionally perceived as more adept at managing complex procedures. For POEM to be safely performed, the endoscopy unit should possess amenities on par to what is available in the typical OR. Needless to say, full institutional support to obtain all necessary equipment and accessories is imperative. In our endoscopy suite, we store all POEM-related equipment and devices in a dedicated “POEM cart” (Figure 1). On this cart we do maintain inventory of the dedicated POEM devices such as the TT and the Hybrid knifes (Figure 2 and 3) but also devices for hemostasis, perforation closure, chest tube placement kits and peritoneal decompression needles. This approach expedites the movement of items in and out of the endoscopy room, permits quick and easy access to devices intra-procedurally, and also facilitates inventory control. Furthermore, it is our opinion that the endoscopy unit should have permanently stationed general anesthesia equipment as the POEM procedure requires general endotracheal anesthesia. This approach may be conducive for efficient anesthesia preoperative planning and set-up with reduced room turnover time.

Support from institutional administrators must also be sought on issues related to credentialing, scheduling, billing and coding, which again, may differ widely among centers. Prior to starting POEM, it is important to discuss the goals of such a program with the credentialing/privileges committee. In the absence of standardized training guidelines, there should be a conjoint effort between POEM operators and the institution’s committee to establish the necessary benchmarks that must be met prior to becoming credentialed for this novel procedure. In addition, we believe that a dedicated preprinted POEM procedure inform consent form should be utilized which describes in detail the procedure and potential complications both of which significantly defer from other endoscopic procedures. With regards to scheduling, based on multiple reports and our own experience, POEM cases can generally be completed within 60-90 minutes. Nonetheless, additional time allotment for set up and room turnover must be factored in order to avoid conflict with the scheduling of other cases in the endoscopy unit. In addition to scheduling, issues related to billing and coding should also be anticipated given the novelty of this endoscopic procedure. There is currently no procedural terminology (CPT) code for POEM. However, many centers apply an unlisted esophageal surgical code (CPT code 43499) billed at the relative value units equivalent of that of a Heller myotomy.5,7 Discussion with stakeholders with regards to billing and coding should be undertaken prior to scheduling procedures in order to avoid subsequent denials from payers and ensure proper reimbursement.

Training

POEM is a technically complex hybrid procedure that demands advanced endoscopic skills, knowledge of both gastrointestinal (GI) intra and extra luminal anatomy, and a grasp on how to manage complications, including hemorrhage, tension pneumothoraxes, pneumomediastinum, and esophageal perforations. Developing a curriculum and defining a learning curve are complicated by background differences among operators and the relative low incidence of achalasia. Not surprisingly, there is a wide discrepancy in the learning curve plateau reported in the literature, ranging anywhere from 8 to 20 cases.^8-10 Since the principles of POEM are in line with ESD techniques, it appears reasonable that training should follow a similar approach to one previously described for ESD.¹¹ An in- depth understanding of the POEM principles, technical aspects and equipment will be a good starting point. A detailed discussion of this subject is beyond the scope of this manuscript, but multiple resources are available in the published literature. Two recent excellent reviews by the POEM pioneer Dr. Inoue highlight his experience and evolving technical concepts.^12,13

In summary, initial exposure can be achieved by attending training courses and observing POEM performed by an expert operator. The trainee should be familiar with all the necessary equipment for POEM and also that required for the management of potential adverse events (i.e. hemostasis equipment, suturing devices, enteral stents). Hands-on training should start with explanted models which may be more cost- effective and allow assessment of the gross specimen following the procedure. Once trainees are comfortable with POEM on the explanted model, progressing to a live animal represents the next natural step. The porcine model is ideal given its long esophagus and anatomical resemblance to that of a human. Following preclinical hands-on training, we strongly recommend that trainees be proctored by an experienced operator, who can provide step-by-step supervision and guidance through the initial cases. There are currently no standardized credentialing requisites for POEM and these are urgently needed as we continue to see the increasing adoption of this technique by interventional endoscopists worldwide.

The POEM Multidisciplinary Team

Establishing a multidisciplinary team is perhaps the most important element when initiating a POEM program. Before the introduction of POEM, a multidisciplinary team approach should be adopted to address various technical and clinical aspects of patient management from pre-procedure evaluation to post-procedural discharge:

1. Motility gastroenterologists play an invaluable role in the nonoperative evaluation of patients and should be involved in the multidisciplinary discussions of potential POEM candidates. Their investment in the POEM program not only aids with the identification and recruitment of patients, but it also facilitates longitudinal patient care and assessment of clinical outcomes post-POEM.
2. Participation of the surgical team is also an indispensable component when initiating the POEM program. The surgical team members should become familiar with the endoscopic aspects of the procedure. In turn, the POEM operator can benefit from the surgeons’ perspective and knowledge of extraluminal anatomy. Surgical team members should be readily available to assist in case of a complex procedure or in the management of adverse events. A contingency plan should be well-outlined prior to initiating cases. Prearrangement of surgical back-up before POEM cases may need to be determined based on their accessibility at each respective institution.
3. Before a POEM program is initiated in the endoscopy unit, it is highly advisable to establish a well-defined anesthesia plan for these patients. Overall, the predetermined anesthesia protocol should include details regarding patient position, type of anesthesia, degree of paralysis, ventilation mode as well as clinical and technical parameters that should be monitored throughout the procedure (i.e. peak airway pressure, tidal volumes, end-tidal carbon dioxide, train-of-4 twitches, oxygen saturation). A standardized anesthesia protocol and clear communication among team members is key; particularly in those endoscopy units where coverage is performed by various different rotating anesthesia providers. Specifics regarding anesthesia management are further detailed in our experience with starting a POEM program in the endoscopy suite.⁴
4. The POEM nurses and technicians should be an integral part of the team. We strongly recommend that the POEM team practice together with explanted or live animal models in order to become familiar with the equipment, steps of the procedure, and management of adverse events. This approach will permit hands-on training and allow the POEM team identify and fine-tune areas for improvement. More importantly, it is an ideal scenario that will foster cohesiveness among team members prior to embarking on human cases. 5. Surveillance imaging post-POEM procedure is routinely performed in all patients to assess for adverse events (i.e. esophageal mucosal injury, leak, perforation). At our institution, we developed a novel computed tomography (CT) esophagram protocol in conjunction with our radiology department. In a prospective study of 84 patients, we demonstrated that numerous and dramatic post-procedural radiographic findings are captured with the CT esophagram; although most of these do not require any intervention.¹⁴ Therefore, radiologists should be educated on the POEM procedure and the spectrum of post-procedure radiographic findings that can be encountered. Their awareness of these imaging findings will facilitate its clinical interpretation and prompt intervention when indicated. Imaging surveillance should be tailored according to local resources, expertise, and feasibility.

In summary, POEM has evolved into a recognized minimally invasive endoscopic approach for the management of achalasia and certain esophageal spastic disorders. POEM can be safely performed by experienced interventional endoscopists in a well-equipped endoscopic suite. Nonetheless, starting a POEM program can be a challenging task. Institutional support, proper training, and developing a multidisciplinary team are the essential building blocks to ensure the successful initiation and establishment of a POEM program.

NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #158

Medicare Coverage for Home Parenteral Nutrition – An Oxymoron? Part I

Penny Allen

Physicians and healthcare providers charged with caring for patients requiring home parenteral nutrition (HPN) face increasing pressure to discharge patients earlier from the acute care setting. This article provides the clinician with a review of the very dated Medicare policy for HPN, the criteria and objective documentation still required by law today, as well as strategies for attempting to provide home infusion therapy when Medicare will not cover patients who appropriately need HPN.

A 67 year old female patient with Stage III ovarian cancer presenting with partial small bowel obstruction, intractable nausea and vomiting is referred to a home infusion provider for home parenteral nutrition on a Friday afternoon. The patient has Medicare as her primary insurance as well as a supplemental policy. The physician and case manager are informed: “I am sorry, your patient does not meet the Medicare criteria for home parenteral nutrition.”

INTRODUCTION

Physicians and healthcare providers charged with caring for patients requiring home parenteral nutrition (HPN) face increasing pressure to discharge patients earlier from the acute care setting. Patients with gastrointestinal (GI) disorders, GI and nutritional complications from cancer, and other conditions may require continuation of parenteral nutrition (PN) therapy in the home setting. As the population of Medicare eligible beneficiaries grows, it is often a surprise at the time of discharge that many patients do not meet criteria for HPN and related medically necessary infusion therapies under Medicare. In a recent abstract by a home infusion provider, 42% of medical records reviewed for Medicare PN coverage over a 7 month period did not include objective testing required for reimbursement coverage, even though the diagnoses with potential for meeting criteria were present in the records.¹

This article provides the clinician with a review of the very dated Medicare policy for HPN, the criteria and objective documentation still required by law today, as well as strategies for attempting to provide home infusion therapy when Medicare will not cover patients who appropriately need HPN. Regardless of insurance plan, if there is any possibility that a patient may require HPN post discharge, the planning process should begin immediately so that all members of the healthcare team as well as the patient are aware of what is required to attempt to secure coverage.

• What is needed to try to successfully qualify this patient for HPN under Medicare?

• If the patient has no coverage under Medicare, what options exist for patients to receive PN and other infusion therapies which are medically necessary?

BACKGROUND
Medicare HPN Policy Remains the Same Over 20 Years Later

Medicare is the federal healthcare program enacted by Congress as part of Title 18 of the Social Security Act of 1965. It is the largest health insurance program in the United States. Medicare coverage is divided into Parts A, B, C, and D, each of which provides different benefits.

For over 20 years, parenteral and enteral nutrition (PEN) therapies fall under the prosthetic device benefit under Medicare Part B. The analogy utilized by the Center for Medicare and Medicaid Services (CMS) is that parenteral nutrition (PN) and enteral tube feeding (or actually the devices to administer them), replace an organ or function of an organ that is permanently impaired. If specific criteria related to any one of 7 GI conditions “permanently” (defined as ≥ 3 months) prevents the patient from absorbing nutrients needed to maintain weight and strength commensurate with health status, and it is documented objectively in the manner required, then Medicare may cover HPN accessories and/or supplies. In addition to the necessary supplies, the oversight of HPN is ideally performed by an inter- disciplinary team on a weekly basis. This oversight of professional services, clinical assessment, monitoring, or the actual ongoing management of the patient has never been covered under Medicare.

The HPN Policy Under Medicare

Currently, the Parenteral Nutrition Policy A52515,^2,3 (which has not changed in over 20 years) states:

“Parenteral Nutrition is covered under the Prosthetic Device benefit (Social Security Act 1861(s)⁸)

Parenteral nutrition is covered for a beneficiary with permanent, severe pathology of the alimentary tract which does not allow absorption of sufficient nutrients to maintain weight and strength commensurate with the beneficiary’s general condition.”

The Medicare concept of permanent impairment of the small intestine is often a challenging one for many clinicians who approach HPN with the hope that it will be temporary and that patients may over time reduce their PN-dependence through bowel adaptation as well as diet and medication management. The policy goes on to read:

“Prosthetic Benefit Requirements

The beneficiary must have a permanent impairment. Permanence does not require a determination that there is no possibility that the beneficiary’s condition may improve sometime in the future. If the judgment of the attending physician, substantiated in the medical record, is that the condition is of long and indefinite duration (ordinarily at least 3 months), the test of permanence is considered met. Parenteral nutrition will be denied as non-covered in situations involving temporary impairments.

The beneficiary must have:
(a.) a condition involving the small intestine and/or its exocrine glands which significantly impairs the absorption of nutrients or,

(b.) disease of the stomach and/or intestine which is a motility disorder and impairs the ability of nutrients to be transported through the GI system. There must be objective evidence supporting the clinical diagnosis.”

Table 1 provides a checklist outlining the clinical situations (A-H) where Medicare will cover HPN. In addition to meeting the test of permanence (Medicare defines permanence as >90 days), there must be clear objective evidence that the GI tract, specifically the small intestine, is non-functioning. A completed Durable Medical Equipment Medicare Administrative Contractor or DME MAC Information Form (DIF), formerly referred to as a Certificate of Medical Necessity (CMN), a Detailed Written Order (DWO), along with extensive objective documentation from the medical record to support the criteria is the minimum required by the Center for Medicare and Medicaid Services (CMS). The original version of Table 2, published and distributed by the former DMERC (now called DME MAC) Region D over a decade ago, outlines the necessary documentation required for each criteria.

Medicare requires an attempt at tube feeding when there is a “moderate abnormality” (see Table 3) of a condition in Situations A-F (Table 1) and the documentation does not exactly meet criteria for coverage. In this instance, additional information such as documented weight loss, a low albumin, attempts at medication and diet modifications and a tube feeding trial is required. There is currently no exception in the policy allowing for situations where a tube feeding trial may not be clinically appropriate or possible. Criteria outlining the documentation necessary for a failed tube feeding trial is outlined in Table 4.

What Has Changed? The Claims Process and Many, Many Audits

The initial claims submission process is different today than in years past causing confusion among some providers, which could potentially place patients/ families at significant financial risk. Qualifying documentation is no longer submitted with the initial claim; in the past, coverage was approved or denied by CMS from the start. Supporting medical records should be obtained by the infusion/PN provider prior to the start of care so they are available for submission when claims are audited, which is a routine occurrence. The initial analysis of whether a patient has coverage falls completely on the infusion provider. If the provider does not fully understand or interpret the policy correctly, physicians and patients may be provided with an incorrect “approval” by the provider/vendor at time of discharge. To make matters more confusing, CMS will pay claims even when a patient does not actually meet criteria–until the provider is audited and then required to submit the initial supporting documentation. This is often months or even years later. CMS can audit a claim up to three years after a claim has been paid, which could potentially end up being as many as five years after an incident of care or shipment was provided.⁴ If documents cannot be produced in an audit, the government recoups all payments and the beneficiary could be at risk for the total amount, which could be tens of thousands of dollars.

The National Medicare Recovery Audit Program was established in 2009. The intent of this program is to identify and correct improper Medicare and Medicaid payments through the detection and collection of overpayments made on claims for health care services provided to Medicare and Medicaid beneficiaries. The frequency and types of audits conducted have increased substantially since 2010. In Fiscal Year 2014, Recovery Auditors collectively identified and corrected 1,117,057 claims that resulted in $2.57 billion dollars in improper payments being corrected and recouped by Medicare.⁵

After an audit has been conducted and a claim is denied, there are 5 levels of appeal for infusion providers within CMS. Statistics for 2015 from the Office of Medicare Hearing and Appeals (OMHA), give an average time frame of 547 days to reach a Level 3 Administrative Law Judge adjudication, indicating a significant backlog in the current system.⁶ Since audits are a common occurrence, infusion providers should understand and adhere to Medicare PN policy by collecting necessary qualifying documents prior to discharge which may help to protect the patient financially in the long run.

“Are other medically necessary infusion therapies like hydration and anti-infectives covered by Medicare?”

“How can my patient obtain access to the therapies they need at home if not?”

Challenges with Medicare and Home Infusion Therapies

The Medicare program is the only payer in the United States that fails to recognize the clinical and cost benefits of providing infusion in the home setting. Currently, many infusion therapies are not covered by Medicare under Part B, even when medically necessary (Table 5).

Since Medicare has not kept up with current utilization and nationally accepted standards for use of PN, organizations including the American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) and the National Home Infusion Association (NHIA) have lobbied CMS for years in an attempt to change existing law so that meaningful home infusion therapy for Medicare beneficiaries is available. Current policy for HPN severely limits access to therapy with few patients meeting the government’s criteria, either due to the test of permanence required, or non-qualifying conditions for PN such as malnutrition, GI/nutritional complications due to cancer treatments or bariatric surgery.

An abstract published in 2007 reported that only 16% of Medicare PN referrals received (over a large geographically and medically diverse sample) by a national infusion provider met CMS HPN policy requirements for coverage.⁷ Almost 10 years later, another national infusion provider with similar referral statistics, demonstrated that even fewer Medicare beneficiaries (10.5%) referred for HPN met the restrictive policy requirements, leaving few options for patients without coverage unless they had a secondary major medical insurance policy.⁸

Transitioning from Commercial Payer to Medicare Coverage-What Then?

A significant challenge for HPN patients, providers, and their physicians is when a patient transitions from a commercial payer to Medicare coverage when they meet disability criteria or turn 65 years old. There is no such thing as “grandfathering” of HPN coverage when a patient flips to Medicare from another insurance company, making it incredibly difficult to meet the stringent rules of Medicare coverage when a patient has already been on HPN for months or even years. There are no clear guidelines from CMS on how to “qualify” patients already on HPN who enroll into the Medicare program, leaving physicians and providers to search and scour through old medical records from the time period when the patient first started on PN (if they even exist) and attempt to qualify them retroactively. Many insurance providers only require a statement of “medical necessity” for HPN coverage; therefore testing, objective studies, and length of need documentation may never have been completed at the time of PN initiation months or years before.

Most commercial payers also do not follow a “permanent impairment” deal breaker for HPN coverage, so documentation required by Medicare when PN was initiated, i.e., a statement of how long the attending physician thought the patient would need HPN, may not exist because the insurance coverage the patient had at the time did not require it. Unfortunately, despite the fact that there is almost always medical necessity for PN, when a patient switches to Medicare, there will be no coverage for the HPN if there is no “qualifying” situation (A-H), the objective evidence is not available to support the qualifying situation, or there is no documented length of need of 90 days or longer, even in cases where a patient has been on HPN for many years.

