Nutrition Reviews in Gastroenterology, SERIES #15

Recognizing Thiamine Deficiency: Keeping Patients Safe and Clinicians Out of Court

July 2024 • Volume XLVIII, Issue 7
Carol Rees Parrish,Neeral Shah,Kate Willcutts

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Considerable effort has gone into identifying and diagnosing malnutrition in recent years, and along with that, recognizing those at risk for refeeding syndrome (RS). Less attention has been given to Wernicke’s Encephalopathy (WE) despite the rising number of cases, not only reported in the literature, but court cases as well. Court cases have revealed that clinicians are failing to identify malnutrition, and as a result, missing the signs and symptoms of WE with devastating consequences. The purpose of this review is to discuss those at risk for both RS and WE, and, by definition, the malnutrition that overlaps both entities. In addition, frequent findings in court cases will be shared to help clinicians better identify and treat patients at substantial risk for malnutrition, RS, and WE in order to keep patients safe and clinicians out of court.

Introduction

Refeeding Syndrome (RS) and Wernicke’s Encephalopathy (WE) are serious complications that can occur with the initiation and consistent delivery of nutrients in malnourished individuals without adequate guardrails (attention to appropriate practice guidelines). RS is the metabolic response to consistent nutrient provision in a malnourished patient leading to hypokalemia, hypophosphatemia, and hypomagnesemia and the potentially severe consequences those electrolyte shifts can bring.1,2 WE is a severe neurological syndrome due to thiamine deficiency that too often goes unrecognized, underdiagnosed, and undertreated (Table 1).3,4

First, however, one must identify the malnourished patient that should subsequently trigger concern for RS and WE. Court cases have repeatedly found that registered dietitian nutritionists (RDN) in particular have failed to meet the American Society of Parenteral Nutrition (ASPEN) / The Academy of  Nutrition and Dietetics (AND)’s consensus standards for nutritional assessment 5-7 by not:

Documenting an adequate nutritional history. 

Documenting an adequate anthropometric evaluation with weight loss history over time and/or physical assessment.

Reviewing prior admission/emergency department (ED) records that demonstrate persistent, or ongoing decline of nutritional health. 

Identifying the risk for developing micronutrient deficiencies.

Nervous System Involvement (Dry Beriberi)
Wernicke’s Encephalopathy – (acute phase & reversible): Classic triad: altered mental status (delirium, confusion, drowsiness), gait ataxia, ocular signs (nystagmus) – only 16% – 30% of patients with Wernicke’s present with all three Also, fatigue, irritability, decreased reflexes, tingling sensation (arms & legs), blurred vision, change in mobility Consider WE in any patient with unexplained delirium in the ICU Korsakoff Syndrome – (chronic phase & irreversible) Permanent mental impairment (memory loss, amnesia, tremor, coma, disorientation, and vision problems)
Cardiac involvement (Wet Beriberi)
Acute high-output cardiac failure with peripheral edema
Gastrointestinal involvement (GI Beriberi)
Abdominal pain (potential clue: elevated serum lactate), nausea, emesis
Major barrier to pt diagnosis → a low index of suspicion by clinicians
Table 1. Signs and Symptoms of Wernicke’s Encephalopathy (“Thiamine-Deficient Encephalopathy”)32,33,34
Absorption Duodenum and proximal jejunum (will your patient be affected based on anatomy?) Active alcohol consumption may alter oral thiamine absorption26
Excretion Losses are significantly increased up to 2 times baseline by loop diuretics9 Renal replacement therapies also significantly decrease plasma thiamine
Treatment considerations Short half-life – 1-12 hours8 Note: Oral gummy multivitamins rarely contain thiamine due to its offensive taste (Table 5) IV thiamine has a 2-hour half-life, hence, to maintain blood levels to treat Wernicke’s,
2-4 doses per day are needed to achieve rapid correction by steep plasma: CNS gradient35 Administer IV thiamine slowly (over 30 minutes), diluted in 100mL of normal saline
as it is very painful otherwise4
Table 2. Thiamine Considerations for the Clinician

Second, malnutrition which generally implies macronutrient “deficiency,” regardless of etiology, rarely appears in isolation from micronutrient deficiency, particularly thiamine (due to its short half-life and limited body stores). Although clinicians are aware of the need for thiamine in the setting of RS, many clinicians have a low index of suspicion for thiamine deficiency in other settings, delaying necessary treatment that can result in the development of WE and its potentially devastating consequences, or worse, Korsakoff’s Syndrome (Table 1). The importance of the clinician’s role in early identification and treatment of patients at risk for both RS and WE cannot be overstated and is the focus of this article in order to avoid serious complications and subsequent malpractice claims.  

About Thiamine

Thiamine (vitamin B1), a renally excreted, inexpensive water-soluble vitamin, has limited body stores of approximately 30 mg and a short half-life of 1-12 hours.8 Thiamine will last only 9-18 days in well-nourished individuals,9 but will deplete sooner if stores are insufficient or have been drawn upon without replenishment (e.g., 5% dextrose [D5W] infusion or parenteral nutrition [PN] administration without added thiamine or multivitamin infusion [MVI]). As thiamine is primarily absorbed in the upper jejunum, and to some extent the duodenum, consideration of the patient’s anatomy will be important when supplementing via the oral/enteral route.

Thiamine is a critical, rate-limiting cofactor to several enzymes involved in carbohydrate metabolism and can be rapidly depleted when carbohydrate is infused or ingested as the need for thiamine pyrophosphate (TPP) increases (such as in refeeding a malnourished patient). Thiamine deficiency exhausts supply to these enzymes, resulting in decreased adenosine triphosphate (ATP) synthesis, oxidative damage, and cell death; metabolic acidosis can also occur, reflected by an elevation in serum lactate concentration.8,10 For thiamine considerations for clinicians, see Table 2.

Refeeding Syndrome and Wernicke’s Encephalopathy: A Continuum

While several national and international nutrition societies have focused on identifying and preventing RS in recent years, WE has not garnered such attention. Unfortunately, too many clinicians are under the impression that WE is limited to those with alcohol use disorder, yet a myriad of other patient populations are also at risk.11-17 In fact, RS and WE often share the same high-risk groups and may occur concurrently 4,11-17 (Table 3). Two major warning signs present in almost all reported WE cases are extreme weight loss and vomiting.16 Many associations have published guidelines recommending thiamine repletion for RS;1,18,19 however, clinicians seldom realize that beyond carbohydrate metabolism, if WE is lurking, much higher thiamine doses are required (Table 4). 

Wernicke’s Encephalopathy (“Thiamine-Deficient Encephalopathy”)

WE is an acute medical neurological emergency, that if left untreated, can progress to chronic Wernicke–Korsakoff syndrome, leading to impaired memory and cognitive functions, and coma and death in severe cases. It has been estimated that 80% of WE cases go undetected,3 likely due to the fact that the classic signs and symptoms may not all be present (Table 1). In fact, WE classically presented as a triad of global confusion, gait ataxia, and ophthalmoplegia, yet this triad is only seen in 16%-20% of cases.14 The current dominant paradigm that WE only appears in those who have alcohol use disorder needs to change in order to prevent the rising cases and consequences of WE. Extensive case reports in patients with conditions other than alcohol use disorder highlight this fact, in particular, the post bariatric surgery patient population.15 Similar case examples from these and other populations resulting in lawsuits due to inadequate early treatment for WE will be addressed later in this article. 