Healthcare practitioners caring for HPN patients would be well advised to guide their patients to examine all insurance options available regarding original Medicare, Medicare Advantage or replacement plans before dropping existing insurance coverage when they turn 65 years old. Table 6. outlines less than ideal potential options to investigate when there is no coverage under Medicare.

What about Medicare Part D? Is there any coverage for PN or Other Infusion Therapies Needed?

In the above situation, if a patient does not meet Medicare Part B criteria for HPN when they transition to Medicare, the logical assumption would be that the patient is entitled to HPN coverage under Medicare Part D.

Part D is a prescription drug only benefit that may or may not have limited coverage for certain ingredients in the PN, for example those deemed prescription drugs such as amino acid or lipid. Rarely are all (if any) PN ingredients covered under Part D and each Part D provider has a different drug formulary. Since Part D is a prescription drug only benefit, there is no coverage for pump, supplies, tubing, delivery, or clinical management/professional services, making it nearly impossible for any provider to accept Part D reimbursement. Patients will almost always have a considerable co-pay for these necessary supplies if they choose to receive care at home. If additional PN related infusion therapies such as hydration or anti-infectives are prescribed, the same scenario presents a challenge for the practitioner trying to find providers willing to accept Part D reimbursement when much of the therapy cost is not covered.

Hoping for Change? Medicare Site of Care Act S. 275/H.R. 605

The Medicare Home Infusion Site of Care Act of 2015 S. 275/H.R. 605 was introduced by Senators Johnny Isakson (R-GA), Mark Warner (D-VA) and Congressmen Eliot Engle (D-NY) and Pat Tiberi (R- OH). The goal is for Medicare beneficiaries to have access to home infusion. This bill would provide a pathway for reimbursement for professional services, supplies and equipment associated with home infusion therapy under Medicare Part B, enabling the Part D coverage of infusion drugs to become more meaningful for Medicare beneficiaries. The bill also requires development of safety standards to ensure the safe and effective provision of infusion therapy, allowing the Medicare program to realize the efficiencies and positive outcomes the private sector has experienced for over 30 years. If passed, many more patients could receive cost-effective, medically necessary infusion treatments such as PN, hydration and anti-infectives in the home setting.

At present, infusion therapy including PN is fully covered by Medicare everywhere but in the home setting: hospitals, skilled nursing facilities (SNFs), hospital outpatient departments, and physician offices. Medicare may pay a portion of certain infusion drugs provided in the home, but due to the lack of reimbursement for the necessary services, supplies and equipment used in the provision of the infusion therapy, most Medicare beneficiaries in reality do not have access to therapy at home since the cost may be prohibitively expensive for the patient, with copays as high as $30-$80 or more per day. If passed, the Medicare Home Infusion Site of Care Act will provide a much needed mechanism for coverage of all that is necessary to infuse a drug and/or PN safely-clinical professional services, supplies and equipment-which would make the Part D coverage of infusion drugs meaningful and logical.

For more information on how to support the passage of this bill (including templates to write to your state representatives) go to:

• http://www.nhia.org/resource/legislative/ MedicareHomeInfusionSiteofCareAct.cfm

• www.nhia.org/resource/legislative/ WriteYourMemberofCongressMHISOCA.cfm

Selection of HPN/infusion providers who are fluent and compliant with Medicare and federal law may protect beneficiaries from financial hardship down the road. Some providers will accept Medicare PN referrals quickly and without a thorough assessment, then later discontinue care when they learn there is no reimbursement from CMS. If an infusion provider quickly accepts a Medicare PN case without a complete review of the documentation prior to discharge, it should be a red flag to the clinician/referral source. Qualified reputable HPN providers should offer consultative guidance in the way of a “records review” at the time of referral to help physicians navigate the complexity of the policy with the ultimate goal of protecting the patient.

During open enrollment time periods, physicians and PN providers should guide patients to investigate alternative insurance options and/or Medicare Advantage or replacement plans with more meaningful benefits should the patient require PN or other home infusion due to a chronic condition. Lastly, although not ideal, Medicare beneficiaries do have coverage for PN in a skilled nursing facility (with Part A restrictions), so if the HPN did not meet coverage criteria because the length of need was not permanent, the patient may have coverage in the SNF setting.

CONCLUSION

Until new laws are passed and coverage for home infusion/PN becomes more meaningful under Medicare, healthcare providers should carefully assess the need for HPN therapy. Referrals for homecare should be made as early as possible to allow for thorough examination and review of medical documentation and allow for the possibility that additional testing may be required by Medicare. This will help ensure that the beneficiary will have coverage for HPN and is not at risk for denial of payment should an audit determine that coverage criteria was not met, potentially leaving the patient and family with a significant bill in the future.

All providers involved in the care of patients requiring HPN and related therapies should develop a stronger understanding of the Medicare reimbursement system in order to advocate for the needs of this challenging patient population. Failing to do this may prevent patients from having access to life sustaining nutrition support and could also expose them to significant financial harm. Given these risks, clinicians would be well advised to carefully document the clinical necessity of HPN backed up by objective evidence and testing, along with an estimated length of need for the therapy for all patients going home on PN-as if they needed to meet Medicare criteria. Patients who currently have private insurance may eventually transition to Medicare and supporting documentation will be required for a successful transition and continuation of HPN therapy. For more information regarding the Medicare Home Infusion Site of Care Act as well as additional resources, see Table 7.

COLORECTAL CANCER: REAL PROGRESS IN DIAGNOSIS AND TREATMENT, SERIES #9

Colonic Capsule as a Screening Test for Colorectal Cancer: We are Improving

Cesera Hassan,

Nadir Arber

Colonoscopy is currently the gold standard of colorectal cancer (CRC) screening. The procedure, however, is invasive and is not without its risk of complication, thus diminishing patient participation in effective screening programs.^1-3 Additionally, patients are reluctant to undergo screening colonoscopy due to the discomfort and inconvenience of the pre-procedure laxative colonic cleansing as well as the anticipated pain of the procedure.^3,4 In an effort to improve patients’ willingness to cooperate in improving their colon health, non-invasive testing of the colon has been trialed over the past few decades. Colonoscopy with colon-capsule is an endoscopic technique developed for a non-invasive, painless exploration of the colon without the need of sedation and injection of air. Its major obstacle is the need for meticulous colonic cleaning. The Check Cap imaging system, which is comprised of an ingestible imaging capsule and an external recorder, is one such device that may overcome the hurdle of pre-procedure bowel preparation. This capsule emits radiological data for constructing three-dimensional images of the colonic mucosa without the need for colonic cleansing. Since the system is safe, easy-to-use, painless, patient-friendly and private, this imaging system may significantly increase participation rates in a CRC screening programs.

Cesera Hassan1 Nadir Arber² 1Endoscopy Unit Nuovo Regina Margherita Hospital, Rome, Italy ²The Integrated Cancer Prevention Center and Department of Gastroenterology, Pathology Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

INTRODUCTION

Colorectal cancer (CRC) is a major health concern with an incidence of 1.2 million new cases per year and a mortality rate close to 600,000 yearly. At the same time, CRC is one of the most preventable and curable malignancies if diagnosed at an early stage.^4,5 Consequently, CRC screening programs were established in more than 50 countries.⁶ Despite participation rates in these programs being below the set targets, CRC incidence and mortality rates are declining.⁷ Colorectal cancer screening in the United States increased significantly from 2000 to 2010 and was essentially unchanged in 2013. Over the same period, the incidence of and deaths from colon cancer have decreased and these are attributed to improvements in screening for CRC, improved treatment strategies and changing patterns in risk factors.⁸ Specifically, CRC death rates declined by 2% per year during the 1990s and approximately 3% each year during the past decade (2001-2010) with the most impact in adults aged 65 and older. In Europe, CRC screening programs have been implemented in 19 of 27 European Union (EU) countries with participation rates nearing 60%.⁹ CRC mortality has fallen in an increasing number of European countries since 1970, despite persistent differences between specific regions in Europe. The largest reductions in CRC mortality have occurred in western and northern European countries because of increased screening participation and improved access to specialized care. In most central European countries, CRC mortality has been stable or slightly decreasing since the early 2000s, but is still increasing in most eastern European countries.¹⁰ These epidemiological findings infer that participation in a CRC screening program will culminate in an improved health outcome.^11,12

CRC Screening Tests

The American College of Gastroenterology (ACG) has classified colorectal cancer screening tests as either CRC prevention tests or CRC detection tests.¹³ Tests that are labeled as prevention are “imaging tests” given their potential to identify both cancer and polyps. These tests either enable visual assessment of the structural integrity of the colon and rectum (e.g. flexible sigmoidoscopy, colonoscopy and capsule colonoscopy) or are non-invasive tests that are able to obtain two-and/ or three-dimensional (3D) images of the colon and its mucosa [e.g. computed tomography (CT) colonography and a double-contrast barium enema]. On the other hand, detection tests are “indirect tests” that probe the stool for the presence of markers of CRC [e.g. fecal occult blood test (FOBT), fecal immunochemical test (FIT) and the fecal DNA test)]. While non-invasive, these tests have low sensitivity for detecting polyps. Colonoscopy is the standard of care for evaluating the colon, either as a primary test or as a follow up to an abnormal imaging modality or positive stool testing.^13,14 The ACG also recommends that a CRC prevention test, preferably a colonoscopy, be first offered to patients with family history of CRC. Hence, colonoscopy has become an invaluable component of most national screening programs. While the entirety of the colon can be evaluated during colonoscopy and abnormal tissue(s) can be sampled or removed during the procedure, the procedure has disadvantages that may limit its use. Some of these considerations include the need for thorough colonic cleansing, sedation and the potential need to stop taking certain medications (especially anticoagulants) as well as the rare but potentially life- threatening complications of bleeding and perforation. Additionally, colonoscopy is avoided by patients as the procedure elicits feelings of fear, embarrassment, loss of dignity or vulnerability, absence from work, lack of awareness on the importance of screening, transportation difficulties, obstacles with scheduling of appointments and financial cost.^6,15

Colonoscopy with Colon-Capsule

In an effort to improve acceptability and safety of lower-GI endoscopy, colonoscopy with colon-capsule (CCE, PillCam Colon, Given Imaging Ltd., Yoqneam, Israel) is an endoscopic technique developed for a non- invasive, painless exploration of the colon without the need of sedation and injection of air.^16,17 Initial studies comparing CCE with colonoscopy (traditional and virtual) performed in Israel and Belgium1,¹⁸ show that CCE allows direct visualization of the mucosa (such as traditional examination), does not use radiation (such as virtual colonoscopy) and does not cause pain, eliminating the need for sedation.¹⁹

Technology

The new generation of CCE (CCE-2) represents a technological evolution of the previous capsule. It measures 11.6 x 31.5 mm. It is equipped with two optical domes with a viewing angle of 172° (the previous version had an angle of 156°), two light sources (one for each optical dome), an antenna that transmits images to an external recorder and a battery (10 hour battery life).²⁰ In addition, CCE-2 owns an advanced system of acquisition and transmission of images. It is in continuous two-way communication with the external data recorder, which is no longer a single recorder of images, but an actual computer. The data recorder receives images from CCE-2, and it processes them to “understand” if the capsule is at rest or in motion and sends signals to the capsule, establishing the speed of acquisition of the images. When the CCE-2 is immobile, it acquires four images per second, however, when it is in motion it acquires 35 images per second.¹⁶ The data recorder also assists and guides the patient during the stages of bowel preparation indicating through a sound system and a display how to proceed with the intake of drugs and when the procedure is finished. Unique to this procedure, aside from picking up the CCE-2 from the hospital, the remainder of the testing is performed at home.

Preparation for the Procedure

Bowel preparation for CCE includes the use of laxatives and drugs to activate intestinal peristalsis in order to achieve three objectives: 1) to ensure an adequate level of cleaning, 2) to stimulate the motility for CCE progression and 3) to fill the colon of transparent liquids to adequately distend the bowel. CCE is not able to insufflate air to distend the bowel, or to aspirate any residues, which therefore need to be completely removed through a dedicated preparation.²¹ The use of drugs stimulating colon motility (usually sodium phosphate or sodium sulfate, more recently) is necessary given minimal colonic peristaltic movements throughout the day. The excretion rate of CCE (about 20%) was too low with the use of traditional colonoscopy preparations.¹ Sodium phosphate (NaP) and sodium sulfate result in a strong activation of peristalsis responsible for the CCE progression and excretion, which occurs in 90% of cases within 10 hours of ingestion. Two recent studies with the new generation capsule.^16,20 assess a novel bowel preparation involving the use of a split regimen with 4 liters of PEG and a reduced dose of NaP.²² Adequate cleaning has been achieved in 78-81% of patients and CCE excretion (which corresponds to complete colonoscopy) in 81-88% with this preparation.^16,20 This new preparation is more tolerable for the patient thus increasing compliance, reduces the NaP which decrease the risk of adverse events and the rate of colon cleansing and excretion of the capsule are encouraging. The Aronchick colon cleansing rating scale is generally utilized to assess the prep (poor, fair, good and excellent) with good inter-observer agreement (kappa = 0.619).¹⁷ Although the four-level system has been widely adopted in research, a recent guideline suggests the use of a simplified two-levels scale for clinical activity.

Accuracy of the Capsule

Most of the studies published in the literature center around data obtained with the first generation of CCE. A meta-analysis with the first generation of CCE ²³ summarized the preliminary experience. Eight studies with a total 837 patients showed a 71% CCE-sensitivity for polyps of any size and a 68% sensitivity for significant lesions (>6 mm polyps or ≥3 polyps). The specificity for polyps of any size and for significant lesions was 75% and 82%, respectively. Finally, CCE identified 16 of 21 cancerous lesions, showing a sensitivity of 76%.

The second generation of CCE was evaluated in^16,20 an Israeli multicenter study and a European multicenter study. Both studies were blinded and compared CCE to conventional colonoscopy with a standardized, split- dose bowel preparation (PEG 2L the day prior to the procedure and 2L the morning of the procedure with a reduced dose of NaP). The prevalence of polyps of any size (in 104 patients, mean age 49.8 years) was 44%, 53% of which were adenomas. (16) CCE sensitivity for polyps ≥6 mm was 89% (95% CI 70%-97%) and 88% (95% CI 56-98) for polyps ≥ 10 mm; specificity was 76% (95% CI 72-78) and 89% (95% CI 86-90), respectively. An adequate level of cleansing was observed in 78% of patients (95% CI 68-86) and CCE colonoscopy was complete (natural excretion of video capsule) within eight hours in 81% of patients.

In the European multicenter study (20), 109 patients were enrolled (mean age 60 years). The sensitivity (“per patient”) of CCE for polyps ≥ 6 mm and ≥ 10 mm was 84% and 88%, with a specificity of 64% and 95%, respectively. All three invasive adenocarcinomas were detected by the capsule. The rate of excretion of the capsule was 88%. Adequate cleansing of the colon was observed in 81% of patients.

Despite only two published studies, some general observations can be made. First, the second-generation capsule has shown a much higher sensitivity for significant lesions compared to the first generation. Secondly, for polyps ≥ 6 mm, the specificity is still sub-optimal. The low specificity is partly due to true polyps ≥ 6 mm that were regarded as false positive because they were missed by colonoscopy, the golden standard in this trial.^14,25 Next, the preparation of the new scheme show encouraging results both in terms of quality of cleansing and in terms of completeness of the examination. Finally, CCE is a safe technique without any report of serious adverse events.^16,20

Check Cap Capsule

The diagnostic accuracy of colonoscopy is very dependent on the quality of the colonic cleansing.^26,27 Inadequate colonic cleansing results in cancellation or rescheduling of the procedure, lessens the procedure’s diagnostic accuracy and discriminative ability, lowers the cecal intubation rates and increases the patient’s discomfort and inconvenience.

The Check Cap Ingestible Imaging Capsule

The Check Cap ingestible imaging capsule (Check Cap, Mount Carmel, Israel), is comprised of a mobile imaging capsule (34 mm x 11.5 mm, 13 grams), which is ingested together with a radiopaque contrast agent by the patient, and a stationary external recorder, which is located in a dermal patch on the patient’s back (Figure 1). The imaging capsule contains three miniaturized systems, an X-ray emitting system, a data acquisition system and a local positioning system (Figure 2).

X-rays from a short-lived radioisotope, housed within a rotating collimator whose rotation is powered by a battery-driven electric motor, are emitted in all directions when the capsule’s position changes. The data acquisition system contains sensors, which can discriminate X-ray fluorescence from ingested radiopaque contrast agent and scattering from the intestinal mucosa. The positioning system uses electromagnetic signals, which are emitted by the capsule and tracked by the dermal patch. Imaging data and position signals are continuously transmitted by telemetry to the external recording unit (Figure 3). The recorder’s data are then uploaded and processed by computer to construct 3D images of the colon’s lumen, structure, and contour.

Human Studies on the Safety and Clinical Utility of the Device

The device’s safety and potential utility were assessed in Germany and Israel at several medical centers.²⁸ In the first section, 75 healthy volunteers aged 41-70 years swallowed dummy capsules. All capsules were retrieved and were undamaged upon inspected. In the second part, 49 capsules were swallowed by 46 volunteers aged 45- 68 years (three patients swallowed the capsule on two different occasions). During this study, a lightweight external recording unit was strapped to the waist of each participant while normal daily routine was maintained. After ingesting the capsule, each participant drank 50- 70 ml of an iodine-based contrast agent daily until the capsule was eliminated. Forty-eight of the 49 capsules were ingested, transited the gastrointestinal tract and were naturally eliminated without any adverse effects. The missing capsule was retrieved from the cecum of an asymptomatic patient during a scheduled colonoscopy for a planned polypectomy. The average radiation dose to each volunteer was 0.03±0.0007 mSv, which is less than the amount of radiation exposure from one chest X-ray. (Figure 4) The 3D images revealed the typical structure and contour of the different colonic segments, such as the hepatic flexure and the triangular shape of the transverse colon. Polyps in several patients were detected by the device and their presence was later validated by colonoscopy. (Figures 5,6)

Beebe and his colleagues.²⁹ investigated whether removal of a laxative preparation would improve CRC screening rates using data that were collected from a mixed-mode and telephone survey. They reported that removing this relatively common disincentive to CRC screening participation can potentially increase patient receptivity to CT colonography. As such, the Check Cap Capsule system could be an alternative method of CRC testing.This imaging system is a safe, easy-to-use, patient-friendly, painless, and private medical device with high diagnostic accuracy discriminating patients with disease from those without disease without the need for a bowel preparation. Another advantage of the system is that the dose of ionizing radiation to the patient is lower not only than that of CT colonography but also less than chest X-ray. (Figure 4) Additionally, use of this concealed imaging system eliminates the need to schedule an appointment at a health facility, be absent from work and enables the patient to continue their daily routine without the negative emotional and physical feelings which may be experienced during colonoscopy. For all of these reasons, this innovative imaging system could potentially increase participation rates in a local and/or national CRC screening program.³⁰ Many features of image reconstruction and measurement of polyp size and colon diameter still need refinement and validation. To resolve these issues, modifications to the imaging capsule are on going and international, randomized, multicenter studies are planned for the end of 2016.

CONCLUSION

While colonoscopy is currently the most utilized and accepted form of colorectal cancer screening, technology has allowed inroads to developing new testing that may improve patient care. Colonic capsules are safe novel systems that are easy-to-use, painless, patient-friendly and private. These devices should significantly increase participation rates in a CRC screening programs.

Acknowledgement

The authors wish to thank Dr. Arieh Bomzon, Consulwrite (consulwrite.com) for his editorial assistance in preparing this manuscript.

Gastrointestinal Motility And Functional Bowel Disorders, Series #20

Current Treatment Strategies for Irritable Bowel Syndrome

November 2016 • Volume XL, Issue 11

Pratik Naik,

Richard W. McCallum

Irritable bowel syndrome (IBS) is a functional bowel disorder which affects 11% of the world’s population. IBS is accompanied by significant socioeconomic burden, and a lack of recognition of the condition leads to many patients left undiagnosed. The pathophysiology of IBS is not well understood but new concepts are emerging. Treatment of irritable bowel has always been challenging and focuses on addressing abnormal stool frequency, abdominal pain and the psychological state. In this article, we provide an update on IBS therapies newly approved by the Food and Drug Administration (FDA), suggest strategies for incorporating the spectrum of the medications that are already being utilized for specific IBS patient settings and also preview new therapeutic directions.

Pratik Naik, MD, GI Motility Fellow and Richard W. McCallum MD, FACP, FRACP, FACG, AGAF, Founding Chair, Department of Medicine, Director, Center for Neurogastroenterology and GI Motility, Texas Tech University, Paul L. Foster School of Medicine El Paso, TX

INTRODUCTION

Irritable bowel syndrome (IBS) is a functional bowel disorder characterized by abdominal pain associated with a change in bowel habit. More specifically, the Rome IV criteria for IBS state that patients should have recurrent abdominal pain for at least one day a week in the last three months associated with at least two of the following: pain related to defecation, onset of pain associated with a change in frequency of stool or onset of pain associated with a change in form of stool (Bristol stool scale criteria).¹ These symptoms must be present for at least six months before diagnosis, however they may be present for years prior to the patient’s initial evaluation. Additionally, clinical criteria, such as symptoms exacerbated by stress, symptoms occurring during the day and not while asleep, incomplete evacuation and bloating and distension, can be utilized in making the diagnosis of IBS.

In the United States, the prevalence of IBS approaches 16% (45 million) of which 70-80% are women.^2,3 IBS can be diagnosed in all age groups⁴ however roughly 50% of patients with IBS report their first symptoms before the age of 35 years.⁵ These symptoms affect quality of life and the patients have many absences from work.³ However, there is a lack of recognition of the condition and up to 75% of patients either do not seek medical attention or are not formally diagnosed.2 There are often concomitant entities, specifically fibromyalgia, chronic fatigue syndrome, chronic migraine headache, interstitial cystitis and temporomandibular joint dysfunction, that can co-exist in half of IBS patients and provide a clinical clue to consider IBS as an underlying diagnosis.^6,7

Improving a patient’s quality of life is the mainstay of treatment. Establishing physician rapport, patient education on IBS and empowering them to accept some responsibility for their care are key as well. Non- pharmacological approaches such as stress management, psychotherapy, behavioral modifications and focus on diet have been shown to improve symptoms and should be sustained long term. In this article we describe the new IBS therapies as well as suggest strategies for incorporating them into the spectrum of the medications that already have been shown to be useful and focus on specific patient challenges.

IBS with Diarrhea (IBS-D)

IBS-D accounts for approximately one third of all IBS patients and affects roughly the same number of men and women. Anti-diarrheal agents such as loperamide, in previous randomized controlled trials (RCTs), have failed to demonstrate benefit in relieving global symptoms of IBS, specifically the abdominal pain.^8,9 However, the fear of fecal incontinence accompanying the urgency of the diarrhea means that loperamide can be efficacious for reducing stool frequency in specific settings such as maintaining daily work schedules, traveling, social outing and stressful events.¹⁰

Available New Therapies for IBS-D Rifaximin (Xifaxin)

The FDA approved rifaximin for treatment of IBS-D in May, 2015. Rifaximin is a minimally absorbed antibiotic whose mechanism of action is inhibiting bacterial protein synthesis and modulation of intestinal microbiota that are contributing to a microscopic inflammatory process in the bowel.¹¹ There were two TARGET (Targeted non-systemic Antibiotic Rifaximin Gut selective Evaluation Treatment of non-constipated IBS) studies where patients were treated with rifaximin 550mg three times daily for 14 days vs. placebo and followed for a 10 week treatment-free observation period. The primary endpoint was adequate relief of IBS signs and symptoms. This was accomplished significantly more in the rifaximin group than in the placebo group during the four weeks of observation after treatment in the two studies combined (40.7% vs. 31.7%, P<0.001). In an assessment of the composite end point of abdominal pain or discomfort and loose or watery stools, significantly more patients in the rifaximin group than in the placebo group had relief during the evaluation period (46.6% vs. 38.5%, P=0.04, in TARGET 1; 46.7% vs. 36.3%, P=0.008, in TARGET 2).¹² Since IBS is a chronic disease, assuming that only two weeks of therapy is going to produce sustained symptom relief was a concern raised by the FDA ultimately leading to an additional study aptly called TARGET 3. In this trial, 2579 patients initially treated with open labeled rifaximin were then followed for 18 weeks and patients received re-treatment in a double blinded fashion if they relapsed. Here, the 636 patients who experienced recurrent IBS symptoms were randomized to receive rifaximin 550mg TID vs. placebo for two weeks followed by a four week treatment-free observation period. The percentage of responders in the retreatment phase was again statistically significant for rifaximin 550 mg vs. placebo-treated patients (37% vs. 29%, p=0.04).¹²

The adverse events observed during these trials, nausea (3%) and elevated alanine aminotransferase (2%), were infrequent.¹³ There was no increased risk of infections, including Clostridium difficile infection, and no substantial differences in any adverse events vs. placebo.¹⁴ The FDA recommends evaluation for C. difficile if there is no improvement or worsening of diarrhea after treatment with rifaximin and cautions use in patients with severe liver impairment (Child- Pugh Class C) or with concomitant administration of drugs that are P-glycoprotein (P-gp) inhibitors (e.g. cyclosporine) due to increased systemic exposure to rifaximin.¹³

Eluxadoline (Viberzi)

The FDA approved eluxadoline for treatment of IBS-D in May, 2015. Eluxadoline is a µ and k-opioid receptor agonist and δ-opioid receptor antagonist and has minimal absorption. This agent binds to peripheral opioid receptors in the gastrointestinal (GI) tract resulting in slowing of GI motility and decreasing gut secretions. However, an additional unexpected mechanism was recognized. Eluxadoline was shown to decrease the sensitivity of afferent neurons (in the submucosa) to pain thus reducing visceral hypersensitivity, a local gut effect, with no central nervous system (CNS) involvement.^16,17 Two double-blinded, placebo-controlled clinical trials were conducted in which 2,427 patients were randomly assigned to receive eluxadoline (at 75 mg or 100 mg) or placebo twice daily (BID) for 26 weeks in both studies. Significantly more patients treated with eluxadoline 100 mg BID vs. placebo (33% vs. 20 %; p< 0.001) experienced improvements in diarrhea and abdominal pain for at least 50% of the trial period. This response was noted within the first week of initiating therapy.¹⁷

The most common side effects were constipation (8% vs 3% placebo), nausea (7% vs 5%) and abdominal pain (7% vs 4%). Upper abdominal pain attributed to sphincter of Oddi spasm was observed in 0.8% of the patients and was more likely to occur in patients with prior cholecystectomy. The presence of opioid receptors in the sphincter of Oddi could contribute to this observation. These symptoms were usually induced within the first two weeks of treatment and resolved upon discontinuation of the drug.¹⁷ In addition, there was a rare occurrence of pancreatitis (less than 0.3%) not associated with sphincter of Oddi spasm and the majority of cases were related to excessive alcohol use. Because of this finding it is recommended that patients with history of chronic pancreatitis or currently consuming at least three or more alcoholic beverages daily do not receive this agent.¹⁶

The current recommended dose for eluxadoline is 100mg twice daily. The reduced dose, 75 mg twice daily, is initially appropriate for patients post cholecystectomy, those who were not able to tolerate the 100 mg dose, who are receiving concomitant OATP1B1 inhibitors (e.g. cyclosporine and gemfibrozil) or who have mild to moderate hepatic impairment. The use of this agent is not recommended if there is suspected mechanical gastrointestinal obstruction or severe liver impairment (Child-Pugh Class C).¹⁶

Alosetron (Lotronex)

Alosetron, a selective 5-HT₃ antagonist, was initially approved by the FDA in 2000 for the treatment of IBS-D in women only. Activation of 5-HT3 receptors leads to neuronal depolarization in enteric neurons which reduces visceral pain as well as colonic transit and inhibits GI secretions.¹⁸ The drug was later withdrawn due to the serious adverse event of ischemic colitis (IC) and constipation. It was reintroduced in 2002 by FDA under a risk management program with a reduced dose (0.5-1 mg BID) for treatment of IBS-D in women only who were not responding to standard therapies.¹⁹

In randomized controlled trials (RCTs), alosetron improved abdominal pain and IBS-related global symptoms compared to placebo.²⁰ Post-marketing safety of alosetron under the risk management program (2002- 2011) reported a low incidence of serious complication of constipation (0.25 cases/1000 patient-years) and ischemic colitis (1.0 case/1000 patient-years).¹⁹ Constipation was dose dependent and noted in 29% of patients receiving the 1 mg BID dose compared to 11% in the 0.5 mg dose. The overall incidence of serious constipation was higher in elderly patients or patients taking additional medications that decrease GI motility. Alosetron should be discontinued in patients who develop constipation and it can be restarted under supervision of a prescriber after constipation resolves.²⁵ Alosetron should not be used in patients with history or have high risk for IC. It is also contraindicated in patients with suspected intestinal obstruction, inflammatory bowel disease (IBD), diverticulitis and severe hepatic dysfunction (Child- Pugh Class C).²¹

IBS with Constipation (IBS-C)

IBS-C accounts for approximately one third of all IBS patients. Over the counter laxatives [polyethylene glycol (Miralax) and bisacodyl (Dulcolax)] can be useful short term in management of constipation in improving stool frequency. However, this type of long- term management does not provide adequate pain relief.

Available New Therapies for IBS-C
Linaclotide (Linzess)

Linaclotide has been approved to treat IBS-C and chronic idiopathic constipation since 2012. Linaclotide, a guanylate cyclase C (GC-C) receptor agonist, induces an increase in both intracellular and extracellular concentrations of cyclic GMP which stimulates secretion of chloride and bicarbonate into intestinal lumen by activation of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel. This increases fluid in the intestine leading to an acceleration of colonic transit.²² Based on data from animal models, linaclotide also was able to decrease abdominal pain through effects on afferent neurons in the gut wall.^22,23 In two phase III multicenter placebo- controlled RCTs, linaclotide significantly increased the frequency of complete spontaneous bowel movements and reduced abdominal pain for at least six of the 12 weeks compared to placebo (Trial 1: 33.6% vs 21%; Trial 2: 33.7% vs 13.9%).^24,25 In all three multicenter placebo-controlled RCTs, linaclotide was shown to be effective in reducing global symptoms of IBS-C.²⁰

Linaclotide 290 mcg is taken once a day on an empty stomach for treatment of IBS-C. Recently a new formulation allows the capsule to be ground and given as a powder with apple sauce orally or through a feeding tube if swallowing problems are present. Diarrhea (20% vs 3% placebo) was the most common adverse reaction noted in trials. Severe diarrhea was reported in 2% compared to less than 1% in placebo group, and diarrhea resulting in discontinuation was 5% vs <1%. The majority of reported cases of diarrhea started within the first two weeks of the treatment and reduced with time.²² Patients with known or suspected mechanical gastrointestinal obstruction or sudden change in clinical states are not appropriate candidates nor should the drug should be used in patients 17 years of age and younger.²³

Lubiprostone (Amitiza)

Lubiprostone (Amitiza) 8 mcg BID was approved by the FDA in 2008 for the treatment of women with IBS-C. It activates type 2 chloride channels in small intestinal cells that promote chloride secretion in intestine.²⁶ These secretions soften the stool and increase colonic transit time, which promotes more complete spontaneous bowel movements. In two phase three RCTs, the percentage of overall responders based on patient-rated assessments of IBS-C symptoms was significantly more in patients treated with lubiprostone 8 mcg twice daily compared to those treated with placebo (17.9% vs. 10.1%, p=0.001).²⁷ The most frequent adverse events were nausea (8% vs 4%) and diarrhea (7% vs 4%). Long term safety, 36 weeks, and tolerability were assessed in an additional study; while not placebo controlled, 41% of patients dropped out due to lack of efficacy.²⁸

Treatment Option for IBS-M

The prevalence of IBS-M is equal in both male and female. Abdominal pain remains a challenge for these patients and anticholinergics have been heavily utilized in their management. Hyoscamine, dicyclomine and chlordiazepoxide/clidinium bromide (Librax) are widely used to alleviate abdominal spasms and cramps associated with IBS as well as deceases GI motility and hypersensitivity.²⁹ Previous studies have shown limited evidence regarding long term efficacy in reducing global IBS symptoms and abdominal pain.²⁰ The most common side effects are anhidrosis, blurred vision, confusion, constipation, urinary retention, xerostomia and drowsiness attributed to anticholinergic effects.^18,20

Available New Therapies for IBS-M
IBgard (Peppermint Oil)

IBgard, purified peppermint oil, reduces lower GI tract and colon motility by acting on intestinal calcium channels to relax smooth muscle within the GI tract.³⁰ It is a enteric-coated preparation permitting it to bypass the stomach and delivers peppermint oil to the small bowel allowing its effect to be maximal on the lower GI tract.31 In a placebo-controlled, double-blinded RCT, 72 patients who met the Rome III criteria for IBS-M and IBS-D were randomized to receive IBgard 180mg TID vs placebo for 4 weeks. There was a significant reduction in the number of severe or unbearable IBS symptoms vs placebo (66% vs 42%, P=0.02) and reduction in severe or unbearable abdominal pain intensity vs placebo (79.4% vs 40.5%, P=0.01). The study also showed improvement in IBS global symptoms.³² The mechanism of action, particularly for reducing pain, remains poorly defined.

Peppermint oil can also relax the lower esophageal sphincter, which can lead to symptoms of acid reflux when taken orally.³¹ Enteric-coated preparations can eliminate this side effect. IBgard is an OTC medication; however, it should be used under physician supervision. It is not recommended in patients with IBS-C since constipation may be worsened.