Why Does Thiamine Deficiency (and Wernicke’s) Elude Clinicians:10

Thiamine deficiency is often missed for several reasons: 1) signs and symptoms of thiamine deficiency can vary and mimic those of unrelated disorders; 2) patients may have micronutrient deficits including a thiamine deficiency in the setting of a secondary medical issue that steers the clinician in a different direction; 3) results of serum thiamine testing take up to 7-10 days, delaying not only the diagnosis, but timely treatment; 4) the best biomarker, as well as normal range cutoffs, have yet to be determined; 5) controversy exists regarding the best treatment regimen for WE as the best universal treatment guidelines have yet to be established.20

Diagnosing and Preventing Wernicke’s Encephalopathy

Patients at Risk for Refeeding and/or Wernicke’s
Nutrient deficit/significant weight loss: Chronic, poor oral intake for ANY reason Food insecurity, homelessness, refugees Eating disorders/malnutrition/ underfeeding Malabsorption syndromes Dysphagia/esophageal disorders Prolonged fasting/NPO post-op for > 7 days Chronic alcohol or drug use disorder  Morbid obesity with significant weight loss Oncology patients  Persistent diabetic ketoacidosis, or non-ketotic, hyperosmolar state  Alcohol misuse/withdrawal Head & neck cancer patients (high alcohol misuse) Anyone with nausea/vomiting x 2 weeks or greater Recurrent visits to emergency departments for dehydration from nausea/vomiting and
D5-containing IV solutions started @ high infusion rates without MVI or thiamine added Hyperemesis gravidarum Bariatric surgery with excessive diarrhea/vomiting/weight loss Gastroparesis Esophageal or pyloric stricture, gastric outlet obstruction, etc. PN-dependent patients not infusing MVI due to intolerance or supply shortages Unexplained heart failure or lactic acidosis Chronic congestive heart failure on diuretics Psychiatric illness with weight loss
Table 3. Patients at Risk for Refeeding Syndrome and/or Wernicke’s Encephalopathy 2,16,36-38

Diagnosing WE begins with a high level of suspicion in the right clinical context: i.e., a patient who has lost a significant amount of weight, persistent vomiting for 2 weeks or more, or consumes an excessive amount of alcohol. Significant or severe weight loss has been defined as:5,7

Significant (1-2%) / severe (>2%)
over 1 week

Significant (5%) / severe (>5%)
over 1 month

Significant (7.5)% / severe (>7.5%)
over 3 months

Significant (10%) / severe (>10%)
over 6 months

Significant (20%) / severe (>20%)
over 1 year

However, clinical judgment must also be used and not rely on the numbers alone. For example, if a patient unintentionally loses 4.8% in 3 weeks, it is still considered a significant loss of weight.

Laboratory Testing

Laboratory testing for a serum thiamine level should never delay thiamine treatment – if a thiamine assay is drawn, thiamine dosing should follow immediately after. If laboratory testing is pursued, use whole blood thiamine (direct measurement of thiamine and its phosphate esters). Results can take up to 7 – 10 days, therefore, if Wernicke’s is suspected, it is important to start treatment with thiamine right after the lab draw. Serum or plasma thiamine testing suffer from poor sensitivity and specificity; < 10% of blood thiamine is contained in plasma and is affected by recent oral intake or IV infusion. Therefore, whole blood thiamine should be ordered instead. Of note, there is no established lab value at which WE is diagnosed.

Imaging

Use of magnetic resonance imaging (MRI) to detect WE has a sensitivity of only 53%, hence, MRI scans can only reliably rule-in suspected cases of WE.21 CT imaging is not suitable to use in patients with suspected WE.22 Brain abnormalities are quickly reversed after thiamine treatment, so an MRI should be performed prior to thiamine administration, but only if the MRI can be done right away, or precious time can be lost as treatment is of the highest priority in these cases. It has been suggested that the brain injury is related to focal lactic acidosis, blood–brain barrier disruption, neural cell excitotoxicity, inflammation, or inadequate ATP at the cellular level.3

Due to the alarming lack of recognition of WE, clinicians must change their differential diagnosis to not only include RS, but also note that WE may also be present in order to prevent the negative clinical, and potentially legal consequences.23  In order to improve identification and subsequent treatment of WE, clinicians must have a high level of suspicion for thiamine deficiency when at risk patients present for care (see examples below).

What do the following cases have in common?

42-year -old male presents with ongoing nausea and vomiting post gastric sleeve bypass surgery; frequent ED admissions treated with intravenous (IV) antiemetics and D5W at 100mL/hour; 

27-year-old pregnant female presents with persistent hyperemesis for the past 5 weeks; 

58-year-old male presents with almost daily nausea and vomiting due to a pyloric stenosis;

36-year-old female admitted with ongoing nausea and vomiting over 2 months due to diabetic gastroparesis;

32-year-old female admitted for an endoscopic retrograde cholangiopancreatography (ERCP) to remove gallstone complicated by acute pancreatitis, unable to eat despite attempts over the course of 5 weeks; D5W initiated, then peripheral parenteral nutrition, then central PN, all without thiamine supplementation;  

63-year-old male with daily excessive alcohol intake and 20 lb. weight loss over past month is admitted for mandibular resection due to carcinoma 

Author/AssociationRecommended Supplementation/Dosing Guideline
European (EFNS) Wernicke’s Guidelines (Galvin 2010)At risk: 200mg IV, TID before any carbohydrate is given Signs of WE: 500mg IV TID x 3 days, then 250mg daily x 5 days
Mechanick 2019Repletion dose for thiamine deficiency varies based on route of administration and severity of symptoms: Oral therapy: 100 mg 2-3 times daily until symptoms resolve IV therapy: 200 mg 3 times daily to 500 mg once or twice daily for 3-5 d, followed by 250 mg/d for 3-5 d or until symptoms resolve, then consider treatment with 100 mg/d orally, indefinitely, or until risk factors have been resolved  IM therapy: 250 mg once daily for 3-5 d or 100-250 mg monthly  Magnesium, potassium, and phosphorus should be given simultaneously to patients at risk for refeeding syndrome.
ASPEN Refeeding Consensus  (da Silva 2020)100mg before feeding or initiating IV dextrose in pts at risk 100mg/day x > 5–7 days in pts with severe starvation/chronic alcoholism/other high-risk/signs of deficiency
Dingwall 2022No clear benefit between 100mg, 300mg, 500mg IV, TID in at risk vs. symptomatic for WE
Wijnia 2022250mg IV or IM, daily x 3-5 days
Note: Guidelines are based on expert opinion, not randomized, controlled trials

The unifying presentation in all of the above cases was one or more of the following: ongoing vomiting for > 2 weeks, inability to eat normally over an extended period of time, and significant, unintentional weight loss. Weights were often not obtained or just “self-reported” by patients, thus frequently inaccurate. ED visits were common, and subsequent hospitalizations were just long enough to relieve the symptoms of nausea/vomiting, but not long enough to generate a nutrition consult from an admission nutrition screen (if one was even done, especially in an ED), or one directly from a provider. Nor was empiric thiamine treatment given. If a nutrition consult was completed in these cases, the focus was on getting the patient to consume adequate calories and protein, rather than exploring the patient’s micronutrient adequacy. It is worth noting that rare is the patient who was previously taking a vitamin/mineral supplement, whether as part of standard post bariatric care or for other reasons, who continues vitamin/mineral supplementation when they stop eating. Further perpetuating the potential for WE, treatments often include a carbohydrate containing hydration fluid such as D5W in response to dehydration from ongoing vomiting. D5W is usually ordered at 100mL/hour, without additional IV micronutrients, thus consuming any serum thiamine remaining along with other micronutrient stores.22,24

Of note, the expected weight loss in the post bariatric surgery patient is often quoted as 2-4 lb/week, or 8-16 pounds per month. The American Society of Metabolic and Bariatric Surgery 2019 guidelines list expected weight loss post-surgery based on the type of bariatric surgery.25 They cite the target weight loss from the original total body weight (not excess weight) as: 20-25% for laparoscopic adjustable gastric banding; 25-30% for sleeve gastrectomy; 30-35% for Roux-en-Y gastric bypass and 35-45% for biliopancreatic diversion with duodenal switch. However, limited literature exists addressing what constitutes an “excessive” loss of weight (too much, too fast) after bariatric surgery that would spark a warning to clinicians to investigate further for possible malnutrition, RS, and WE. One systematic review of bariatric surgical procedures found that those patients admitted with WE had a median weight loss from surgical procedure to admission of 35 kg and a weight loss rate of 0.44 kg/day (~ 1 lb/day).22 Hence, if this amount of weight loss is associated with WE, until further data is available, to prevent WE in the first place, a weight loss less than this amount should prompt further assessment at this time.

Contains small amount of thiamine  Smarty Pants® Women’s Formula
(only 0.12 mg in 6 gummies)

Vitamin or vitamin/mineral gummy combinations that do not have thiamine:
KirklandTM Adult multivitamin Gummies
VitafusionTM MultiVites
VitafusionTM Men’s Multi
VitafusionTM Women’s Multi
KirklandTM Children’s Daily Multivitamin Gummies
Smarty Pants® Kids formula Gummies
L’ilCrittersTM Gummy Vites
One A Day® Women’s VitaCraves
One A Day® Women’s Prenatals
Centrum® Adults Multigummies
Centrum® Men 50+ Multigummies
Nature’s Promise® Prenatal Multivitamin
Nature’s Promise® Men’s Multivitamin
Nature’s Promise® Women’s Multivitamin
Table 5. Thiamine Content of a Few Selected Gummy Vitamins (DRI = 1.2 mg)

Treatment

WE prevention is simple. It is repletion of thiamine, an inexpensive water-soluble vitamin. Advantages of prompt administration of thiamine, in adequate doses (Table 4), are that it leads to improvement in ocular signs within hours to days, vestibular function and gait ataxia during the second week, and confusion subsides over days to weeks.26 However, based on the findings reported in this article, it behooves clinicians to use thiamine judiciously, especially in the IV form, to prevent shortages already experienced at individual facilities as well as nationally vs. treat every patient “just in case.”