Suggested Strategic Approaches Based on These New Therapies in IBS-D

1. Choice of Rifaximin

Rifaximin may be considered as a reasonable treatment of choice in the following clinical settings:

A patient with suspected post infectious (PI) IBS-D based on a very suggestive history of food poisoning, travel, military deployments etc.
Patients where the IBS presentation has been relatively short (< 5 years) with or without a typical post infection history.
Patients over 50 years of age where onset has been recent, this suggesting a higher likelihood for PI- IBS even when no specific event can be recalled.
Patients with IBS-D where gas, bloating and postprandial abdominal distension are prevalent suggesting a component of small intestine bacterial overgrowth (SIBO) as a manifestation of a recent GI infection or change in microbiota.

Rifaximin is not a stand-alone therapy. Patients seeing a gastroenterologist may already be following a low FODMAP (fermentable oligo-di-monosaccharide and polyol) diet and antidepressants but still have remaining symptoms. Here a course of rifaximin is a reasonable step in addition to the medications being received. Since it is a two-week regimen, there will be evidence for improvement within a short time.

Questions Remaining Regarding Rifaximin

How does one can explain the improvements in the abdominal pain with rifaximin when the rationale for its use is modulating microbiota? The current rationale is that its anti-inflammatory effects reduce microscopic inflammation in the gut wall including improving the concept of “leaky cell junctions”, although there is no clear evidence of this to date.
Can two weeks of therapy sustain the reduction in abdominal pain? The FDA approval for rifaximin does allow for two more re-treatments to be given over time. The timing of the re-treatment course has been vague. The follow up in clinical trials was approximately five months so one could infer that re-treatment may be considered during that time frame for that subset of patients who initially achieved improvement and relapsed.
Will other agents be required to address pain relapses over greater time periods? Here there could be a role for antispasmodics as needed as well as assessing a role for tricyclic antidepressants in obvious stress related settings
Should patients completing a course of rifaximin then start probiotics in order to sustain a better microbiota environment? This has not been addressed in a study format. If gas and bloating were the deciding factors to initiate rifaximin initially then follow up probiotics seems reasonable
Can there be a profile of the best candidate? For the future, stool analysis of gut microbiota by polymerase chain reaction (PCR) may define particular subtypes who can be shown to be the best responders. This may be particularly relevant to explain a subset where effective pain reduction is being sustained.

2. Choice of Eluxadoline

The primary choice of eluxadoline may be considered in the following clinical settings:

Patients with IBS-D whose predominant symptoms are stool urgency and fear of having a “bowel accident” or actually experiencing intermittent fecal incontinence. The activation of opioid receptors in the gut wall makes sense in decreasing stool volume and transit as well as secretions. This is particularly relevant to morning diarrhea preventing timely arrival at work or leaving the home.
A history of chronicity (>5 years) would all favor eluxadoline since long term use has been studied (at least 1 year) and the FDA approval is also for chronic use since there was also an excellent safety profile.
Treatment with eluxadoline does not preclude concomitant therapies e.g. antidepressants, low FODMAP diets and addressing excessive bloating and gas to address the “peaks and valleys” during the course of chronic IBS where treatment with eluxadoline may be for months or years.

Questions Remaining Regarding Eluxadoline

There is a pressing need to clarify how the interactions of eluxadoline as an agonist of mu and kappa receptors and at the same time antagonizing delta receptors leads to decreased pain via afferent submucosal neurons. The role of kappa receptors still remains to be studied.

3. Choice of Alosetron

Alosetron could be a preferred consideration only in women with IBS-D where the diarrhea is such that bowel movements and stool urgency with possible fecal incontinence are frequent and who have failed all other management strategies. As a part of a risk evaluation and mitigation strategy, patients and prescribers are required to enroll in a prescribing program and medication guide should be provided with each prescription.

Suggested Strategic Approaches Based on New Therapies in IBS-C
1. Choice of Linaclotide

Linaclotide should be considered as a treatment of choice in patients with predominant symptoms of constipation and abdominal pain. There are two main challenges:

The effects of the medication on abdominal pain can take up to 10 weeks to fully maximize presenting a challenge to keep patients motivated to take the medication with the possibility that a suboptimal pain relief will result. Anticholinergics may be needed as adjuncts to address pain during this time. A short acting agent such as hyoscyamine is preferred since long acting agents such as dicyclomine, librax and donnatal (belladonna alkaloids, phenobarbital) may worsen constipation. The good news for the patients is that increased frequency of stools occurs in the first 48 hours indicating to the patients that the drug is working (they are responders) and hence there is a high likelihood that abdominal pain relief should follow over the next few weeks
Initial diarrhea can be prominent and although the 290 mcg dose is recommended in IBS-C to achieve the long-term pain benefits, starting at 145 mcg and building up to 290 mcg will overcome the concern that diarrhea may result in a patient prematurely stopping the agent. An alternative strategy is to use 290 mcg every other day until the bowel adapts to the increase in luminal fluid and diarrhea is not a concern. This usually occurs over two to three weeks and then daily dosing can be initiated.

2. Choice of Lubiprostone

Lubiprostone was associated with mild to moderate nausea and vomiting (11%) which could be major limiting factor as well as the BID dosing and also the fact that it was only approved in women. There is also lack of evidence for long term safety and tolerability because the previous long term study had a high dropout rate (41%). Recently, Amitiza 24ug BID has been approved for opioid induced constipation. Hence in IBS patients taking opioids for other reasons e.g. back pain, neuropathy or headache, this high dose can be considered.

Strategies Approaches Based on These New Therapies in IBS-M
1. Choice of IBgard

IBgard is an OTC medication is only intended for use in D and IBS-M. It can be used as a short term adjunct when abdominal pain, spasm and discomfort are the main symptoms. However, more definition is required of the mechanism of action regarding reducing abdominal pain which is thought to be more colonic in origin yet the agent is largely presented to the small bowel. More RCTs are needed to evaluated long tern efficacy and tolerability. IBgard is an OTC medication but it should be taken under physician supervision.

Future Therapy Approaches

Role of Methanogens and Methane in IBS-C

Recently data has suggested an association of methane production with chronic constipation and IBS-D. The proposed mechanism is based on an animal model where methane was found to act as a neuromuscular transmitter and delayed intestinal transit.³³ Methanogens such as Methaninobrevibacter smithii have been found to have 80% – 100% colonization rate of the human colon by PCR techniques.³⁴

In a study by Pimentel et al., methane production from a lactulose breath test showed 100% association with IBS-C patients and the prevalence of methane positivity was very low among patients with IBD and IBS-D. In that study, higher constipation severity scores were reported by subjects who produced methane.³⁵ However, this association with constipation is unclear as up to 50% of healthy individuals have been reported to be methane formers.³⁴ In addition, relying on the lactulose breath test is a major flaw since it is actually measuring colonic flora and not the small bowel flora as first assumed.

In a retrospective study, rifaximin and neomycin have shown promising results on methane eradication as measured by the breath test. Pharmacotherapy such as chloro/fluoromethanes, 2-bromo- and 2-chloro-ethane sulfonates also have been shown to block key reactions leading to methane biosynthesis. In a phase two trial, a modified-release formulation of lovastain lactone (SYN-010) was shown to act primarily in the intestinal lumen and reduced methane production by M. smithii with minimal impact on gut microbiome.³⁶

Better understanding regarding the role of SIBO and microbiota in IBS patients is needed. Recent studies have demonstrated the utility of sampling small bowel contents and using PCR techniques in identifying differences in gut flora of IBS patients, specifically different phyla compared to healthy individuals. By using these techniques in the future, we may be able to identify subgroups of IBS patients who can be considered the most likely responders to targeted therapies.

Bile Acid Malabsorption

Bile acids (BA) are produced in the liver and have major roles in the absorption of lipids in the small intestine. Bile acid malabsorption (BAM) is estimated to occur in one third of the patients with IBS-D and up to 50% of the patients with functional diarrhea. SeHCAT (23-seleno-25-homotaurocholic acid, selenium homocholic acid taurine, or tauroselcholic acid) is a test used to diagnose BAM. This test is done by measuring retention of the SeHCAT by external scintigraphy one week after administration of a gamma- emitting synthetic bile acid and less that 15% retention after seven days is considered abnormal. In a systemic review in patients with IBD-D, BAM was noted as severe in 10%, moderate in 32% and mild in 26%.³⁷ The bile acid binder cholestyramine has been shown to improve BAM and potentially reduce diarrhea.

TAKE HOME MESSEGES

In this article we review current pharmacotherapy for all IBS subtypes. Treating IBS remains daunting for clinicians: abdominal pain and abnormal bowel function are dual challenges. In fact the statement is often made that the true measure of the skill of a gastroenterologist is how well he or she can treat patients with IBS in their practice. This article emphasizes the background and evidence for new pharmacotherapies now available to practicing gastroenterologists and primary care physicians and also proposes treatment strategies in specific patient settings. It also reminds us that IBS is a chronic entity and our goals are to minimize bad days and maximize good days and improve quality of life. Physician rapport and trust is key. It all begins with actually telling patients their diagnosis: you have irritable bowel syndrome. There are no stand- alone approaches. Current therapies as well as the new agents reviewed are integrated into the setting of addressing stress with antidepressants (e.g. tricyclics), psychological counseling and holistic approaches including relaxation techniques while always focusing on the role of diet. Evolving therapies and concepts regarding biomarkers particularly related to bile acid malabsorption and changes in gut microbiota specifically methanogens are also reviewed. The future will be more targeted therapies but this will also rely on unraveling an entity which will remain poorly understood until the big umbrella term of “IBS” can be replaced by describing entities based on specific mechanisms and pathology.

Nutrition Issues In Gastroenterology, Series #157

Achalasia And Nutrition: Is it Simple Physics or Biology?

November 2016 • Volume XL, Issue 11

Dhyanesh A. Patel,

Michael F. Vaezi

Achalasia is one of the most studied motility disorders of the esophagus and delay in diagnosis can result in significant patient morbidity and impaired quality of life. Esophagogastroduodenoscopy is necessary to rule out potential malignancy that can mimic achalasia. Although there are no curative therapies currently, excellent palliation of symptoms can be achieved in <90% of patients with the use of graded pneumatic dilatation, surgical myotomy or per-oral endoscopic myotomy. This article briefly discusses the clinical presentation, diagnosis, and management options in patients with achalasia followed by insights into nutritional implications that are often neglected.

Achalasia is one of the most studied motility disorders of the esophagus. Patients often present with dysphagia, regurgitation and varying degrees of weight loss. Delay in diagnosis can result in significant patient morbidity and impaired quality of life. The diagnosis is made based on clinical history and esophageal high resolution motility testing. Esophagogastroduodenoscopy is necessary to rule out potential malignancy that can mimic achalasia. Although there are no curative therapies currently, excellent palliation of symptoms can be achieved in >90% of patients with the use of graded pneumatic dilatation, surgical myotomy or per-oral endoscopic myotomy. This article briefly discusses the clinical presentation, diagnosis, and management options in patients with achalasia followed by insights into nutritional implications that are often neglected.

Dhyanesh A. Patel, MD and Michael F. Vaezi, MD, PhD, MSc (Epi), FACG, Professor of Medicine, Clinical Director, Division of Gastroenterology, Hepatology and Nutrition Director, Center for Swallowing and Esophageal Disorders. Division of Gastroenterology, Hepatology and Nutrition. Vanderbilt University Medical Center, Nashville, TN

INTRODUCTION

Achalasia is a rare esophageal motility disorder that is characterized manometrically by esophageal aperistalsis and impaired relaxation of the lower esophageal sphincter (LES) in response to deglutition. Thus, primary symptoms at presentation include dysphagia and regurgitation of undigested food with varying degrees of weight loss.¹ Achalasia was first described by Sir Thomas Willis in 1674 with recent evidence suggesting an annual incidence and prevalence of approximately 2/100,000 and 10/100,000 respectively.^2,3 The disease can occur at any age, but is usually diagnosed between 30 and 60 years with a mean age at diagnosis of > 50 years.⁴

The underlying etiology of achalasia is loss of myenteric neurons that coordinate esophageal peristalsis and LES relaxation. Despite its initial description in 1674, the inciting event that leads to loss of these inhibitory neurons is still unclear.¹ Thus, the most common form of achalasia is idiopathic achalasia. However, approximately 2-4% of patients with suspected achalasia have pseudoachalasia (due to malignancies or secondary achalasia from extrinsic processes such as prior tight fundoplication).⁵ Similar clinical presentation can also occur with other diseases (see Table 1).⁶

In this review article, we provide a brief overview of the clinical presentation, diagnosis, and management options in patients with achalasia followed by a detailed review of nutritional aspects that are often overlooked in these patients.

CLINICAL PRESENTATION

Patients with achalasia exhibit a varied clinical presentation, however, progressive dysphagia to solids followed by liquids is usually the first clinical symptom.⁷ Other symptoms include regurgitation that is often non-responsive to adequate proton pump inhibitor (PPI) trial, weight loss, chest pain, and respiratory symptoms (cough, hoarseness, shortness of breath, and sore throat).¹ Table 2 shows the most common symptoms in patients with achalasia and their prevalence based on available data. Chest pain is more frequent in younger female patients. Although achalasia as a disease entity overall is rare, it is important for primary care providers to have a low clinical threshold for referral to specialists given that in early stages of the disease, dysphagia may be very subtle and can be misinterpreted as dyspepsia or poor gastric emptying. In addition, these patients will often have heartburn due to food stasis and can lead to an erroneous diagnosis of gastro-esophageal reflux disease (GERD), which is often unresponsive to PPI therapy, and might result in inappropriate referral for anti-reflux surgery (which would significantly exacerbate the underlying problem). Weight loss in these patients is also widely variable with average loss of 20 ± 16 lbs; it is unclear why certain patients with achalasia lose significantly more weight compared to others.⁸

DIAGNOSIS

The diagnosis of achalasia can be relatively straightforward with a well-documented clinical history, radiography/endoscopy, and esophageal motility testing. Manometry is the gold standard diagnostic test for establishing the diagnosis of achalasia and can also help characterize motor patterns with treatment outcome implications. It is required regardless of findings on barium esophagram and esophagogastroduodenoscopy (EGD). Table 3 identifies the advantages and disadvantages of the various methods used in diagnosing achalasia.

Esophageal Manometry

Characteristic findings for achalasia on conventional manometry is absence of esophageal peristalsis and incomplete LES relaxation on deglutition (usually residual pressures of >10mmHg).¹ However, most academic centers have now replaced conventional manometry with high-resolution manometry (HRM) with esophageal pressure topography (EPT), which allows for improvement in pressure sensing technology. This has allowed clinicians to develop a sub- classification of achalasia into 3 clinical groups based on the pattern of esophageal contractility:

• Type I (classic achalasia; quiescent esophageal body)
• Type II (isobaric pan-esophageal pressurization)
• Type III (simultaneous contractions)

Three retrospective studies have showed treatment outcome implications based on the subtype of achalasia suggesting type II having the best prognosis, followed by subtype I; subtype III can be difficult to treat.^9-11

Endoscopy

All patients with suspected achalasia are recommended to have an upper endoscopy to exclude mechanical obstruction or pseudoachalasia that can mimic achalasia. At endoscopy, the esophageal body usually appears normal or can be dilated, but can occasionally have friable mucosa with even superficial ulcers secondary to chronic stasis or candida esophagitis.¹ The LES is closed even with insufflations of air, showing the appearance of puckering, but the endoscope can pass this area with gentle pressure. If there is high concern for malignancy due to rapid progression of symptoms, biopsies and endoscopic ultrasound or chest CT are obligatory.

Barium Esophagram

Barium esophagram is a non-invasive test for examination of the esophagus that, although less sensitive compared to manometry, can still provide important clinical information with ruling out structural abnormalities and estimating the diameter of the esophagus. Typical findings in achalasia is the presence of smooth tapering of the lower esophagus leading to a closed LES, resembling a “bird’s beak” as showed in Figure 1.¹ In more advanced stages of the disease, it can also show a “mega-esophagus,” with massive dilatation of the esophageal body, which can have significant implications for treatment.¹² Furthermore, in 1997, de Oliverira et al. described timed barium esophagram with films taken at 1, 2, and 5 minutes after the last swallow of barium for evaluating esophageal emptying in patients with achalasia.¹³ This and subsequent studies found that the rate of barium emptying was predictive of long term success after treatment.¹⁴

MANAGEMENT

Treatment for achalasia is aimed towards palliation of symptoms, as there are no curative therapies for achalasia at present. The goal of management is to reduce LES pressure to allow adequate esophageal emptying and prevent late complications of the disease such as severe malnutrition and recurrent aspiration pneumonia. Current therapeutic options include pharmacologic treatment, pneumatic dilatation, surgical myotomy and more recently per-oral endoscopic myotomy (POEM). We briefly review these options below.

Pharmacologic Treatment

Pharmacological therapy is primarily aimed at lowering LES pressure. Two of the most common agents are calcium channel blockers and nitrates.^15,16 These medications can decrease LES pressure by 47-64%, but are often limited due to their adverse effects including headaches, orthostatic hypotension, and edema.¹⁷ In a study comparing the effect of sublingual nifedipine to sublingual isosorbide dinitrate, both drugs decreased LES pressure, but the effect of nitrate was slightly better than that of nifedipine (65% vs. 49%, respectively).¹⁶ However, patients often develop tachyphylaxis and will lose response to these medications after short-term benefit. Thus, these treatment options are reserved for patients:

1. As bridge to more effective therapy
2. Who have failed botulinum toxin injections
3. Who are not candidates for pneumatic
dilatation or surgery.

Another pharmacologic option is injection of botulinum toxin into the muscle of the LES, which blocks acetylcholine release from nerve endings temporarily causing chemical denervation resulting in increased relaxation. It is highly effective with initial symptom relief in >75% of patients, but the effect wears off over time. Approximately 50% of patients require repeat injections at 6 to 24 month intervals; repeated injections can be progressively less effective.¹⁸ In addition, repeated injections into the LES have been shown to make subsequent Heller myotomy more challenging, and thus, are rarely used as a first-line therapy and is primarily reserved for patients who are not candidates for more definitive therapy.¹⁹ Table 4 shows pharmacologic therapies that have been shown to lower the LES pressure.

Pneumatic Dilation

Pneumatic dilatation (PD) involves use of a rigid balloon that is positioned across the lower esophageal sphincter with or without fluoroscopy with the goal of disrupting the circular muscle fibers of the LES (Figure 2). The most commonly used balloon is the Rigiflex dilator, which comes in three different diameters (3.0, 3.5, and 4.0 cm). Multiple randomized controlled trials have shown efficacy from 62-90% and is arguably the most effective non-surgical treatment option in these patients.^{20, 21} It is also very well tolerated with a recent systematic review concluding that using modern technique, the risk of perforation was < 1% and comparable to the risk of perforation during Heller myotomy.²² Predictors of favorable clinical response to PD include older age (>45 years), female gender, narrow esophagus, LES pressure after dilation of <10 mmHg, and type II pattern on high-resolution manometry (HRM).

Surgical Myotomy

Laparoscopic Heller myotomy (HM) combined with an antireflux fundoplication (Dor vs. posterior Toupet) is also a highly effective treatment option with studies showing efficacy rates in the 88-95% range.^20,21 Although laparoscopic HM is superior to a single pneumatic dilatation in terms of efficacy and durability, the difference is significantly less when compared with a graded approach to pneumatic dilation using repeated dilatations.²³ Thus, pneumatic dilatation and surgical myotomy should both be offered to low surgical risk patients as the initial therapy. Surgery might have a more favorable clinical response in younger male patients or patients with tortuous esophagus, esophageal diverticula or previous surgery on the gastroesophageal junction.¹

Per-Oral Endoscopic Myotomy

Per-oral endoscopic myotomy (POEM) is the newest treatment option available at some centers and consists of an endoscopic approach to esophagomyotomy. It involves creating a submucosal tunnel through an esophageal mucosal incision approximately 10cm proximal to esophagogastric junction and then dissecting the muscle fibers beginning at 3cm distal to the mucosal entry site and extending 2cm in to the cardia.²⁴ Treatment success has been reported as high as 90% with significant decreases in LES pressure with improved quality of life measurements and low complication rates.²⁵ There have been no randomized trials comparing PD to laparoscopic HM to POEM and long term outcomes after POEM still need to be studied.

ACHALASIA AND NUTRITION

Weight Loss: Is it Related to Physiology or Inflammation?

Why some patients with achalasia lose weight and other patients do not is unknown due to paucity of focus in this area. One of the first studies evaluating clinical response in achalasia with pneumatic dilatations noted weight loss in approximately 91% of patients (n= 264) with 16 patients reporting > 20kg and 18 patients reporting < 5kg of weight loss.²⁶ However, this might have been skewed given most patients in this study noted duration of symptoms ranging from 2 to >20 years prior to diagnosis and treatment with pneumatic dilatation. This “diagnosis latency” of achalasia is very common; many patients have had symptoms for years before seeking medical treatment. Subsequently, 3 to 13 years after treatment, these patients rapidly gained weight and weight loss was only observed in <6% of patients.²⁶ Thus, post-therapy patients that have lost weight are able to gain it back.

What is interesting about achalasia is that despite the mechanical obstruction in all, many do not lose weight, and in fact, some are obese. One small surgical series reported 3 patients with achalasia and morbid obesity (BMI of 43.3, 60, and 52.7), who did not have typical symptomatic presentation with dysphagia, but all 3 reported significant respiratory symptoms with nocturnal cough and recurrent aspiration.²⁷ The question of sub-types of achalasia and weight loss may be of physiologic interest. In a retrospective study assessing clinical, radiological, and manometric profiles of 145 patients with untreated achalasia, the authors reported that 31% of patients with classic achalasia reported weight loss compared to 43% of patients with vigorous achalasia.8 Although the degree of weight loss was not significantly different between the two at 20 ± 16 lbs, patients with vigorous achalasia had a significantly higher percent with normal LES pressure (49% vs. 13%).⁸ Thus, it is not clear if LES physiology is related to presence or absence of weight loss, as one would expect patients with higher LES pressure to report more weight loss.

Another prospective study evaluating 213 achalasia patients (110 men and 103 women) investigated differences in clinical presentation based on gender. They noted that mean duration of symptoms, age at diagnosis, and mean weight loss (3.2 kg) were not significantly different between men and women; however, they did not differentiate between the sub- types of achalasia.²⁸

Interestingly, a recent cross-sectional study evaluating 623 patients with dysphagia in Iran tried to explore the sensitivity, specificity, and predictive accuracy of presenting esophageal symptoms to normal or abnormal esophageal motility testing.²⁹ They noted that no clinical symptoms were sensitive enough to discriminate between normal and abnormal esophageal motility testing, but did find that presence of dysphagia, non-cardiac chest pain, hoarseness, vomiting, and weight loss had high specificity and high accuracy in distinguishing esophageal motor disorders from normal findings. Eighty-five out of 623 (14%) had achalasia; the type II achalasia group reported more frequent weight loss (26%), followed by Type I (11%), then Type III (1%).29 Why patients with type II would be at higher risk of losing weight remains a mystery.

Furthermore, if weight loss is not predicted by physiology, it may be related to an inflammatory process by an increase in cytokines (such as in patients with IBD). A recent study evaluated histopathologic patterns among achalasia subtypes and noted that type I achalasia specimens had significantly more myenteric plexus ganglion cell loss compared to type II, suggesting that type I achalasia likely represented disease progression from type II.³⁰ Whether a higher degree of histopathologic inflammation in type II achalasia patients might explain the weight loss in this group compared to type I needs further study. In addition, it is also possible that certain patients eat significantly less and make calorie-poor choices compared to other patients; unfortunately, these patients are rarely referred to dietitians for appropriate nutritional education until after achalasia is treated.

NUTRTIONAL IMPLICATIONS

Nutrition in patients with achalasia has often been overlooked. In fact, there are currently no published studies or reviews in this area. The advice that is often given is “eat what you can tolerate.” This is likely due to high treatment success in achalasia, which often allows the patient to resume their regular diet without significant alterations almost immediately. However, dietary modifications should be highly considered as adjunctive treatment in patients that undergo other less effective treatment modalities such as Botox injections or pharmacologic treatment with medications as it could potentially assist with maintaining adequate nutrition. We prospectively evaluated the nutritional status of 19 patients with untreated achalasia with 80% reporting having altered their diet due to swallowing difficulties; 90% reported consuming less than usual. In addition, 80% of patients reported an estimated weight loss of 40 pounds over the course of approximately 6 months.³¹ Studies are now underway to assess the magnitude and mechanism of nutritional deficiencies in achalasia as well as prospectively assess response to therapy.

Physiologically, a low fiber diet (defined as maximum of 10g fiber/day) could be considered in these patients similar to patients who have small bowel stricture. Soluble fiber increases the viscosity of the bolus, which reduces absorption and insoluble fiber possess high water-binding capacity and increases the bulk of the bolus. However, in the setting of luminal narrowing, as in achalasia due to high LES pressure, a low fiber diet would be physiologically advantageous to allow easier passage through a small narrowing. Fiber bulking agents should also be avoided until treated. Some patients may need to switch to high calorie/ protein liquids also. It is also prudent to consider prompt referral to a registered dietitian in patients who are having difficulty regaining weight. In those with significant weight loss, refeeding will need to be done cautiously to prevent refeeding syndrome. Thiamine supplementation (as well as other vitamins and minerals) might also be needed in patients with persistent vomiting.

Eating frequent, small, low-fiber meals with higher liquid content should be encouraged until they are able to get definitive treatment for achalasia. In those who continue to have trouble meeting their nutrient requirements orally, gastric access for enteral feeding may be necessary, but rarely needed due to effective therapeutic options available for achalasia. However, given the paucity of data regarding nutrition in achalasia patients, we strongly recommend future focus in this very important clinical area.

CONCLUSION

Achalasia is one of the most studied motility disorders of the esophagus and is characterized by impaired LES relaxation. Patients often present with dysphagia, significant regurgitation, and some have a tremendous degree of weight loss. Despite significant resources allocated to understanding the physiology and treatment options in patients with achalasia, it is still unclear why certain patients with achalasia lose significantly more weight compared to others. Although achalasia cannot be permanently cured, excellent palliation of symptoms is possible in > 90% of patients with currently available treatment modalities. In patients that are not candidates for more definitive therapies such as pneumatic dilatation, Heller myotomy, or POEM, we advocate combination of botulinum toxin injection and focus on dietary alterations with eating small, frequent, low- fiber meals with higher liquid content to help maintain nutritional needs.

Frontiers In Endoscopy, Series #31

Endoscopic Management of Barretts Esophagus An Update on Radiofrequency Ablation

November 2016 • Volume XL, Issue 11

Amaninder S. Dhaliwal,

Benjamin Tharian,

Mohit Girotra

Barrett’s esophagus (BE) is a precancerous state with a field defect, and is the first step in the metaplasia-dysplasia-cancer sequence, in which molecular aberrations precede neoplasia; Radiofrequency ablation (RFA) can eliminate such mutations. A wait and watch policy might be inadequate to reliably detect early changes. Here we discuss BE risk factors, diagnosis and management, and present an update on the use of RFA in the management of BE.

Amaninder S. Dhaliwal, MBBS, Resident in Internal Medicine, Department of Medicine, NYU School of Medicine/Brooklyn Campus, NY, Benjamin Tharian, MD, MRCP (Med, Gastro), FRACP, Assistant Professor, Division of Gastroenterology and Hepatology, Department of Medicine, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, Mohit Girotra, MD, FACP, Assistant Professor, Division of Gastroenterology and Hepatology, Department of Medicine, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR

Acknowledgements

The authors are grateful to Dr. Lauren G. Khanna (Assistant Professor, Division of Gastroenterology, NYU Langone Medical Center, New York) and Dr. Farshad Aduli (Former Associate Professor, University of Arkansas for Medical Sciences, Little Rock, AR) for allowing us to utilize Barrett’s and RFA pictures from their patients. We also thank Mr. Jared Pittman from Medtronic, for providing us the consolidated image of all available RFA catheters.

BACKGROUND

Barrett’s esophagus (BE), first described in 1950 by Dr. Norman Barrett, a British thoracic surgeon, refers to replacement of normal squamous epithelium of the esophagus by columnar epithelium, at least 1cm above the gastro-esophageal junction (GEJ).¹ It is considered a precursor lesion of esophageal adenocarcinoma (EAC). The incidence of BE is increasing in the western world has paralleled the increase in endoscopic procedures worldwide. The risk of EAC in patients with BE, which was earlier projected to be significantly higher, is now estimated at least 10 fold higher when compared to the general population.² The reason for this decline in risk as compared to the previous studies may be due to the earlier recognition of dysplastic changes and improved endoscopic ablative therapies.³ In the United States, the overall mortality with EAC is high, and 5-year survival rate is under 20% per SEER cancer statistics review (1975-2011). Since transformation of BE into EAC involves progression of dysplasia, surveillance is important at an early stage, for the reduction in the overall mortality in EAC.³

Risk Factors for BE

Gastro-esophageal reflux disease (GERD) is considered an independent risk factor for BE and has been on a rise in the western world with a prevalence of 10-20%.⁵ About 15% patients with chronic GERD can develop BE, as compared to 1-2% of general population.⁶ Males are more predisposed to develop BE/EAC than females with ratio of 2:1. Caucasian males over the age of 60 years with chronic GERD symptoms are at higher risk for developing BE/EAC than males under the age of 50 years or women.⁷

While cigarette smoking is strongly associated with both BE and GERD,^8,9 the relationship of alcohol consumption and BE is conflicting.10 Classically, alcohol has been considered as a risk factor, especially in combination with smoking. A recent study proposed that wine consumption was associated with reduced risk of BE, although no consistent dose-response relationship could be established for this protective effect.¹⁰ Central obesity is another significant risk factor for BE, independent of overall body fat (measured by body mass index, BMI), in both men and women.¹¹ Metabolic syndrome, obstructive sleep apnea, and some germ-line mutations have also been implicated as additional risk factors for BE.

Diagnosis of BE

BE is traditionally classified based on endoscopic length of salmon colored mucosa, as long segment (LSBE > 3cm) or short segment (SSBE < 3 cm).¹² However, diagnosis of BE needs histological correlation in addition to endoscopic appearance, which takes into account replacement of esophageal squamous epithelium by columnar epithelium (CE) along with presence of goblet cells, a marker of intestinal metaplasia (IM).^15,16 The significance of these two histological features can be appraised by considering the debate around insufficient diagnosis of BE in presence of CE in distal esophagus (1cm above GEJ) but without IM.¹³ Moreover, epidemiological evidence suggests that patients with CE without IM are at low risk of developing EAC as compared to patients with CE and IM (0.07% vs 0.38%.¹⁴ Hence, the current American College of Gastroenterology (ACG) clinical guideline recommends obtaining at least 8 biopsies in patients with suspected BE < 2cm and four quadrant 2-cm biopsies in segments > 2cm, whereas it recommends against endoscopic biopsy of normal or irregular Z-line of less than 1 cm from GEJ.^15,18

In cases of suspected BE, documentation of endoscopic landmarks (GEJ, diaphragmatic hiatus: DH) along with measurement of maximal (M) and circumferential (C) length of visible segment of BE should be mandatorily performed using the Prague classification (Figure 1). Sharma et al. have demonstrated that reliability coefficient (RC) for endoscopic landmarks (GEJ: RC 0.88; DH: RC 0.85) and of BE segment >1 cm (RC 0.72) is high when Prague classification is used.¹⁷

Screening Methods for BE

Currently, screening for BE is limited to patients with recognized high-risk factors like chronic GERD, caucasian race, male gender, age > 60 years, smoking, central obesity and confirmed family history of BE, but not extended to the general population. While this can be achieved using various techniques like conventional endoscopy (CEGD), unsedated transnasal endoscopy (TNE), esophageal video capsule endoscopy (VCE) and cytosponge, CEGD remains the gold standard because of its ability to achieve histological correlation. While limited evidence may support TNE for its comparable efficacy to CEGD (sensitivity and specificity 91% and 100% respectively) for diagnosing BE, especially given its ease of performance with minimal complications,¹⁹ it still needs multi-centric validation. VCE appeals as a non-invasive screening method, but should be reserved for patients who refuse CEGD, given its lower sensitivity and specificity (78% and 73% respectively), no cost advantage and inability of histological sampling.²⁰ Contrarily, cytosponge is an emerging non-invasive yet cost effective screening tool, which if followed by dysplasia and intra-mucosal cancer treatment, may reduce the incidence of symptomatic EAC in high-risk patients by 19%.²¹

High-definition white light endoscopy (HD-WLE) is superior for both screening and surveillance of BE, over standard-definition endoscopy, for detecting dysplastic lesions.²² Since standard protocol biopsies have high miss rate of dysplasia, advance imaging, including chromoendoscopy, narrow band imaging (NBI) and confocal laser endomicroscopy (CLE), are increasingly being employed to further increase the rate of detection of dysplastic lesions as well as EAC. Chromoendoscopy utilizes a special dye (methylene blue, acetic acid or indigo carmine) to enhance the dysplastic lesions, which helps in better visualization during the endoscopy. NBI also referred to as virtual chromoendoscopy, works on the same principle as above, except that it utilizes narrow band filters instead of spraying dyes.²³ Sharma et al. compared NBI to HD-WLE using Seattle protocol and found that fewer biopsies were required using NBI when compared to HD-WLE, with similar overall IM detection rates.²⁴ Although NBI is considered superior to HD-WLE, it’s yield of detecting early neoplasia is controversial, but is still being suggested as the diagnostic modality of choice for surveillance in BE.23 CLE magnifies the mucosal patterns of dysplastic lesions by thousand folds enabling to visualize them to the cellular level.25 However, its use is limited as evidence from the prospective studies suggests that CLE does not help in increasing the overall detection rates of IM.²⁵ Increased time to examine during endoscopy is associated with higher detection rates of dysplasia and EAC.²⁶

Management of BE

The strong argument for endoscopic eradication of BE rather than a permissive surveillance approach arises from several facts, as elucidated. BE is a precancerous state with a “field defect”, and is the first step in the “metaplasia-dysplasia-cancer” sequence, in which molecular aberrations precede neoplasia and radiofrequency ablation (RFA) can eliminate such mutations.^27,28 Furthermore, a multicenter study found that over 50% of those who developed high- grade dysplasia (HGD) or cancer while undergoing surveillance did not have prior findings of dysplasia, suggesting that the “wait and watch” policy might be inadequate to reliably detect early changes.^29,30

The incidence of EAC in the general population (0.003%) goes up by 200 (0.6%), 560 (1.7%) and 2,200 (6.6%) folds once an individual develops BE, low-grade dysplasia (LGD) and HGD respectively,³¹ per SEER cancer statistics review (1975-2011). This is in sharp contrast to the incidence of colon cancer (0.048%), which increases 12 folds (0.58%) with development of a polyp.³² Like colonic polyps are actively managed with polypectomy followed by surveillance, experts endorse similar philosophy in BE management, to steer the paradigm from surveillance only to dysplasia treatment followed by surveillance.³³ It is noteworthy that less than 50% endoscopists adhere to the Seattle Protocol for BE biopsies. Even if adherence is sustained, it still leaves behind a large unsampled segment of esophagus. Lastly, there still remains a high interobserver variation between pathologists, especially in the diagnosis of indefinite or indeterminate dysplasia (ID) and low-grade dysplasia (LGD). All these facts must be deliberated to maintain a perspective during management of BE.