Other Nutrients Required for Thiamine Utilization

Magnesium, a necessary cofactor in carbohydrate metabolism, if depleted, impedes conversion of thiamine to TPP, further accelerating thiamine deficiency. Folate, similarly, is required to regenerate TPP. Although it is not consumed in the process, additional folate may be required.27 The examples of the role of magnesium and folate demonstrate that in caring for the malnourished patient, it is important that the clinician presume pan-nutrient deficiency and ensure that all vitamins and minerals are adequately provided in the repletion process. This can be achieved by providing a complete vitamin and mineral supplement. Additional thiamine should also be given in the case of RS and WE (Table 4). Of importance for the clinician and patient, popular chewable gummy multivitamin supplements, rarely contain thiamine due to the objectionable taste (Table 5). 

1. Nutrition Screening – Is It Working? Ensure that there are proper institutional triggers for timely evaluation and follow up by a registered dietitian nutritionist (RDN) when a pt is admitted with persistent nausea/vomiting, oral nutrition intolerance, and significant weight loss history.  

2. Failing to Identify Malnutrition: By not meeting ASPEN/AND’s consensus standards5-7 for nutritional assessment including failure to:
Document an adequate nutritional history. 
Document an adequate anthropometric evaluation including weight loss history and physical assessment.
Look at prior admission/ED records that may show nutritional decline.
Document risk for development of permanent neurological impairments of micronutrient deficiencies.

3. Relying on other providers’ review of nutrition progress notes rather than communicating and collaborating directly with other providers when orders for vitamin levels and empiric vitamin repletion are warranted to prevent adverse outcomes. 

4. NOT Relying on other providers’ progress notes that document patient showing signs of micronutrient deficiencies such as acute neurological symptoms.

5. Failing to: Acknowledge Ongoing Problems with Poor Oral Intake
Nutrition interventions which repeatedly recommend supplements that the patient either cannot, or will not tolerate, i.e.: 
Ensure, Boost, or oral multivitamins and minerals without confirming the patient has been able to take or tolerate them when nausea and vomiting persist.  Nutrition notes that continue to recommend:
“Advance diet as tolerated,”  “Honor food preferences,” or  “Oral nutrition supplements (Ensure or Boost) as tolerated.”  In such cases, the RDN has failed to confer with physicians and recommend the addition of enteral, parenteral, or vitamin/mineral supplementation. 

6. Failing to:
Evaluate and treat micronutrient deficiencies and focus only on macronutrient deficiencies. Recommend earlier B vitamins, including IV thiamine repletion, for patients with persistent nausea/vomiting and oral nutrition intolerance.
Follow ASPEN Parenteral Nutrition Safety Consensus Recommendations stating41,42  The clinician responsible for prescribing and/or charting the PN macronutrient formulation(s) is ultimately responsible for prescribing the IV micronutrients to ensure complete nutrition is provided.  The highest risk regarding routine doses is not delivering them with PN.  Multivitamins (MVI) shall be prescribed daily in PN admixtures.  When MVI products are not available, thiamine, ascorbic acid, pyridoxine, and folic acid shall be prescribed daily.
If RDNs are only responsible for recommending macronutrients in PN at a particular facility, because “the pharmacist is responsible for electrolytes, MVI, and trace elements,” make sure this is in writing in hospital policy and procedures and consider a smart phrase for this.
Table 6. Findings from Attorneys Trying Wernicke’s that Clinicians Need to Change
Adapted from the version compiled by Steven R. Davis, J.D., Davis & Davis Law Firm, Houston, TX, and used with permission.

Legal Ramifications

As the problem of WE grows, a sub-culture of lawyers who specialize in this diagnosis has emerged. A quick internet search reveals the vast scope of law firms marketing their services to those who have suffered WE due to inadequate medical treatment. To provide optimal patient care and avoid such malpractice lawsuits, it behooves the clinician to become familiar with common errors leading to lawsuits. Informal communications with an attorney specializing in Wernicke’s cases (who has tried over 27 cases so far) resulted in a list of common errors made by clinicians (Table 6). Recognizing these errors provides a road map for change for clinicians to prevent WE and subsequent lawsuits.

Special Issue: Bariatric Vitamin/Mineral Supplementation

Post bariatric surgery patients are one of the more prevalent populations in which WE has arisen including all types of bariatric surgery, even vertical sleeve gastrectomy,15,28 prompting numerous court cases. Since post bariatric surgery patients are at high risk of micronutrient deficiency, it is incumbent upon the clinician during the assessment process to question whether they are still taking their prescribed vitamin and mineral supplements,29 which ones, and how much. If a patient has stopped taking the supplements, the clinician should determine when they stopped and for how long. It is not uncommon for some patients to stop these supplements, not recognizing their importance. Some of the documented reasons why patients stop their supplementation are listed below:30,31

I understand that I am required to take the following vitamins and minerals (dosing may vary amongst institutions) as specified for the rest of my life (or until my bariatric surgeon or PCP advises me otherwise), example:

Initials:  _________  50 mg thiamine
Initials:  _________  500mg B12
Initials:  _________  3000 units vitamin D3
Initials:  _________  Complete vitamin and mineral supplement

If there comes a time that I am not taking the prescribed vitamins and minerals for any reason, I will contact my PCP or bariatric surgeon to let them know.

Sign & Print name______________________________________ Date _________
Table 7. Sample Contract with Bariatric Patients Regarding Vitamin/Mineral Supplement Adherence29

Did not think they still needed them

Did not like taking them

Could not find them

Did not like the taste

Could not remember to take them

Could not afford them

To help keep post bariatric surgery patients safe, at every hospital or clinic encounter, clinicians should: 

Inquire about and document the following: 

What vitamins and minerals is the patient taking – how often, and in what doses?

The patient’s history of taking these supplements, including whether the intake is consistent or sporadic. If sporadic, how long do they go without taking them?

For patients not taking vitamins or minerals, inquire why this is the case, and make a new plan with the patient to ensure adherence to the prescribed regimen.

Create a smart phrase (in electronic medical record) stating what was specifically reviewed with the patient in terms of the importance of vitamin and mineral adherence and, for each vitamin and mineral, the prescribed dose and frequency of administration.  

Finally, it may be prudent to ask every patient choosing to undergo bariatric surgery to sign a contract that is kept in the patient’s chart addressing vitamin/mineral supplementation (Table 7).

1. Ensure the nutrition screening tool is working, if not, change it to better capture high-risk patients. If it is not being filled out, address that with nursing, or hire diet technicians whose sole job is to screen new admissions. Consider the use of artificial intelligence or dietetic technicians for more focused admission nutrition screening, etc.

2. Consider creating a smart phrase for both refeeding syndrome and Wernicke’s such as: 100mg thiamine daily (tab or IV) x 3-5 days (if refeeding). 500mg thiamine IV, TID x 3 days (if Wernicke’s), followed by 250mg daily vs. BID, IV
(or enteral) x 5 more days. Start a complete vitamin/mineral supplement daily x 5 days, then reevaluate. Check refeeding labs (basic metabolic, magnesium, phosphorus) BID x 3 days, then reevaluate.

3. Obtain accurate weight history, not just the current admission, but from 1, 3, and 6 months prior → ensure accurate weights are done when patient is admitted.

4. If a patient is severely malnourished, assume the patient at risk for both RS and WE (Table 3).

5. Did the patient present with nausea/vomiting for > 2 weeks? Include ED visits, outside hospital admissions, etc.

6. Be specific in your nutrition recommendations: 15-20kcal/kg to start (include ALL calorie sources including D5 drips).

7. Refeeding: start thiamine, 100mg daily (tab or IV) x 3-5 days – including with all D5 IV fluids, PN, enteral feedings.

8. Wernicke’s: 500mg thiamine IV, TID x 3 days; then, 250mg daily vs. BID, IV (or enteral) x 5 more days.

9. Ensure adequate magnesium status.

10. Start complete vitamin and mineral supplement daily x 5 days – find out the actual names in the hospital formulary EMR and recommend by name to providers for ease of ordering.  