The treatment modalities for BE can be categorized as endoscopic, surgical and chemoprophylaxis.

Endoscopic Management

Per Seattle protocol, targeted biopsies of suspicious dysplastic lesions should be performed along with random 4-quadrant biopsies every 1 cm versus every 2 cm in patients with and without prior history of dysplasia respectively.³⁴ (Figure 2). Subsequent management depends on whether the BE is smooth or nodular. Most of the ablation treatments like RFA and cryotherapy are effective only on a smooth non-nodular esophagus. Hence any nodularity or mucosal / vascular abnormality visualized on endoscopy should be managed by endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) for histopathological staging of the lesion (Figure 3). A study on 293 consecutive endoscopic resections demonstrated that use of EMR alone changed the diagnosis and treatment policy in 49% and 30% of the lesions respectively.³⁵ The subsequent management after EMR depends upon the histological staging of the endoscopic resections.

Patients with non-dysplastic BE (NDBE) should be engaged in endoscopic surveillance every 3-5 years and do not need endoscopic ablative techniques (EAT), given the low incidence of dysplasia and EAC in this population. Recent data estimates that 98.6% and 97.1% NDBE patients remain cancer free after 5-year and 10-year follow-up respectively.³⁶ On the other hand, presence of indefinite/indeterminate dysplasia (ID) is a trickier situation, and such patients should undergo repeat endoscopic evaluation after aggressive PPI treatment in 3-6 months. It is now proposed that patients with ID may carry a significant risk of harboring prevalent dysplasia, although the risk of incident dysplasia is similar to the general BE population.³⁷ Hence, ACG guideline suggests surveillance for these patients like those with LGD, especially because the risk of progression to cancer or dysplasia (LGD/HGD) is highest during the first year. Skacel et al. showed that LGD progressed to HGD over a median of 11 months, in 41% and 80% respectively, depending on whether two or three independent pathologists concurred with the initial diagnosis of LGD.³⁸

The confirmed cases of BE with LGD (BE-LGD) should be reviewed by a second pathologist for adequate staging of dysplasia and risk stratification³⁹ followed by aggressive acid suppression aimed at downgrading the dysplasia. If dysplasia resolves, these patients can be surveyed annually for 2 years after which this interval may be increased. If LGD persists, the current ACG guideline endorses endoscopic treatment, although acknowledges yearly endoscopic surveillance as an acceptable alternative. However, there is emerging data favoring endoscopic therapy over surveillance by demonstrating decreased risk of neoplastic progression after 3 years.⁴⁰ Similarly, patients with HGD require histological confirmation by a second expert pathologist, concomitant acid suppression, but are candidates for endoscopic interventions. Currently, EAT is preferred over esophagectomy as the treatment choice for patients with BE-HGD for its proven efficacy, cost effectiveness and better adverse event profile.⁴¹

EAC is staged depending upon the depth of invasion as T1a (limited to mucosa), T1b sm1 (extension into upper one-third of submucosa), T1b sm2 (extension into middle one-third of submucosa) and T1b sm3 (extension into deep one-third of submucosa). The risk of lymph node (LN) metastases in patients with BE-HGD and IMC is estimated at 0% and <2% respectively,⁴² hence EAT makes sense as the preferred treatment strategy. However, situation gets murkier with EAC. Surgical literature estimates up to 7% and 27% LN metastases risk in patients with EAC T1a and T1b respectively⁴³, therefore making this distinction of paramount importance. However, data on accuracy of EUS for staging of superficial esophageal cancers (T1a, T1b sm1) is limited, and hence EMR remains the gold standard.^44-46

EAT remains the treatment of choice for BE patients with dysplasia, T1a EAC and well-differentiated T1b sm1 EAC with no lympho-vascular spread.⁴⁷ The various EAT include radiofrequency ablation (RFA), photodynamic therapy (PDT) and cryotherapy. For limited surface areas, argon plasma coagulation and bipolar probes are a less expensive alternative, although they may have higher recurrence rates, and hence rarely preferred. RFA is the preferred modality for most patients as it is cost effective and has better adverse event profile than PDT or cryotherapy, and would be the main focus of discussion in this article.

Surgical Management

Endoscopic therapy for HGD/IMC has similar survival (94% at 3 years both groups) but lower morbidity (0% vs. 39%; P<0.0001) compared to esophagectomy.⁴⁸ Esophagectomy in combination with chemo-radiation is the treatment of choice for patients with advanced EAC (T1b sm2-3) or high-risk superficial EAC (poor differentiation or lymphovascular invasion).⁴⁹ While robust acid suppression is an accepted strategy to decrease neoplastic progression of BE, anti-reflux surgeries have no proven efficacy and hence not recommended.⁵⁰ The SAGES guideline also endorses endoscopic treatment modalities.⁵¹ Reflux surgery should be considered in individuals with objective evidence of reflux that fails to respond to PPI, especially those with hiatus hernia, before, during or after ablation treatment.

Chemoprophylaxis

In addition to symptomatic control of GERD, PPIs also serve an additional role as chemoprophylactic agents, given their effect on decrease dysplasia/EAC in patients with BE.⁵² Additionally, data exists describing beneficial effects of NSAID’S, aspirin and statins in reducing incidence of EAC in BE patients, but none are currently endorsed exclusively for their anti-neoplastic effects.^53-54

An Update on Radiofrequency Ablation (RFA)

a. Types of RFA catheters and Biophysiology

RFA combined with EMR has become the standard treatment for BE because of increased efficacy, cost effectiveness and better side effect profile. The biophysical principle of RFA ablation therapy is using electricity in the radiofrequency range of 450- 500 kHz for small vessel and tissue destruction.⁵⁵ Barrett’s epithelium is approximately 500 µm thick, and RFA is designed to achieve a uniform, superficial depth of ablation between ∼ 500 µm and ∼ 1,000 µm in short bursts of ∼ 1 sec, thus achieving optimal removal of esophageal epithelium with minimal risk for complications like buried glands or stricture formation. The ablative energy ranges between 12J/ cm2 to 15J/cm2; the use of N-acetyl cysteine sprayed over esophageal mucosa is encouraged for effective contact between RFA catheter and the mucosa.⁵⁶ There are different RFA catheters available for circumferential and focal therapies, as depicted in Figure 4. (BarrxTM ablation system, Covidien-Medtronic, Sunnyvale, CA). The Barrx360 3cm catheter is used for ablation of circumferential dysplastic mucosa, whereas Barrx90 focal/ultra-long, Barrx60 and channel catheters are employed for focal ablation of small isolated areas/ islands of dysplasia and possibly for short segment BE. Smaller and channel catheters have added advantage of being useful in patients with difficult anatomy and strictures.⁵⁷

b. Efficacy and Safety of RFA

In a sham-controlled trial performed on patients with dysplastic BE, RFA was associated with a high rate of complete eradication of both dysplasia (CED = 90.5% vs. 22.7%; p<0.001) and intestinal metaplasia (CEIM = 77.4% vs. 2.3%; p<0.001) and a reduced risk of disease progression (3.6% versus 16.3%; p=0.03).⁵⁸ at 12 months. A subsequent multi-centric study reported eradication of dysplasia and CEIM in 98% and 91% patients respectively, thus establishing durability of this therapy.59 In addition to the proven role of RFA in BE with dysplasia, its utility in patients with NDBE is often discussed. In a multi-centric trial from 8 centers in the US, Fleischer et al. reported 98% complete eradication of intestinal metaplasia (CEIM) in NDBE patients with ablative therapies over 2.5 years follow-up.⁶⁰ The same authors later obtained biopsies from previous known length of BE at 5 years to demonstrate 92% (46/50) CEIM and the remaining 8% had easy conversion to CEIM with single session of focal RFA.⁶¹ Although RFA is efficacious and durable in NDBE patients, however, given the low risk of its progression to cancer, the current ACG guideline recommends against routine application of endoscopic therapies in these patients.

Although these studies established RFA as the cornerstone treatment for dysplastic BE, our understanding regarding indications is still evolving and we are constantly striving to improve in this area. The major RFA studies have been tabulated in Table 1. We also know that RFA is associated with improved quality of life (QoL) in dysplastic BE. Ablation alters the natural history of BE.⁶² Wani et al. in their meta analysis showed that the progression risk to cancer went down to 0.16%, 0.16% and 1.7% for NDBE, LGD and HGD respectively with ablation, with the number needed to treat (to avoid one cancer over 5 years) being 45, 13 and 4 respectively.31 Das et al. concluded from his economic analysis study that radiofrequency ablation was more cost-effective than surveillance even for non- dysplastic BE.⁶³

c. Efficacy of RFA+EMR over RFA

In patients with dysplastic BE (both HGD and LGD), EMR+RFA is superior to RFA alone, based on higher efficacy (18% vs. 10%).⁶⁴ Also, EMR prior to RFA was found to be as safe in patients with BE/EAC as was RFA alone with no higher stricture formation rates.⁶⁵ Furthermore, a comparison of outcomes in BE patients between 2011-2013 and 2008-2010 from the UK demonstrated significantly higher CEIM (83% vs. 56%) and CED (92% vs. 77%) in recent time period, most of which was attributable to improved lesion recognition and aggressive resection of visible lesions prior to RFA (with EMR), though progression to EAC was not statistically different (2.1% vs 3.4%)66. Most importantly, EMR provides the most accurate staging, and helps plan further management of patients with BE/EAC.

Extensive EMR alone may be an alternative strategy for management of dysplastic BE. However, a multicenter trial established that in patients with ≤ 5cm segment BE/HGD, stepwise radical EMR (SEMR) and RFA+EMR achieved high rates of CED (100% vs. 96%), but SEMR group had more stenosis (88% vs. 14%; p<0.001) requiring subsequent endoscopic treatments.⁶⁷

Hence, EMR+RFA is now recognized to be efficacious, safe and superior to RFA or EMR alone, in management of dysplastic BE.

d. Association of Acid Control and RFA Outcomes

Concurrent anti-reflux therapy is an important concept in patients with BE, especially in those who undergo therapy. A retrospective study of RFA outcomes in patients with BE suggested better CEIM rates in BE patients with normal-mild esophageal acid exposure as compared to patients with moderate-severe acid exposure (44% vs. 15%),⁶⁸ thus endorsing effective intra- esophageal pH control for improved RFA outcomes.^68,69 Moreover, inadequate control of reflux post ablation may result in recurrence.^69,70 The ACG endorses use of PPI in daily doses in BE patients, unless warranted in twice-daily doses because of reflux symptoms or esophagitis.¹⁵ Although not a recommendation, most experts use PPI in twice daily dose after RFA to minimize complications, especially stricture formation.

e. Recurrence of IM after RFA

In a recent retrospective cohort of patients with BE and dysplasia/IMC who achieved CEIM, the post-RFA recurrence rates for IM and EAC progression were ascertained to be 5.2%/year and 1.9%/year respectively.⁷¹ Subsequently using the much larger US RFA registry, it was demonstrated that after CEIM, BE recurrence may occur in upto 20% patients, and is usually very short (0.6 cm average length) and non-dysplastic/indefinite for dysplasia in 86%.⁷² The study identified older age, non-Caucasian race, increasing length of BE length and advanced pre-treatment histology as risk factors for recurrence, and these are now taken into account while planning post-RFA surveillance intervals.⁷³ Subsequent studies revealed area around GEJ as most vulnerable for IM recurrence.⁷⁴

Since no specific characteristics are currently established which accurately predict recurrence, it is important for subjects undergoing RFA for dysplastic BE to be retained in endoscopic surveillance programs. Modalities like laser assisted Optical coherence tomography (OCT) and Confocal laser endomicroscopy (CLE) have been used to assist the endoscopist in the post RFA surveillance phase to pick up “buried glands” and early recurrence, and to target treatment.

CONCLUSIONS

In summary, while cryotherapy and PDT are available alternatives, RFA in conjunction with EMR is the most robustly studied and practiced endoscopic technique for management of dysplastic BE, with high success, cost effectiveness and very few limitations. The modality and equipment are a work-in-evolution, and have plenty of areas requiring continued research. However, the bottom line remains that endoscopists should carefully inspect the Barrett’s mucosa, both pre and post ablation as part of surveillance. We endorse that the modality of choice for endoscopic eradication of Barrett’s esophagus must be in accordance with endoscopist’s training and preference, institutional availability and patient characteristics.

A Case Report

Pneumoperitoneum Due to a Transmural Anal Fissure

October 2016 • Volume XL, Issue 10

Glen Huang,Hussam Bitar

Sheeva Parbhu MD, Douglas G. Adler MD, FACG, AGAF, FASGE Professor of Medicine, Director of Therapeutic Endoscopy Director, GI Fellowship Program, Gastroenterology and Hepatology, University of Utah School of Medicine, Huntsman Cancer Center, Salt Lake City, UT

INTRODUCTION

Esophageal strictures are a common cause of dysphagia, the abnormal passage of solids or liquids through the esophagus. While gastroesophageal reflux disease (GERD) is the most common cause of benign esophageal strictures, they can be due to a multitude of factors, including external beam radiation, post-surgical injury, caustic ingestions or eosinophilic esophagitis. For some patients with benign esophageal strictures, fully covered metal stents can be used to dilate the stricture, alleviate dysphagia and allow for the passage of liquid and solid food. In this case report, we describe a novel, “off label” use of an existing fully covered self-expanding metal stent (AXIOS, Boston Scientific, Natick MA) for the treatment of a patient who presented with a refractory benign esophageal stricture.

Case Report

A 57 year-old man with a history of moderately differentiated, metastatic squamous cell carcinoma of the esophagus was seen in follow-up for worsening dysphagia. After the initial cancer diagnosis, the patient was treated with both radiation therapy as well as chemotherapy with paclitaxel and carboplatin. Computed tomography (CT) scans showed complete response to therapy with no evidence of cancer in the esophagus. In December 2015, an esophagogastroduodenoscopy (EGD) was performed which elucidated a severe esophageal stricture with an inner diameter measuring 3 millimeters (mm) in diameter and less than 1 centimeter (cm) in length in the upper third of the esophagus. This was a benign-appearing lesion, and biopsy was negative for malignancy. The etiology of this stricture was felt to be likely due to post-radiation and chemotherapy effects. Dilation was performed with a 10-11-12 mm x 5.5cm CRE balloon dilator. The patient responded well to this procedure, and in one month follow-up, reported improved dysphagia symptoms and had gained 7 pounds.

The patient presented again in July 2016 with complaints of progressive dysphagia, weight loss as well as occasional post-prandial, non-cardiac chest pain. On repeat EGD a severe, benign-appearing, intrinsic stenosis was found 20 cm from the incisors. (Figure 1) This again measured 3 mm in diameter and less than one cm in length, and was unable to be traversed by the endoscope. The lesion had a very similar appearance to the prior examination. Prior to the procedure, a discussion was had with the patient regarding the risks and benefits of repeat dilation as well as endoscopic stent placement for relief of symptoms, including off- label placement of an Axios stent. In accordance with this discussion, a 15mm wide x 10mm long AXIOS stent was advanced across the stenosis over a guidewire. (Figure 2) The stent was deployed without difficulty and on the first attempt, and was in excellent position as seen both endoscopically and fluoroscopically. (Figure 3) The patient had no post-procedural complications and was able to tolerate a full liquid and solid mechanical diet afterwards. Of note, he was not able to perceive the stent in his esophagus and had no post-procedure pain. Five weeks after stent deployment, the patient was again seen in follow-up. He had gained 5 pounds, and was tolerating a full diet. A repeat EGD was performed, and the AXIOS stent was removed with raptor forceps without difficulty. (Figure 4) The mucosa was examined after removal of the stent with no obvious complications of stent removal. The esophageal lumen was widely patent. The patient was discharged to home the same day, able to tolerate a regular diet, and has done well thereafter without recurrence of his dysphagia symptoms to date.