11. Check refeeding labs (basic metabolic, magnesium, phosphorus) BID x 3 days, then reevaluate.

12. If appropriate → good glycemic control to ensure nutrient utilization and protect endogenous stores.
Table 8. Actionable Interventions the Clinician Can Do Now 

Conclusion

Much attention has been paid to identifying and diagnosing malnutrition; and in addition, recognizing those at risk for RS. WE continues to be thought of, incorrectly, as a complication solely of too much alcohol intake combined with poor nutrition. WE can be found in any patient, not just bariatric patients presenting with prolonged nausea and vomiting or those at risk for RS and should be treated with thiamine and other micronutrients accordingly. Sadly, litigation of  WE cases continues to rise displaying the fact that clinicians are failing to identify malnutrition, RS, and WE with dreadful consequences. It is clear that an evaluation of why nutritional screening practices are failing and patients with severe malnutrition and nutrient deficiencies are not being recognized is warranted.  We owe it to our patients to keep them safe, and no clinician wants to find themselves in court for malpractice. See Table 8 for actionable suggestions that can begin to start addressing this pressing issue; Table 9 provides additional resources of interest for clinicians.  

Video recording – available free:
“Advanced Practice Provider (APP) Lecture Series – Vitamin B1: The Management and Treatment in Clinical Practice – American Society for Metabolic and Bariatric Surgery”
(asmbs.org); recorded 4/20/23 presented by Emma J. Patterson, MD, FRCSC FACS FASMBS:
asmbs.org/videos/advanced-practice-provider-app-lecture-series-vitamin-b1-the-management-and-treatment-in-clinical-practice/

What nystagmus looks like: youtube.com/watch?v=HXOaRGNnijU
Table 9. Additional Resources

References

1. da Silva JSV, Seres DS, Sabino K, et al; Parenteral
Nutrition Safety and Clinical Practice Committees,
American Society for Parenteral and Enteral
Nutrition. ASPEN Consensus Recommendations for
Refeeding Syndrome. Nutr Clin Pract. 2020;35(2):178-
195.
2. Krutkyte G, Wenk L, Odermatt J, et al. Refeeding
Syndrome: A Critical Reality in Patients with Chronic
Disease. Nutrients. 2022;14(14):2859.
3. Kohnke S, Meek CL. Don’t seek, don’t find: The diagnostic
challenge of Wernicke’s encephalopathy. Ann
Clin Biochem. 2021;58(1):38-46.
4. Wijnia JW. A Clinician’s View of Wernicke-
Korsakoff Syndrome. J Clin Med. 2022;11(22):6755.
5. Malone A, Hamilton C. The Academy of Nutrition
and Dietetics/the American Society for Parenteral
and Enteral Nutrition consensus malnutrition characteristics:
application in practice. Nutr Clin Pract.
2013;28(6):639-50.
6. The Academy of Nutrition and Dietetics New Revised
2024 Scope and Standards of Practice for the Registered
Dietitian Nutritionist; pp 42-45.
7. White JV, Guenter P, Jensen G, et al. Academy
Malnutrition Work Group; ASPEN Malnutrition
Task Force; ASPEN Board of Directors. Consensus
statement: Academy of Nutrition and Dietetics and
American Society for Parenteral and Enteral Nutrition:
characteristics recommended for the identification and
documentation of adult malnutrition (undernutrition).
JPEN J Parenter Enteral Nutr. 2012;36(3):275-283.
8. Marrs C, Lonsdale D. Hiding in Plain Sight: Modern
Thiamine Deficiency. Cells. 2021;10(10):2595.
9. Frank LL. Thiamin in Clinical Practice. JPEN J
Parenter Enteral Nutr. 2015;39(5):503-20.
10. Smith TJ, Johnson CR, Koshy R, et al. Thiamine deficiency
disorders: a clinical perspective. Ann N Y Acad
Sci. 2021;1498(1):9-28.
11. Antel K, Singh N, Chisholm B, et al. Encephalopathy
after persistent vomiting: Three cases of non-alcohol-
related Wernicke’s encephalopathy. S Afr Med
J. 2015;105(6):442-3.
12. Mangione D, Vassiliadis A, Gullo G, et al. Wernicke
Syndrome: Case Report and Literature Review of
Contributing Factors-Can Malpractice Dynamics Be
Identified? J Clin Med. 2024;13(3):716.
13. Mifsud F, Messager D, Jannot AS, et al. Clinical diagnosis,
outcomes and treatment of thiamine deficiency
in a tertiary hospital. Clin Nutr. 2022;41(1):33-39.
14. Okafor C, Nimmagadda M, Soin S, et al. Non-alcoholic
Wernicke encephalopathy: great masquerader. BMJ
Case Rep 2018;11:e227731.
15. Oudman E, Wijnia JW, van Dam M, et al. Preventing
Wernicke Encephalopathy After Bariatric Surgery.
Obes Surg. 2018;28(7):2060-2068.
16. Oudman E, Wijnia JW, Oey MJ, et al. Wernicke-
Korsakoff syndrome despite no alcohol abuse:
A summary of systematic reports. J Neurol
Sci. 2021;426:117482.
17. Scalzo SJ, Bowden SC, Ambrose ML, et al.
Wernicke-Korsakoff syndrome not related to alcohol
use: a systematic review. J Neurol Neurosurg
Psychiatry. 2015;86(12):1362-8.
18. Friedli N, Stanga Z, Culkin A, et al. Management and
prevention of refeeding syndrome in medical inpatients:
An evidence-based and consensus-supported
algorithm. Nutrition. 2018;47:13-20.
19. Mehanna HM, Moledina J, Travis J. Refeeding syndrome:
what it is, and how to prevent and treat it. BMJ.
2008;336(7659):1495-8.
20. Cantu-Weinstein A, Branning R, Alamir M, et al.
Diagnosis and treatment of Wernicke’s encephalopathy:
A systematic literature review. Gen Hosp
Psychiatry. 2024;87:48-59.
Table 9. Additional Resources
¨ Video recording – available free:
Ø “Advanced Practice Provider (APP) Lecture Series – Vitamin B1: The Management and
Treatment in Clinical Practice – American Society for Metabolic and Bariatric Surgery”
(asmbs.org); recorded 4/20/23 presented by Emma J. Patterson, MD, FRCSC FACS FASMBS:
asmbs.org/videos/advanced-practice-provider-app-lecture-series-vitamin-b1-themanagement-
and-treatment-in-clinical-practice/
¨ What nystagmus looks like: youtube.com/watch?v=HXOaRGNnijU
NUTRITION REVIEWS IN GASTROENTEROLOGY, SERIES #15
PRACTICAL GASTROENTEROLOGY • JULY 2024 37
Recognizing Thiamine Deficiency: Keeping Patients Safe and Clinicians Out of Court
21. Antunez E, Estruch R, Cardenal C, et al. Usefulness
of CT and MR imaging in the diagnosis of acute
Wernicke’s encephalopathy. AJR Am J Roentgenol.
1998;171(4):1131–1137.
22. Aasheim ET. Wernicke encephalopathy after
bariatric surgery: a systemic review. Ann Surg.
2008;248(5):714-720.
23. Hershkowitz E, Reshef A, Munich O, et al. Thiamine
deficiency in self-induced refeeding syndrome, an
undetected and potentially lethal condition. Case Rep
Med. 2014:2014:605707.
24. Li L, Shin J-H, Sharma K, et al. Wernicke encephalopathy
after sleeve gastrectomy. AIM Clinical Cases.
2024;3:e230116.
25. Mechanick JI, Apovian C, Brethauer S, et al. Clinical
Practice Guidelines for the Perioperative Nutrition,
Metabolic, and Nonsurgical Support of Patients
Undergoing Bariatric Procedures – 2019 Update:
Cosponsored by American Association of Clinical
Endocrinologists/American College of Endocrinology,
The Obesity Society, American Society for Metabolic
& Bariatric Surgery, Obesity Medicine Association,
And American Society of Anesthesiologists – Executive
Summary. Endocr Pract. 2019;25(12):1346-1359.
26. Patel S, Topiwala K, Hudson L. Wernicke’s
Encephalopathy. Cureus. 2018;10(8):e3187.
27. McLean J, Manchip S. Wernicke’s encephalopathy
induced by magnesium depletion. Lancet.
1999;353(9166):1768.
28. Tang L, Alsulaim HA, Canner JK, et al. Prevalence
and predictors of postoperative thiamine deficiency
after vertical sleeve gastrectomy. Surg Obes Relat Dis.
2018;14(7):943-950.
29. Parrott J, Frank L, Rabena R, et al. American Society
for Metabolic and Bariatric Surgery Integrated Health
Nutritional Guidelines for the Surgical Weight Loss
Patient 2016 Update: Micronutrients. Surg Obes Relat
Dis. 2017;13:727–741.
30. Ahmad DS, Esmadi M, Hammad H, et al. Malnutrition
secondary to non-compliance with vitamin and mineral
supplements after gastric bypass surgery: What can we
do about it? Am J Case Rep. 2012;13:209–213.
31. Smelt HJM, Pouwels S, Smulders JF, et al. Patient
adherence to multivitamin supplementation after bariatric
surgery: a narrative review. J Nutr Sci. 2020;9:e46.
32. Crook MA, Sriram K. Thiamine deficiency: The
importance of recognition and prompt management.
Nutrition. 2014;30(7-8):953-954.
33. Nakamura ZM, Tatreau JR, Rosenstein DL, et al.
Clinical Characteristics and Outcomes Associated
with High-Dose Intravenous Thiamine Administration
in Patients with Encephalopathy. Psychosomatics.
2018;59(4):379-387.
34. Peterson BD, Stotts MJ. Beyond the Banana
Bag: Treating Nutritional Deficiencies of Alcohol
Withdrawal Syndrome. Practical Gastroenterol.
2021;June(6):48-58.
35. Donnino MW, Vega J, Miller J, et al. Myths and
misconceptions of Wernicke’s encephalopathy: what
every emergency physician should know. Ann Emerg
Med. 2007;50(6):715-21.
36. Erick M. Gestational malnutrition, hyperemesis gravidarum,
and Wernicke’s encephalopathy: What is missing?
Nutr Clin Pract. 2022;37(6):1273-1290.
37. Marziliano A, Teckie S, Diefenbach MA, et al.
Alcohol-related head and neck cancer: Summary of
the literature. Head Neck. 2020;42(4):732-738.
38. Matz R. Parallels between treated uncontrolled diabetes
and the refeeding syndrome with emphasis
on fluid and electrolyte abnormalities. Diabetes
Care. 1994;17(10):1209-13.
39. Galvin R, Bråthen G, Ivashynka A, et al. EFNS guidelines
for diagnosis, therapy and prevention of Wernicke
encephalopathy. Eur J Neurol. 2010;17(12):1408–
1418.
40. Dingwall KM, Delima JF, Binks P, et al. What is the
optimum thiamine dose to prevent Wernicke’s encephalopathy
or Wernicke-Korsakoff syndrome? Alcohol
Clin Exp Res. 2022;46(6):1133-1147.
41. Ayers P, Adams S, Boullata J, et al. ASPEN parenteral
nutrition safety consensus recommendations. JPEN J
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42. Blaauw R, Osland E, Sriram K, et al. Parenteral
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Gut Inflammation in the Pediatric Patient with Cystic Fibrosis

July 2024 • Volume XLVIII, Issue 7

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Patients with cystic fibrosis (CF) have associated gastrointestinal (GI) inflammation, and such inflammation is associated with worsening pulmonary outcomes. The authors of this study evaluated clinical markers of GI inflammation in pediatric patients with CF to see if specific markers were helpful in determining clinical outcomes. Pediatric patients with CF who were between 1 and 21 years of age were recruited from a single, tertiary children’s hospital. These patients did not have any alternative cause for intestinal inflammation such as inflammatory bowel disease or celiac disease, did not have a colostomy or ileostomy, and were not on total parenteral nutrition. The pediatric study patients were compared to 20 control patients under 21 years of age who had a prior esophagogastroduodenoscopy demonstrating no GI inflammation.

Study patients with CF had blood and stool samples obtained at study entry and then 2 weeks and 3 months later. Questionnaires about GI symptoms were also obtained at these time points. Body mass index (BMI) and forced expiratory volume in 1 second (FEV1) were obtained in study patients who were 4 years of age or older. It should be noted that 90% of control patients had blood and stool samples available for analysis. Intestinal permeability on all patients was measured by testing serum E. coli anti-core lipopolysaccharide (LPS) and lipopolysaccharide-binding protein (LPB). Intestinal inflammation on all patients was measured by stool biomarkers, including fecal calprotectin (FC), fecal lipocalin-2 (FL2), and fecal neopterin (FN).

A total of 26 patients with CF completed the entire study, and these study subjects were compared to the 18 control patients who had existing blood and stool samples available.The control group was noted to be older than the study group with CF. FL2 and FN levels in patients with CF were significantly higher compared to control patients based on age-matched controls. Patients with CF who were on CF transmembrane conductance regulator (CFTR) modulators had less intestinal inflammation compared to patients with CF not on CFTR modulator therapy although the inflammation occurring with those patients on CFTR therapy was still increased compared to control patients. Increased FC and increased FL2 appeared to correlate with decreases in FEV1% predicted. No biomarker correlated with changes in BMI z-scores or weight-for-length z-scores after model adjustments for age and presence of pancreatic insufficiency. FL2 levels had statistically significant correlation with FC and FN levels, and LPS levels had statistically significant correlation with LPB levels. However, no other correlations between biomarkers were present.

This study demonstrates that FL2 may prove eventually to be a reliable marker for GI dysfunction in patients with CF. FL2 levels were increased in patients with CF compared to controls suggesting GI inflammation in the setting of CF, and FL2 levels were inversely correlated to FEV1 function while simultaneously having correlation with other serum and stool biomarkers. Further studies should look for specific microbiome signatures associated with increased FL2 levels in patients with CF while also looking for a correlation of such levels with other aspects of lung disease seen in CF.

Duckworth L, Sutton K, Shaikh N, Wang J, Hall-Moore C, Holtz L, Tarr P, Rubenstein R.  Quantification of Enteric Dysfunction in Cystic Fibrosis: Inter- and Intraindividual Variability. J Pediatr 2024; 265: 113800.

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Impact of Bariatric Surgery on Perianal Fistulas: A Case Report and Review of the Literature

July 2024 • Volume XLVIII, Issue 7
Uma Mahadevan,Jonathan Carter,Afshin A. Khan,Emily Finlayson

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Complex perianal fistulas can be a challenging manifestation of inflammatory bowel disease (IBD) for both gastroenterologists and surgeons. We present a patient with Crohn’s disease in endoscopic remission on monoclonal antibody therapy. Despite adequate control of her luminal disease, there was no improvement in her complex perianal fistulas with antibiotic treatment, surgical drainage, seton placement, and ultimately diversion colostomy. Bariatric surgery, which resulted in weight loss of 135-pounds, was associated with immediate control of her fistulas. Bariatric surgery in a select subset of patients may reduce the pro-inflammatory state that obesity, central or otherwise, promotes and may help IBD patients have improved health outcomes.

Case Presentation

A 28-year-old female with a BMI (body mass index) 47 kg/m2 was diagnosed with fistulizing ileocolonic and perianal Crohn’s disease 10 years ago. She was initially treated with infliximab and developed anti-drug antibodies. Upon switching to ustekinumab she achieved complete endoscopic remission but continued to have active perianal disease. Initial treatment with antibiotics were unsuccessful and she required regular exam under anesthesia (EUA) with seton placement. Within two years, the frequency of EUA with seton placement increased to five episodes in the same year. A switch to adalimumab with methotrexate was unsuccessful. She underwent diverting loop transverse colostomy to provide relief from recurrent perianal fistulas. Despite the diversion, she continued to have rectal pain, new abscesses and drainage. 

After failing non-surgical weight loss, she underwent laparoscopic sleeve gastrectomy after discussion with both colorectal and bariatric surgery. Reversal of the loop colostomy occurred a year later. Her post-operative course was complicated by a peri-gastric fistula and abscess that was endoscopically drained. Post-bariatric surgery, she lost 135 pounds and only experienced a single perianal abscess in 12 months as compared to multiple annual episodes prior to bariatric surgery. Subsequent colonoscopy showed continued normal luminal findings and significantly improved perianal disease with no active fistulas or abscess. 

Discussion 

This case highlights the impact of bariatric surgery on a patient suffering from recurrent, fistulizing, perianal Crohn’s disease previously refractory to medical and surgical management even with endoscopic remission. From a surgical perspective, she had multiple seton placements and eventually a diversion colostomy without control of her perianal disease. A multidisciplinary approach determined that obesity may be playing a key role in limiting drug efficacy, impairing wound healing from mechanical pressure, and driving inflammation with ongoing fistulas. Therefore, the risks of bariatric surgery would be outweighed by the benefit of controlling her recurrent perianal Crohn’s disease. 