Discussion

Benign esophageal strictures are caused by a variety of etiologies, including after radiotherapy, caustic ingestions, eosinophilic esophagitis and GERD.¹ Post-surgical stenosis is also very common and occurs frequently following esophagectomy. Endoscopic treatment options include dilation, placement of stents, cryotherapy ablation, and bypass of the obstruction via enteral feeding. Although feeding tubes are commonly used for enteric delivery of nutrition, dysphagia scores are not improved by feeding tubes, and mortality has not been shown to be significantly influenced by these interventions.²

In some patients with benign esophageal strictures, repeated dilations may fail to provide sustained relief of symptoms. In these situations, some treatment algorithms suggest dilation combined with steroid injections or incisions made via electrocautery.³ Patients with strictures due to GERD or a history of ablation therapy tend to respond well to steroid injections. Refractory benign esophageal strictures (RBES) have been defined by one author as strictures which do not appropriately respond to at least 5 dilations of at least 14mm, although definitions vary on this point. RBES represent a difficult problem to treat, and are also associated with significant symptoms and decreased quality of life for patients. In these cases, further endoscopic therapy is typically warranted.³

Self-expandable metal stents (SEMS) are a cornerstone of treatment for patients with dysphagia due to esophageal strictures. These stents are constrained with a small diameter before placement, thus avoiding aggressive dilation of the esophagus (and associated complications).⁴ In addition, they provide persistent dilation of the stenosed esophagus while in place, a significant benefit over intermittent dilation with bougie or balloons.⁵ Partially covered or uncovered SEMS are generally avoided in patients with benign esophageal strictures due to the high occurrence of tissue in-growth which leads to recurrent dysphagia and difficult stent removal.^6,7 Newer, biodegradable stents offer promise in that they dissolve in the esophagus and patients do not need repeat EGD for stent removal, but this technology is not currently approved for use in the United States. Fully covered SEMS are removable stents that are most commonly used to treat benign esophageal strictures.⁸

SEMS are composed of nitinol or other similar metals, and differ in their width, length, amount of force they exert as well as their design. Several retrospective and prospective studies have evaluated efficacy of fully covered SEMS for benign esophageal strictures causing dysphagia. Initial success rates have been as high as 56%, with one large meta-analysis finding sustained improvement of dysphagia at the end of follow-up in 46.2% of patients.^9,10 Stent selection is typically determined by endoscopist preference as no studies have definitively shown improved outcomes with a specific SEMS.

One drawback of fully covered SEMS is the high potential of stent migration, found to be as high as 31% in a different meta-analysis.¹¹ Stents are generally 5cm longer than the stricture, which can lead to post-deployment issues such as abutment with gastric or cricopharyngeal tissue or mucosal damage to normal esophageal tissue. Adverse events related to stent placement include chest pain, GERD, upper gastrointestinal bleeding, perforation, fistula formation, food impaction, airway compromise and aspiration events.¹²

A novel, fully covered, lumen apposing metal stent (LAMS) called the AXIOS stent has been developed in recent years and is now commercially available. Its primary use has been to drain pancreatic fluid collections including pseudocysts, walled-off pancreatic necrosis and acute peri-pancreatic fluid collections.¹³ These stents have dual-anchor flanges in a “dumbbell” shape which helps to maintain position and minimize the risk of migration. Several retrospective studies have reported the clinical success rate of the AXIOS system for drainage of pancreatic fluid collections to be greater than 95%.^14,15 In one large multicenter retrospective study, the LAMS was successfully placed in 97.5% of patients, with only one (1.3%) instance of pancreatic fluid collection recurrence and a very low incidence (2.5%) of spontaneous dislodgement or stent migration.¹⁶ In a review of the literature, only case reports or very small case series have thus far been published about experience with endoluminal placement of the AXIOS stent.^17,18

In this case report, we describe a novel, “off label” use of an existing fully covered SEMS for the treatment of a refractory benign esophageal stricture. The use of this technology was clinically successful in our patient, and accentuates the need for further evaluation and possibly increased use of this treatment for luminal strictures. At this time, it is unclear if the long term efficacy of the AXIOS stent for treatment of benign esophageal strictures will yield better results than the use of existing esophageal SEMS. The smaller diameter and decreased radial force of the LAMS when compared to standard esophageal stents may allow patients to better tolerate placement and lead to decreased complaints of chest pain. The AXIOS stent is also much shorter in length than standard esophageal SEMS, and as it is placed only across the stricture, may result in decreased frequency or severity of GERD symptoms as it did in our patient. These stents can be deployed with or without fluoroscopy as they are “through-the scope” devices. In addition, the double-flanged ends may help to decrease the relatively high migration rate that is seen after placement of standard SEMS. Our case report highlights the necessity of more experience with the novel use of this stent technology.

Frontiers In Endoscopy, Series #30

Use of a Lumen Apposing Metal Stent to Treat a Refractory Benign Esophageal Stricture

October 2016 • Volume XL, Issue 10

Sheeva Parbhu,

Douglas G. Adler

Esophageal strictures are a common cause of dysphagia, the abnormal passage of solids or liquids through the esophagus. For some patients with benign esophageal strictures, fully covered metal stents can be used to dilate the stricture, alleviate dysphagia and allow for the passage of liquid and solid food. In this case report, we describe a novel, off label use of an existing fully covered self-expanding metal stent (AXIOS, Boston Scientific, Natick MA) for the treatment of a patient who presented with a refractory benign esophageal stricture.

INTRODUCTION

Case Report

Discussion

Liver Disorders, Series #6

A Review of the Pathogenesis, Management and Complications of Portal Hypertension and Ascites

October 2016 • Volume XL, Issue 10

Gaurav Singhvi

Courtney Reynolds, MD/PhD¹ Emily Law, MD¹ Duminda Suraweera, MD¹ Gaurav Singhvi, MD² ¹Department of Medicine, Olive View-UCLA Medical Center, Sylmar, CA ²David Geffen School of Medicine at UCLA, Los Angeles, CA

INTRODUCTION

Worldwide, the etiology of portal hypertension is divided between Western and non-Western countries, where 90% of cases in the former are caused by cirrhosis. In the latter, non-cirrhotic conditions such as schistosomiasis or portal vein thrombosis predominate.¹ In some cases, the exact cause of portal hypertension is unclear. Globally, idiopathic non-cirrhotic portal hypertension (INCPH) is a rare disorder associated with infections such as human immunodeficiency virus (HIV) and an array of autoimmune and immunodeficiency disorders ranging from combined variable immunodeficiency to Crohn’s disease.² Here, we will review portal hypertension focusing upon the etiology of cirrhosis. In the US, the prevalence of cirrhosis has been calculated between 0.15% and 0.27% of the population (roughly 400,000 to 660,000 people).^3-4 Among those with cirrhosis, it is estimated that 80-90% have portal hypertension, even if they are otherwise asymptomatic.¹ In 2013, the Center for Disease Control (CDC) reported that chronic liver disease and cirrhosis caused approximately 36,000 deaths in the United States.⁵ In other words, there is a 5-9% annual mortality associated with cirrhosis; this high mortality is largely attributed to complications of portal hypertension.

Alterations in the Circulatory System

The pathophysiology of portal hypertension involves alteration of both the splanchnic and the systemic circulatory systems (Figure 1). While portal hypertension had previously been conceptualized as the result simply of increased resistance within the portal system, there is mounting evidence that elevated pressure is also the consequence of increased blood volume or hyperemia, particularly in later stages. It is thought that early hypoxia due to resistance to blood flow triggers the development of collateral blood supply and a local hyperdynamic state characterized by vasodilation. This vasodilation is driven primarily by increased splanchnic production of nitrous oxide (which also contributes to the collateral angiogenesis), leading to decreased responsiveness to vasoconstrictors and overall increased blood volume within the portal system. These changes lead to decreased blood volume and pressure sensed at carotid and renal baroreceptors, leading to similar neurohumoral activation as seen in heart failure (i.e., upregulation of the renin-angiotensin system and anti- diuretic hormone). Thus, portal hypertension spurs a hyperdynamic response in the systemic circulation characterized by increased cardiac output, expansion of plasma volume and reduced systemic vascular resistance.^6-15

Alterations in Liver Structure and Function

In the setting of cirrhosis, there are characteristic structural and vascular changes within the liver that contribute to portal hypertension. It is well known that hepatic stellate cells (HSC), which function as quiescent lipid and vitamin storage cells in normal liver, become activated as a result of ongoing hepatic injury. This activation results in altered gene activity thought to produce the characteristic fibrotic changes of cirrhosis. However, preceding this development there are substantial changes to the sinusoid endothelial cells as well. The sinusoids ordinarily allow passage of macromolecules to the liver parenchyma through large fenestrations. Capillarization, or loss of endothelial cell fenestration, is an early response to liver injury that appears to occur prior to HSC activation and leads to increased vascular resistance. Interestingly, animal models suggest that reversal of the capillarization process can restore HSC quiescence and reverse fibrosis.6,16 Thus, cirrhosis triggers alterations in liver architecture that contribute to portal hypertension by increased mechanical and vascular resistance.

Pathophysiology of Ascites In the Setting of Portal Hypertension

While the etiologies of ascites are diverse-including malignancy, infection, hypoalbuminemia and lymphatic obstruction-the overwhelming majority of cases are due to portal hypertension from cirrhosis.¹⁷ In the US in particular, an estimated 80% of patients with ascites are due to cirrhosis. Ascites is the most common complication of portal hypertension. The development of ascites is a poor prognostic indicator; median survival for patients with refractory ascites is six months.¹⁸ The formation of ascites is similar to edema developing in other parts of the body: ascites emerges when there is a gradient in the hydraulic and oncotic pressures within blood vessels versus the interstitial space. With portal hypertension, ascites is partly the result of the arterial vasodilation that occurs as mentioned above; this vasodilation and the resulting increased blood volume render increased hydraulic pressure within the vascular bed causing ascites. On the other hand, decreased oncotic pressure, which also contributes to ascites, is primarily due to decreased synthetic function of the cirrhotic liver rather than from portal hypertension directly.

The development of ascites exacerbates the neurohumoral responses activated by portal hypertension. Venous return and renal perfusion are further compromised by ascites and lead to water and sodium retention. It is believed that the presence of ascites corresponds to a decrease in liver function of 60% or less, according to perfused hepatic mass imaging.¹⁹ Renal hypoperfusion may initially be countered by increased production of nitric oxide and prostaglandins, however long-standing decompensated cirrhosis usually leads to chronic kidney disease and in some cases the often fatal hepatorenal syndrome. Clinically, patients with ascites develop volume overload and dilutional hyponatremia despite increased total body sodium. Hyponatremia is associated with a poor prognosis and has been shown to predict the development of hepatic encephalopathy, the hepatorenal syndrome and mortality both from cirrhosis and in the short term following liver transplantation.²⁰

Complications of Portal Hypertension

Portal hypertension can result in several severe complications leading to significant morbidity and mortality. Generally these complications manifest when hepatic venous pressure gradient exceeds 10 to 12 mm Hg.²¹ Ascites is the most common complication of portal hypertension as discussed above.

Gastroesophageal Varices

It is estimated that 5-15% of cirrhotic patients develop gastroesophageal (GE) varices per year, with the development of GE varices correlating with the degree of severity of cirrhosis. About 40% of Child-Pugh A patients have varices as compared to 85% of Child- Pugh C patients.²² Approximately 50% of patients with cirrhosis have gastroesophageal varices at any given time, while the majority of patients with cirrhosis develop GE varices at some point during their lifetime.

Esophageal variceal bleeding occurs at a yearly rate of 5-15%.²³ Risk factors for esophageal variceal hemorrhage include size of varices, severity of cirrhosis, variceal pressure and endoscopic presence of variceal red spots. An acute episode of variceal hemorrhage carries a six week mortality rate in excess of 20%.²⁴

Gastric varices are present in 5-44% of patients with portal hypertension.²⁵ Risk factors for gastric variceal hemorrhage include the size of fundal varices, Child- Pugh class and endoscopic presence of variceal red spots.²⁶ Gastric varices can be subdivided into two groups:²⁷ those associated with esophageal varices (gastroesophageal varices) and those not associated with esophageal varices (isolated gastric varices). Gastroesophgeal varices can be further subdivided into two groups depending on their distribution. Type 1 extend along the lesser curvature, and Type 2 extend along the fundus. Isolated gastric varices can also be subdivided into two types by distribution: Type 1 are located in the fundus while Type 2 are located in the body, antrum or around the pylorus (Figure 2).

Esophagogastroduodenoscopy (EGD) is the gold standard for the diagnosis of gastroesophageal varices. Varices can be classified as small, medium or large. Small varices are minimally elevated veins above the mucosal surface, medium varices are tortuous veins occupying less than one-third of the esophageal lumen while large varices occupy greater than one-third of the lumen. It is recommended by the American College of Gastroenterology that patients undergo screening for varices at the time of diagnosis of cirrhosis.^27-29

Hepatorenal Syndrome

Hepatorenal syndrome (HRS) is a manifestation of acute renal dysfunction that is seen in severe cirrhosis.³⁰ Risk of developing hepatorenal syndrome from cirrhosis is estimated at 20% after one year and 40% after five years with an incidence of 10% among hospitalized patients with cirrhosis and ascites.³¹ While the exact mechanism is unknown, it is likely due to a decrease in peripheral arterial circulation from arterial vasodilation in the splanchnic circulation.³² A reduction in cardiac output may also play a concurrent role.³³ Patients often present with profound volume overload and electrolyte abnormalities. The diagnosis of hepatorenal syndrome is one of exclusion. Criteria include a plasma creatinine concentration of greater than 1.5 mg/dL, presence of liver disease and portal hypertension, absence of apparent other causes of kidney injury and lack of improvement in renal function after volume expansion with intravenous albumin.³⁴ There are two described types of hepatorenal syndrome. Type 1 is a rapidly developing renal failure defined as a doubling of the serum creatinine to above 2.5 mg/dL or a decrease in glomerular filtration by more than 50% in less than two weeks.³⁵ In contrast, Type 2 hepatorenal syndrome is a gradually developing renal failure with creatinine above 1.5 mg/dL (Table 1).³⁴

Ideally, hepatorenal syndrome is treated with recovery of liver function either through treatment of the underlying cause (abstinence from alcohol, antiviral therapy, etc.) or through liver transplantation. One study of liver transplantation for Type 1 hepatorenal syndrome found 75% of patients had complete recovery of kidney function after transplant; non-response was associated with prolonged courses of dialysis proceeding transplant, suggesting that prompt referral is key.³⁶ Medical therapy targeted at HRS itself aims to increase perfusion to the kidneys by increasing arterial pressure. In the United States, a combination of octreotide, midodrine and albumin is most frequently used, and the usual course of treatment is two weeks. Alternatives include norephinephrine and vasopressin. Although small studies suggest the effectiveness of vasoconstrictors in this setting, the mortality of HRS remains high.^37-38 Patients who fail medical therapy but are either expected to recover liver function or await liver transplantation can transition to dialysis.

Hepatic Encephalopathy

Hepatic encephalopathy is a neurologic dysfunction seen in patients with liver disease and portal hypertension. The pathogenesis of hepatic encephalopathy is likely multifactorial. Ammonia produced by gut bacteria is typically processed in the liver. However, in the setting of portal hypertension, portosystemic shunts result in ammonia bypassing the liver and accumulating in the systemic circulation and crossing the blood-brain barrier.³⁹ Patients can present with a wide spectrum of neurocognitive manifestations. Hepatic encephalopathy can be divided into minimal hepatic encephalopathy- patients with abnormal psychometric tests but no obvious clinical changes-and overt hepatic encephalopathy, in which patients have obvious clinical manifestations. These manifestations include personality changes, irritability and disinhibition. The West Haven Criteria is used to grade hepatic encephalopathy.40 Grade 1 is considered minimal hepatic encephalopathy, grades 2-3 are intermediate, and grade 4 is a comatose patient. Management of encephalopathy is primarily with non- absorbable disaccharides, such as lactulose and non- absorbable antibiotics, such as rifaximin.^41-42 Probiotics, polyethylene glycol, flumazenil ammonia scavengers and zinc have also been shown to be of benefit in the management of hepatic encephalopathy.^43-47

Hepatopulmonary Syndrome

Hepatopulmonary syndrome (HPS) is a syndrome defined by liver disease, increased alveolar-arterial oxygen gradient and intrapulmonary vascular dilatations.⁴⁸ It is more common than portopulmonary hypertension, but both can occur in the same patient. Prevalence ranges from 4 to 34% of patients with liver disease.^49-50 While the development of HPS does not require the presence of cirrhosis, it is more common in this setting.^51-53 Still, HPS does not correlate with the severity of liver disease.⁵⁴ The proposed pathophysiology of HPS involves pulmonary production of excess vasoactive mediators, nitric oxide (NO) and carbon monoxide (CO). Arterial hypoxemia is then caused by intrapulmonary vascular dilatation. Other mechanisms or pathways are under investigation, however some studies suggest that there may be increased pulmonary angiogenesis, resulting from greater macrophage production of vascular endothelial growth factor (VEGF)-A.^55-56 Screening for HPS with an arterial blood gas is recommended in liver transplant candidates and patients with liver disease who have shortness of breath. The ABG then directs whether the patient needs a contrast-enhanced echocardiography (CEE) which is diagnostic.48

Clinical features of HPS include dyspnea, cyanosis and progressive hypoxemia.^57-59 A hallmark finding is platypnea or increased dyspnea with upright positioning that is relieved by lying down; quantitatively platypnea corresponds with orthodeoxia or a decrease in arterial oxygenation by more than 4mmHg moving from recumbency to sitting. A variety of medical therapies exist for HPS but there is a dearth of evidence on their efficacy in improving oxygenation or dyspnea; these agents include somatostatin analogues, beta- blockers, cyclooxygenase inhibitors, glucocorticoids, immunosuppression, pulmonary vasoconstrictors, NO inhibitors, inhaled NO, antimicrobials and garlic.60-77 Supplemental oxygen is often used for symptom relief. Case reports suggest a benefit from TIPS, however this is not routinely recommended due to otherwise variable outcomes and theoretical risk of worsening HPS.78-81 Definitive treatment of HPS is liver transplantation, which results in complete resolution of HPS in greater than 80% of patients.^82-88

Porto-Pulmonary Hypertension

Pulmonary hypertension is a complication of portal hypertension, with or without cirrhosis, and is considered to be a type of pulmonary arterial hypertension.⁸⁹ Portopulmonary hypertension (POPH) is more commonly found in females and in patients with autoimmune liver diseases, namely primary biliary cholangitis and autoimmune hepatitis.⁹⁰ It is not, however, found to be related to the severity of liver dysfunction, whether by Child Turcotte Pugh (CTP) classification or model for endstage liver disease (MELD) score.⁹¹ The pathophysiology of POPH is not clearly defined, however current research has shown remodeling of the pulmonary arterial wall which causes an obstructive thickening and fibrosis of the arteries.^92-93 The remodeling is a consequence of the hyperdynamic state caused by splanchnic vasodilation, and the dysfunctional imbalance of mediators such as endothelin-1, prostacyclin and nitric oxide.