Obesity, a public health epidemic, is also a concern in patients with IBD, traditionally thought to be a disease of those with low BMI. Current estimates show that 25-30% of patients with IBD have obesity, with 5-6% of them severely obese.1-4  These estimates reflect a similar trend in the general population. Until recently, Crohn’s disease has been considered a relative contraindication to Roux-en-Y gastric bypass (RYGB) surgery, according to the Guidelines for Clinical Application of Laparoscopic Bariatric Surgery of the Society of American Gastrointestinal and Endoscopic Surgeons, which is further endorsed by the American Society for Metabolic and Bariatric Surgery.5 The hesitation surrounding bariatric surgery in patients with IBD is layered. Patients with obesity have increased post-operative complications and micronutrient deficiencies become more pronounced in patients with IBD.6,7 Sleeve gastrectomy is less invasive with fewer potential complications for the patient with IBD.

Increasing evidence suggests that patients with IBD and obesity have worse clinical outcomes as they are more likely to have extraintestinal manifestations of IBD, prolonged hospitalizations and increased healthcare costs.8,9 Studies have also highlighted suboptimal response to biologic therapy in patients with obesity possibly attributed to rapid clearance of biologic agents which subsequently leads to low serum trough concentrations 10 versus increased inflammatory burden from cytokines produced by adipose cells. Additionally, significant obesity precludes ileal pouch-anal anastomosis, thus, obesity management becomes an imperative target as part of IBD management.

Prospective and retrospective studies have now suggested safety and efficacy of bariatric surgery in patients with IBD.11-13 Beyond showing that IBD should not be considered a contraindication for bariatric surgery, these studies have also exhibited an additional advantage of weight loss. Bariatric surgery reduces the number of IBD related complications including reduced corticosteroid use, IBD related surgeries, dose reduction in IBD medications, and overall improvement in quality of life.14 These benefits may be due to a decrease in the chronic pro-inflammatory state associated with obesity, including low production of C-reactive protein, tumor necrosis factor-alpha (TNF), and interleukin-6. These studies emphasize a multidisciplinary approach prior to opting for bariatric surgery and determining the best surgical approach.

Perianal fistulas cause significant morbidity including persistent drainage, fecal incontinence, scarring, and poor disease related outcomes. The desired treatment outcome is fistula closure. The Guidelines for the Multidisciplinary Management of Crohn’s Perianal Fistulas recommend the following treatment algorithm for perianal fistula management:15 simple fistulas rely on treatment with antibiotics, immunomodulators, with or without anti-TNF alpha agents. Surgical intervention (e.g., setons) in addition to the aforementioned therapies may be necessary for complex fistulas. Those with refractory fistulas may require other surgical treatments including use of fibrin glue, fistula plug, diverting colostomy, and proctectomy or protocolectomy. 

Conclusion

The potential benefit of weight loss surgery in disease management of significantly obese patients with IBD is discussed above. IBD should not be considered a contraindication for bariatric surgery. Instead, with a multidisciplinary team approach, it should be seen as an opportunity for improving overall management of IBD, particularly in a subset of patients who have disease refractory to current medical and or surgical treatments. 

References

References
1. Steed H, Walsh S, Reynolds N. A brief report of the epidemiology of obesity in the inflammatory bowel disease population of Tayside, Scotland. Obes Facts. 2009;2(6):370-2. doi:10.1159/000262276
2. Long MD, Crandall WV, Leibowitz IH, et al. Prevalence and epidemiology of overweight and obesity in children with inflammatory bowel disease. Inflamm Bowel Dis. Oct 2011;17(10):2162-8. doi:10.1002/ibd.21585
3. Flores A, Burstein E, Cipher DJ, Feagins LA. Obesity in Inflammatory Bowel Disease: A Marker of Less Severe Disease. Dig Dis Sci. Aug 2015;60(8):2436-45. doi:10.1007/s10620-015-3629-5
4. Hass DJ, Brensinger CM, Lewis JD, Lichtenstein GR. The impact of increased body mass index on the clinical course of Crohn’s disease. Clin Gastroenterol Hepatol. Apr 2006;4(4):482-8. doi:10.1016/j.cgh.2005.12.015
5. Committee SG. SAGES guideline for clinical application of laparoscopic bariatric surgery. Surg Obes Relat Dis. May-Jun 2009;5(3):387-405. doi:10.1016/j.soard.2009.01.010
6. Dogan K, Aarts EO, Koehestanie P, et al. Optimization of vitamin suppletion after Roux-en-Y gastric bypass surgery can lower postoperative deficiencies: a randomized controlled trial. Medicine (Baltimore). Nov 2014;93(25):e169. doi:10.1097/MD.0000000000000169
7. Flancbaum L, Belsley S, Drake V, Colarusso T, Tayler E. Preoperative nutritional status of patients undergoing Roux-en-Y gastric bypass for morbid obesity. J Gastrointest Surg. Jul-Aug 2006;10(7):1033-7. doi:10.1016/j.gassur.2006.03.004
8. Nguyen NH, Ohno-Machado L, Sandborn WJ, Singh S. Obesity Is Independently Associated with Higher Annual Burden and Costs of Hospitalization in Patients with Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol. Mar 2019;17(4):709-718 e7. doi:10.1016/j.cgh.2018.07.004
9. Singla MB, Eickhoff C, Betteridge J. Extraintestinal Manifestations Are Common in Obese Patients with Crohn’s Disease. Inflamm Bowel Dis. Sep 2017;23(9):1637-1642. doi:10.1097/MIB.0000000000001187
10. Singh S, Dulai PS, Zarrinpar A, Ramamoorthy S, Sandborn WJ. Obesity in IBD: epidemiology, pathogenesis, disease course and treatment outcomes. Nat Rev Gastroenterol Hepatol. Feb 2017;14(2):110-121. doi:10.1038/nrgastro.2016.181
11. Aelfers S, Janssen IMC, Aarts EO, Smids C, Groenen MJ, Berends FJ. Inflammatory Bowel Disease Is Not a Contraindication for Bariatric Surgery. Obes Surg. Jun 2018;28(6):1681-1687. doi:10.1007/s11695-017-3076-9
12. Gupta R, MacIsaac M, Wright EK. Sleeve Gastrectomy in Patients with Inflammatory Bowel Disease Is Not Associated with Worsening Disease. J Crohns Colitis. Jun 24 2022;16(5):865-866. doi:10.1093/ecco-jcc/jjab195
13. Keidar A, Hazan D, Sadot E, Kashtan H, Wasserberg N. The role of bariatric surgery in morbidly obese patients with inflammatory bowel disease. Surg Obes Relat Dis. Jan-Feb 2015;11(1):132-6. doi:10.1016/j.soard.2014.06.022
14. Braga Neto MB, Gregory MH, Ramos GP, et al. Impact of Bariatric Surgery on the Long-term Disease Course of Inflammatory Bowel Disease. Inflamm Bowel Dis. Jun 18 2020;26(7):1089-1097. doi:10.1093/ibd/izz236
15. Schwartz DA, Ghazi LJ, Regueiro M, et al. Guidelines for the multidisciplinary management of Crohn’s perianal fistulas: summary statement. Inflamm Bowel Dis. Apr 2015;21(4):723-30. doi:10.1097/

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Dispatches from the GUILD Conference, Series #58

Tailoring Therapy Toward the Management of Extraintestinal Manifestations of IBD: Neurological, Ocular, Cutaneous and Musculoskeletal

June 2024 • Volume XLVIII, Issue 4
Gil Y. Melmed,Paula Prieto-Jimenez

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Extraintestinal manifestations (EIM) of inflammation are common among patients with inflammatory bowel disease (IBD), many of which have distinct etiologies and treatment approaches. In the past decade, there has been a significant expansion of treatment modalities for IBD, with distinct mechanisms of action that may allow for targeting of multiple organ systems with a single agent. We review common neurologic, dermatologic, ocular, and musculoskeletal EIMs associated with IBD, and identify opportunities to address EIMs together with IBD using specific agents or therapeutic classes in order to optimally personalize treatment toward both bowel and extraintestinal inflammation. 

Extraintestinal manifestations in patients with inflammatory bowel disease (IBD) can significantly impact health-related quality of life. Advances in pathophysiology knowledge and immunomodulatory targeted therapies bring diverse treatment options for IBD and inflammatory manifestations outside the bowel which should be considered when choosing the most appropriate approach for treating both intestinal and extraintestinal manifestations of IBD. This review provides an overview of treatment approaches of IBD and extra intestinal presentations of neurological, ocular, cutaneous, and musculoskeletal manifestations. 

NEUROLOGICAL MANIFESTATIONS

Neurological extraintestinal manifestations are relatively rare in IBD. Multiple Sclerosis (MS), optic neuritis (ON) and transverse myelitis (TM) are chronic, inflammatory, demyelinating and neurodegenerative diseases, which have a heterogeneous, multifactorial, immune-mediated background caused by complex gene–environment interactions. As MS is the most common disease, most studies between IBD and CNS have been focused on MS.

Anti-TNFα therapy has been putatively associated with demyelinating syndromes.1,2 The mechanism for which anti-TNFα might potentially cause demyelination in patients with rheumatological disease and IBD is still not fully understood. Current hypotheses include an increased influx of peripheral autoreactive T cells into the CNS, dysregulation of myelin repair, downregulation of interleukin-10 and upregulation of interleukin-12 and interferon γ; and possible increase in the risk of an underlying latent infections by anti-TNFα which could lead to demyelination.6,7

Consequently, TNF inhibitors should be avoided in patients with MS or other demyelinating diseases. Some advocate that this restriction should be applied as well to first-degree relatives of patients with MS given an increased risk of developing MS, with a sibling relative risk being as high as 18 to 36.8

In patients with MS or high risk of developing demyelinating diseases, recommendations for IBD treatment depend on the type of IBD (e.g. Crohn’s disease (CD) or ulcerative colitis (UC)). For moderate to severe CD, natalizumab may be appropriate due to its effectiveness in both CD and in MS. Natalizumab is a humanized monoclonal antibody which targets the lymphocyte adhesion molecule α4β1 integrin, disrupting the interaction of α4β1 integrin with vascular adhesion molecule (VCAM) -1 and interfering with the migration of the peripheral lymphocytes from blood vessels into the CNS and into the gut lamina propria, hence its beneficial effects for both MS and CD. It is FDA approved for the treatment of relapsing – remitting MS and for CD. However, uptake of natalizumab has been limited by increased risks of progressive multifocal leukoencephalopathy (PML) through reactivation of John Cunningham (JC) virus at a rate of approximately 1 in 1000 among individuals demonstrating antibody reactivity to JC virus, a ubiquitous virus present in large proportions of the population.9 Thus, individuals with CD initiating natalizumab should not receive concomitant immunomodulators, and steroids should be tapered off within 6 months of drug initiation. Furthermore, monitoring for JC virus every 6 months is warranted while on natalizumab maintenance therapy, with shared decision-making discussions to stop therapy for patients who seroconvert while on treatment. 

Sphingosine 1-phosphate (S1P) receptor modulators are approved as disease-modifying treatments for MS and UC based on a mechanism of limiting lymphocyte trafficking to the CNS and to the gut by trapping activated lymphocytes in lymph nodes. Ozanimod is currently approved for the treatment of both relapsing and remitting MS, as well as for moderately to severely active UC in adults. Thus, ozanimod may be an appropriate treatment option for those with UC, who also have or are at-risk for MS. 

Nonspecific white matter lesions have also been described in patients with IBD without presenting concomitant CNS degenerative diseases. It has been proposed that asymptomatic white matter lesions may be correlated with anxiety and disease duration, and that these findings may serve as a biomarker of neuropsychiatric comorbidities of CD.10 These lesions are generally asymptomatic, although their pathogenesis is unknown. Several mechanisms have been proposed for their etiology including thromboembolism, immunologic abnormalities, drug side effects, malabsorption, and infections.11,12

OCULAR

Nearly 5-7% of patients with IBD experience ocular inflammation, most commonly episcleritis, scleritis or non-infectious uveitis (NIU). 

Episcleritis, or inflammation of the episclera, is the most frequent ocular EIM. It is associated with active intestinal inflammation, and usually responds to topical steroids. On the other hand, scleritis, the inflammation of the sclera, is more challenging to treat, it usually requires nonsteroidal anti-inflammatory drugs, systemic steroids or immunosuppressants. If not controlled, scleritis can lead to necrotizing scleritis, anterior scleritis and posterior scleritis with secondary potential vision loss.14 In contrast, uveitis, the inflammation of the iris, ciliary body, and choroids, is less frequently associated with IBD flares but may precede a diagnosis of IBD by months or years. Although ophthalmological manifestations are present in any type of IBD, they are more common in CD patients. 

Infliximab and adalimumab, both anti-tumor necrosis factor (TNF)-α antibodies, are frequently used first-line in patients with ocular manifestations of scleritis or uveitis. Infliximab is effective in the treatment of NIU unresponsive to other drugs, with approximately 82% of patients achieving clinical remission in a median time of 127 days. For patient with uveitis, brain magnetic resonance imaging (MRI) is indicated to screen for demyelination before the commencement of TNFα inhibitors. TNF-alpha inhibitors were shown to significantly reduce relapses, and to control scleral inflammation both rapidly and with a long-lasting effects.15,16

Most recently, therapies targeting interleukin (IL) 23 and Janus kinase inhibitor (JAK) inhibitors have emerged as treatment options for ocular EIMs. Ustekinumab, a monoclonal antibody against human IL-12/IL-23 p40 subunit, has been described in case reports for the successful treatment of non-infectious uveitis including a patient with psoriatic arthritis and psoriasis, and 2 patients with CD, including 1 with comorbid MS.17,18

Tofacitinib, a nonselective small molecule JAK inhibitor approved for UC, has been used successfully in patients with severe refractory juvenile idiopathic arthritis (JIA)-associated uveitis,19,20 but further studies are needed to show the safety and efficacy of JAK inhibitors in larger cohorts.

SKIN MANIFESTATIONS

Cutaneous extraintestinal manifestations have been described in up to 15% of patients with IBD, often preceding their IBD diagnosis and not necessarily linked with IBD disease activity. 

Erythema nodosum (EN), affecting up to 15% of those with IBD and pyoderma gangrenosum (PG), affecting up to 5% of those with IBD are the most common skin manifestations in those with CD or UC.21 It is important to note that while PG is associated with IBD, EN may be associated with a variety of conditions such as infection, medications, sarcoidosis, pregnancy, IBD, autoimmune diseases, vaccination, malignancy, and miscellaneous causes.22 PG is also linked with some degree of colonic inflammation, in up to 50% of patients underlying active disease is present, and often requires multiple therapies to achieve complete healing.23

There is an association between psoriasis and IBD, with a risk in UC patients 1.6 times higher than in the general population. Paradoxically, psoriasis can also be triggered in up to 5% of patients using anti-TNF drugs,24 and it may present in atypical locations, including new scaly and dry plaques that may be confused for eczema; therefore requiring a high suspicion by the medical provider for medication side effects. Paradoxical psoriasis may be treated with topical steroids or oral methotrexate, but if severe may require discontinuation of anti-TNF medication. 

The IL23/IL17 axis plays a critical role in the pathogenesis of skin EIMs. IL-23 stimulates the production of IL-17, an essential proinflammatory cytokine, mainly secreted by CD4+ helper T cells (Th17); therefore, biologic therapies targeting IL-23 in IBD may play a significant role in improving cutaneous inflammation such as psoriasis.26 In a similar vein, the expression of TNFα and its receptors are increased in PG and EN lesions in skin suggesting a mechanistic explanation for the effectiveness of anti-TNF therapy for these conditions.

Anti-TNFα agents, especially infliximab and adalimumab may thus be effective for some cutaneous manifestations and IBD including psoriasis and PG, and they can also be considered as sparing agents to avoid long-term side effects from systemic corticosteroids.26 Biologics against IL-23 can also be considered in patients with IBD and psoriasis, PG or EN. Considering the role of IL23 in the pathophysiology of skin inflammation, biologics such as ustekinumab, which targets IL12/23 and is approved for moderate to severely active CD and UC; and risankizumab, a humanized immunoglobulin G1 antibody targeting the p19 subunit of IL-23 approved for moderate to severe CD, may be appropriate therapeutic options for patients with IBD and concomitant psoriasis, EN, or PG.

MUSCULOSKELETAL 

Musculoskeletal involvement is the most common extraintestinal manifestations in IBD. Arthritis may affect up to 46% of patients with IBD, and its prevalence decreases with age. Patients with IBD and concomitant musculoskeletal symptoms are typically seronegative for rheumatoid factor (RF) and anti-citrullinated peptide antibodies. Seronegative spondyloarthropathies (SpA) include ankylosing spondylitis, reactive arthritis, and psoriatic arthritis (PsA). Rheumatoid arthritis (RA) has also been linked with IBD population.