Right heart catheterization is required to establish the diagnosis of POPH. According to the criteria established by the 2004 European/US Consensus Study Group, the diagnosis requires 1) portal hypertension with or without hepatic cirrhosis and 2) pulmonary arterial hypertension by right heart catheterization (RHC) with mPAP > 25 mmHg, PVR > 240 dynes.s.cm^-5 and PAWP < 15 mmHg. The severity of portopulmonary hypertension depends on the mPAP: mild is mPAP 25-34 mmHg, moderate is mPAP 35-44 mmHg, and severe is 45 mmHg and greater. In terms of screening, the American Association for the Study of Liver Disease (AASLD) recommends patients being evaluated for liver transplant undergo echocardiogram followed by right heart cardiac catheterization if the RVSP is greater than or equal to 45 mmHg. There is currently no screening recommendation regarding patients with portal hypertension not undergoing liver transplant.48

Medical therapies for POPH include agents used for pulmonary arterial hypertension: endothelin receptor antagonists, prostanoids, phosphodiesterase-5 inhibitors and soluble guanylate cyclase stimulators. Liver transplantation is the only potentially curative option; after transplant, about half of patients can be weaned from POPH medications.^94-95

Hepatic Hydrothorax

Hepatic hydrothorax (HH) is an uncommon complication in patients with liver disease, found in only 5-10% of patients.^96-98 It is defined as a transudative pleural effusion greater than 500 mL in a patient with portal hypertension without any other etiology of the effusion.^99-101 The pathologic process is presumed to result from translocation of peritoneal ascetic fluid into the pleural cavity through small diaphragmatic defects.¹⁰² This occurs more frequently on the right side than the left, possibly due to embryogenic defects.^103-104 Subsequently, the hydrothorax can cause an acute tension hydrothorax or infection, namely spontaneous bacterial empyema. The diagnosis is often clinical, and symptoms include shortness of breath, nonproductive cough, chest discomfort and hypoxia. Thoracentesis is performed mainly to exclude other causes, whereas treatment options for HH include medical management with dietary sodium restriction and combined loop diuretic and aldosterone receptor antagonist therapy.¹⁰⁵ When HH is refractory to medications, therapeutic thoracentesis can be pursued but it has a high rate of recurrence. Similarly, pleurodesis has a limited role in the management of non-malignant pleural effusions and has been associated with recurrence and significant morbidity such as infection.¹⁰⁶ Other options available are transjugular intrahepatic portosystemic shunt (TIPS) and liver transplantation, although due to high associated morbidity TIPS is reserved for patients with relatively preserved liver function (Child-Pugh score <13 or MELD <15).^107-108

Diagnosis and Management of Portal Hypertension and Ascites
Diagnosis of Portal Hypertension and Ascites

The gold standard for diagnosis of portal hypertension is hepatic venous pressure gradient testing (HVPG), which indirectly measures portal pressure as the difference between the wedged and free hepatic venous pressures. Normal values for HVPG are 1-5mmHg. Any pressure above this range is considered portal hypertension, however HVPG of >10mmHg has been termed “clinically significant” as this level is predictive of the development of ascites and varices. Variceal bleeding becomes more likely with HVPG of 12 or more.¹⁰⁹ While less invasive diagnostic techniques are being investigated, such as contrast enhanced ultrasound, in practice, most patients with cirrhosis (or other conditions known to cause portal hypertension) who develop complications such as ascites or varices are presumed to have portal hypertension without further testing.¹¹⁰ The diagnosis of ascites is usually prompted by patient presentation of increased abdominal girth, weight gain and dyspnea. Free fluid within the abdomen can be visualized and graded by imaging, most often ultrasound, while paracentesis allows sample collection to analyze the fluid. The range of tests performed on ascitic fluid depends on clinical suspicion, however one essential test for diagnostic paracentesis is to calculate the serum ascites albumin gradient (SAAG) comparing the serum and ascites albumin levels. A high gradient indicates ascites with a low protein content, consistent with cirrhosis or heart failure. Low gradients occur in the setting of malignancy or infection.¹¹¹ Beyond this, it is standard to obtain cytology, cell count, culture and Gram stain on an initial, diagnostic paracentesis and to evaluate for the presence of spontaneous bacterial peritonitis (SBP), which is heralded by the presence of >250 polymorphonuclear cells/mm³.

Primary Management of Portal Hypertension

While management of portal hypertension most often focuses upon its complications, there is evidence to support treating the underlying cause as well. In the case of portal hypertension caused by cirrhosis, the regression of cirrhosis after stopping the offending agent or treating the underlying cause has been demonstrated for several disparate etiologies (autoimmune hepatitis, biliary obstruction, iron overload, NASH and hepatitis B and C).^112-118 Treatment response to antiviral therapy in patients with Hepatitis C has been correlated with improvement in hepatic fibrosis.^119-121 Similar findings have been demonstrated in chronic hepatitis B, where regression of cirrhosis is feasible with long-term suppression with tenofovir.¹²² The evidence is more limited for improvement of fibrosis following treatment of alcoholic cirrhosis, however abstinence from alcohol has been shown to lead to improved liver function and decreased inflammation and is associated with significantly improved survival compared to cirrhotic patients who continue to drink.¹²³ Nonetheless, although there is evidence to suggest regression in fibrosis, the degree of regression is highly variable, and an actual reversal of cirrhosis has not been demonstrated in humans.¹²⁴

Management of Gastroesophageal Varices

Management of varices consists of primary prevention, acute treatment of variceal bleeding and secondary prevention. In patients newly diagnosed with cirrhosis, it is currently a Class IIa recommendation from the American College of Gastroenterology (ACG) to perform a baseline upper endoscopy to assess for gastroesophageal varices.¹²⁵ On the initial EGD screening, varices should be graded as small, medium or large as mentioned above, and evaluated for the presence or absence of red signs (wale marks or red spot). In patients with compensated cirrhosis and no varices on the initial EGD, an EGD screening should be repeated in three years. In patients with decompensated cirrhosis and no varices, EGD should be repeated annually.¹²⁶

In patients with small varices that have not bled and who are not on a non-selective beta-blocker (NSBB), an EGD should be repeated in 2 years. However, in patients with small varices who are on a NSBB, no follow-up EGD is needed. In patients with medium/large varices who are on a NSBB, the dose should be adjusted to the maximum tolerated and a follow-up or surveillance EGD is not needed.¹²⁵ NSBB is an accepted therapy for primary prophylaxis of variceal hemorrhage. Through blockade of beta-1 receptors, these agents reduce cardiac output and thereby portal pressure. Through blockade of beta-2 receptors, they reduce portal blood inflow from splanchnic vasoconstriction. Propranolol and nadolol are NSBBs that have demonstrated efficacy in much of the literature. They can decrease the incidence of a first variceal hemorrhage from 25 to 15% in a median follow-up of 24 months.¹²⁷ There is also a lower mortality in patients on NSBBs (propranolol or nadolol) versus placebo.¹²⁸ In addition to propranolol and nadolol, there are recent studies on carvedilol, a non-selective beta-blocker with a vasodilatory effect through anti- alpha adrenergic activity. In a randomized placebo- controlled trial, carvedilol was effective in preventing the progression of small to large esophageal varices in patients with cirrhosis.¹²⁹ Some trials have shown that carvedilol can lower HVPG^130-131 and in a systematic review with meta-analysis, reduce HVPG more than propranolol.^132-135 In a randomized controlled trial, in comparison to endoscopic variceal ligation (EVL), carvedilol has lower rates of a first variceal bleed but with no significant difference in overall mortality and bleeding-related mortality.¹³⁶ There are limited studies on carvedilol and its comparison to other therapies in regards to their side effect profiles. However, other studies have failed to show that NSBB agents affect the natural history of varices. A recent meta-analysis of cirrhotic patients with no or small varices showed that patients started on a NSBB experienced no difference in rates of development of large varices, first occurrence of upper gastrointestinal bleeding or death.¹³⁷ The use of NSBB in patients with Child’s class C cirrhosis or renal dysfunction has become controversial, as some studies have associated their use in this setting with higher mortality.^138-139 One theory is that since NSBB reduce cardiac output, there is reduced renal perfusion and thus increased risk for hepatorenal syndrome.¹⁴⁰

If patients with medium or large varices undergo endoscopic variceal ligation, then EVL should be repeated every 1 to 2 weeks until obliteration of varices is acchieved. The first surveillance EGD should be performed 1 to 3 months after obliteration, and then every 6 to 12 months to check for recurrent varices.¹²⁵ Two recent meta-analyses comparing EVL and NSBB use in the preventive setting showed that while EVL did result in significantly lower occurrence of variceal bleeding, there was no difference in mortality.^141-142 Further, episodes of bleeding tended to be more severe after EVL, which has been attributed to post-ligation ulceration.

Although EVL can be used in the primary prevention setting as mentioned, it is most often used for treatment of acute variceal bleeding or prevention of re-bleeding. In an episode of acute variceal bleeding, specific measures (vs general management of gastrointestinal bleeding) are divided into pharmacologic management and endoscopic therapy (mainly sclerotherapy and EVL). Pharmacologic agents include vasopressin, somatostatin and their analogues (most commonly terlipressin and octreotide, respectively) that function as splanchnic vasoconstrictors, reducing blood flow and thus pressure within the portal system. In practice, somatostatin analogues have a more favorable safety profile for extended use, and of these octreotide is most widely used in the US. For endoscopic therapy, EVL has been shown to achieve better initial control of bleeding and is also superior for secondary prophylaxis vs sclerotherapy.¹⁴³ In the acute setting, combined use of pharmacologic and endoscopic measures has been shown to improve both initial and five-day control of hemostasis without a significant impact on mortality or increase in adverse events.¹⁴⁴ In the event of persistent uncontrolled bleeding, balloon tamponade or expedited TIPS can be performed; other indications for TIPS will be discussed later in this section. The one-year rate of recurrent variceal hemorrhage is roughly 60%.¹⁴⁵ Recurrent variceal bleeding in patients on appropriate medical therapy should prompt consideration for referral to liver transplantation.

While the management of Type 1 gastric varices (gastroesophageal) is similar to that outlined above, the treatment of isolated gastric varices, which occur most often in the fundus, differs greatly. During an acute bleed, gastric varices can be temporized with injection of cyanoacrylate (“glue”), a safe and well- tolerated procedure that may also prevent future bleeding. Band ligation has not proven as effective for acute treatment of gastric varices, while NSBB have not been shown to decrease the risk of future bleeding events.^146-148 Balloon-occluded retrograde transvenous obliteration (BRTO) is a relatively new procedure that occludes gastric varices using a sclerosing agent. A recent meta-analysis determined that BRTO resulted in lower rates of re-bleeding compared to TIPS, without any differences in procedure-related complications.¹⁴⁹ However, BRTO can worsen esophageal varices and ascites, leading some to combine TIPS with BRTO.

Management of Ascites

The development of ascites is also associated with a poor prognosis and high mortality, chiefly due to the resulting risk of spontaneous bacterial peritonitis and hepatorenal syndrome. However, unlike with varices there is no standard for primary prevention, and treatment is usually reserved for development of clinically apparent fluid accumulation. Initial management includes sodium restriction and diuretic medications. Of note, sodium restriction (to less than two grams daily) is most effective in patients with relatively intact renal function, as sodium excretion becomes more impaired with disease progression. Concomitant fluid restriction is usually only implemented if severe hyponatremia has developed (i.e., serum sodium less than 120 mEq/L).¹⁵⁰ In one randomized controlled trial, cirrhotic patients with ascites on diuretics were randomized to a low sodium diet versus unrestricted sodium intake. There was no significant difference between the two groups among the endpoints measured (mortality, time for complete resolution of ascites, hospital stays and cost).¹⁵¹ However, in patients with no previous history of gastrointestinal bleeding, there was a higher survival rate in those on a low sodium diet. In practice, the effectiveness of sodium restriction is limited by patient compliance.

Diuretic therapy is a complement to, rather than a replacement for, sodium restriction and is usually instituted concurrently. The diuretic of choice is spironolactone, as it works to combat the renin- angiotensin system activation triggered by portal hypertension and ascites.¹⁵² Patients who do not respond to an adequate dose of spironolactone (200 to 400mg daily), may also receive oral furosemide; the ratio of spironolactone to furosemide dosing is generally 100mg: 40mg respectively. Rapid fluid or weight loss from diuretics should be avoided, and patients in the dose titration phase need to be monitored closely for complications of diuretic treatment including hyponatremia, hyperkalemia, encephalopathy and renal failure. The additional benefit of albumin to diuretic therapy has been controversial. In one randomized controlled trial, cirrhotic patients in an outpatient setting received either diuretics alone versus diuretics with albumin. They found a higher clinical response rate in those who received diuretics with albumin compared to diuretics alone, resulting in shorter hospital stays, lower probability of re-developing ascites and lower probability of readmission to the hospital.¹⁵³ Practically, the routine use of albumin is limited by expense and patient adherence. Finally, therapeutic paracentesis is often used in the setting of severe or tense ascites. Refractory ascites is defined as ascites that fails the above measures or recurs rapidly after therapeutic paracentesis; it occurs in approximately 5-10% of patients with ascites. Treatment options include large volume paracentesis (up to 5L), liver transplantation or TIPS.

Transjugular Intrahepatic Portosystemic Shunting for Refractory Bleeding or Ascites

TIPS, which creates a shunt from the portal vein to the hepatic vein, has emerged as a second line treatment for severe complications of portal hypertension including recurrent variceal bleeding and refractory ascites. Before TIPS is performed, the patient must be evaluated to determine if they are an appropriate candidate. Risk factors for poor outcome and complications from the procedure include prior encephalopathy, hyperbilirubinemia and cardiopulmonary disease. These risks must be considered, along with the possibility of referral for definitive treatment with liver transplant. Absolute contraindications to TIPS include congestive heart failure, multiple hepatic cysts, uncontrolled sepsis, biliary obstruction and severe pulmonary hypertension. For variceal bleeding, TIPS has been shown to be superior to NSBB plus sclerotherapy in preventing recurrence in one meta-analysis; despite this, no difference in mortality has been proven.¹⁵⁴ One retrospective study comparing TIPS with EVL did find a survival benefit, however this has yet to be demonstrated in controlled prospective trials.¹⁵⁵ For refractory ascites, there is conflicting evidence from randomized controlled trials (and meta-analyses of these trials) about whether TIPS confers a survival benefit compared to large volume paracentesis. Available trials are limited by small sample size and heterogeneous patient selection, however there may be an advantage for using TIPS in patients with ascites and relatively preserved renal function.^156-158 In one retrospective study, patients who had MELD scores greater than 15 were evaluated in two groups, those who received TIPS and whose who did not. In the first two months post-TIPS, patients had increased mortality compared to their counterparts, however this was not statistically significant. After two months, TIPS was associated with lower mortality and need for liver transplantation versus cirrhotic patients who did not undergo TIPS.¹⁵⁹ Further, prospective, controlled studies are needed to confirm this result.

CONCLUSION

Portal hypertension is an important cause of mortality globally and a frequent consequence of end stage liver disease in the United States. If untreated, portal hypertension results in the associated conditions of ascites, variceal bleeding, hepatorenal syndrome and cardiopulmonary disease. Effort should be focused upon the prevention of these outcomes, by screening and treating the common etiologies of cirrhosis including alcohol, Hepatitis B and C. Further studies are needed to guide the management of portal hypertension and its complications, which continues to present many challenges.