CDUCMSScleritisNIUENPGPsARASpA
Anti-TNF++x++(+)(+)+++
Anti IL12/23++

(+)(+)(+)+

Anti IL-23++

(+)(+)(+)+

JAK inhibitors++

(+)(+)(+)+++
Natalizumab+
+






Sphingosine 1-phosphate 
++






Anti IL17Ax





+
+
Table 1. Advanced Therapies used for Inflammatory Bowel Disease and Extraintestinal Manifestations

Musculoskeletal conditions associated with IBD can be mainly divided into axial and peripheral arthritis (PA). Although both are present in patients with UC and CD, they are more commonly seen in CD sub-population; and while peripheral arthritis is typically correlated with active intestinal inflammation, axial arthritis is generally independent of it.

Patients with peripheral arthritis may respond to a course of nonsteroidal anti-inflammatory drugs (NSAIDs), but chronic NSAIDs use is discouraged in patients with IBD given the possibility of intestinal ulcer development and disease exacerbation; COX-2 inhibitors have been proposed as an acceptable first line treatment option for up to 14 days.27,28

Corticosteroids, on the other hand, are well known for their anti-inflammatory effects and are used in IBD as well as for peripheral arthropathies pains and flares, however they are generally ineffective for the treatment of axial arthritis and should be limited in use due to systemic side-effects. 

Sulfasalazine may be effective for peripheral and axial inflammatory arthritis, but it may be more effective in UC and peripheral arthritis than in CD. Although methotrexate has not shown efficacy in axial arthropathy either, when treating PA and CD patients, it has provided clinical improvement and may be used to achieve higher levels of anti-TNFs.29

When biologic treatments need to be considered, anti-tumor necrosis factors including infliximab and adalimumab continue to be the first line treatment as they have shown significant efficacy in both peripheral and axial arthropathy. Additional therapeutic considerations like IL12/23 and JAK inhibitors can be alternative approaches depending on the specific rheumatologic diagnosis, PsA, RA, or SpA. (Table 1.)

Ustekinumab, has shown to be effective for peripheral arthritis, including PsA, enthesitis and dactylitis, however it does not seem to be effective for treatment of axial arthropathies as SpA nor RA.30

Jak inhibitors are fast acting, oral medications, only available after not responding to TNF blockers due to safety considerations, and are effective for the treatment of SpA, RA and PsA.

Upadacitinib, a JAK inhibitor with high selectivity for JAK1 is approved for moderate to severe CD and UC as well as for moderate to severe RA, psoriatic arthritis, ankylosing spondylitis and non-radiographical axial spondyloarthropathy. Its efficacy has been demonstrated as a monotherapy with similar efficacy that combining upadacitinib with methotrexate.31,32 Tofacitinib acts by preferentially inhibiting JAK1 and JAK3, with reduced inhibition for JAK2 and tyrosine kinase 2, it is used for moderate to severe UC as well as RA, PsA and active ankylosing spondylitis.32,33

Monoclonal IgG4 antibodies directed against IL-17A such as secukinumab and ixekizumab; or against IL-17 receptor, brodalumab, are highly effective for psoriasis, enthesitis and peripheral arthritis. However, they have not only shown to be ineffective in IBD but are associated with exacerbation and new onset of IBD and colitis and its use in patients with MSK manifestations is thus not recommended.34

Summary

IBD may present with a single or multiple extraintestinal manifestations. EIMs may affect any organ system and are chronic inflammatory diseases capable of causing a major debilitating comorbidity if left untreated or partially treated. Detailed consideration of EIMs needs to be taken into account when deciding which biologic to use when co-treating IBD and EIMs. 

References

1. Gharib MH, AlKahlout MA, Garcia Canibano B, Theophiel Deleu D, Malallah AlEssa H, AlEmadi S. Demyelinating Neurological Adverse Events following the Use of Anti-TNF-α Agents: A Double-Edged Sword. Case Rep Neurol Med. 2022 Mar 7;2022:3784938. doi: 10.1155/2022/3784938. PMID: 35296124; PMCID: PMC8920694.

2. Kunchok A, Aksamit AJ, Davis JM, et al. Association between tumor necrosis factor inhibitor exposure and inflammatory central nervous system events. JAMA Neurol. 2020;77(8):937-946. doi: 10.1001/jamaneurol.2020.1162

3. Kopp TI, Delcoigne B, Arkema EV, et al. Risk of neuroinflammatory events in arthritis patients treated with tumour necrosis factor alpha inhibitors: a collaborative population-based cohort study from Denmark and Sweden. Ann Rheum Dis. 2020;79(5):566-572. doi: 10.1136/annrheumdis-2019-216693

4. Li L, Aviña-Zubieta JA, Bernstein CN, Kaplan GG, Tremlett H, Xie H, Peña-Sánchez JN, Marrie RA, Etminan M. Risk of Multiple Sclerosis Among Users of Antitumor Necrosis Factor α in 4 Canadian Provinces: A Population-Based Study. Neurology. 2023 Feb 7;100(6):e558-e567. doi: 10.1212/WNL.0000000000201472. Epub 2022 Oct 28. PMID: 36307225; PMCID: PMC9946189

5. Song J, Westerlind H, McKay KA, Almqvist C, Stridh P, Kockum I, Hillert J, Manouchehrinia A. Familial risk of early- and late-onset multiple sclerosis: a Swedish nationwide study. J Neurol. 2019 Feb;266(2):481-486. doi: 10.1007/s00415-018-9163-6. Epub 2018 Dec 21. PMID: 30578428; PMCID: PMC6373346.

6. Gonzalez Caldito N. Role of tumor necrosis factor-alpha in the central nervous system: a focus on autoimmune disorders. Front Immunol. 2023 Jul 7;14:1213448. doi: 10.3389/fimmu.2023.1213448. PMID: 37483590; PMCID: PMC10360935.

7. Kemanetzoglou E, Andreadou E. CNS Demyelination with TNF-α Blockers. Curr Neurol Neurosci Rep. 2017 Apr;17(4):36. doi: 10.1007/s11910-017-0742-1. PMID: 28337644; PMCID: PMC5364240.

8. Mansouri B, Horner ME, Menter A. Tumor Necrosis Factor-α Inhibitor Use in Psoriasis Patients with a First-degree Relative With Multiple Sclerosis. J Drugs Dermatol. 2015 Aug;14(8):876-8. PMID: 26267733.

9. Dryden GW. Natalizumab for Moderate-to-Severe Crohn’s Disease. Gastroenterol Hepatol (N Y). 2008 Apr;4(4):296. PMID: 21960916; PMCID: PMC3093736

10. Hou J, Dodd K, Nair VA, Rajan S, Beniwal-Patel P, Saha S, Prabhakaran V. Alterations in brain white matter microstructural properties in patients with Crohn’s disease in remission. Sci Rep. 2020 Feb 7;10(1):2145. doi: 10.1038/s41598-020-59098-w. PMID: 32034257; PMCID: PMC7005825.

11. Dolapcioglu C, Dolapcioglu H. Structural brain lesions in inflammatory bowel disease. World J Gastrointest Pathophysiol. 2015 Nov 15;6(4):124-30. doi: 10.4291/wjgp.v6.i4.124. PMID: 26600970; PMCID: PMC4644876.

12. Paul T. Parks, Alexander S. Easton, “Cerebral Vasculitis in Ulcerative Colitis Is Predominantly Venular: Case Report and Review of the Literature”, Case Reports in Rheumatology, vol. 2019, Article ID 9563874, 6 pages, 2019. https://doi.org/10.1155/2019/9563874

13. Hou J, Dodd K, Nair VA, Rajan S, Beniwal-Patel P, Saha S, Prabhakaran V. Alterations in brain white matter microstructural properties in patients with Crohn’s disease in remission. Sci Rep. 2020 Feb 7;10(1):2145. doi: 10.1038/s41598-020-59098-w. PMID: 32034257; PMCID: PMC7005825.

14. Jabs DA, Mudun A, Dunn JP, Marsh MJ. Episcleritis and scleritis: clinical features and treatment results. Am J Ophthalmol. 2000 Oct;130(4):469-76. doi: 10.1016/s0002-9394(00)00710-8. PMID: 11024419.

15. Ferreira, Lisia Barros MD; Smith, Anthony J. FRACP, PhD; Smith, Justine R. FRANZCO, PhD. Biologic Drugs for the Treatment of Noninfectious Uveitis. Asia-Pacific Journal of Ophthalmology 10(1):p 63-73, January-February 2021. | DOI: 10.1097/APO.0000000000000371

16. Sota J, Girolamo MM, Frediani B, Tosi GM, Cantarini L, Fabiani C. Biologic Therapies and Small Molecules for the Management of Non-Infectious Scleritis: A Narrative Review. Ophthalmol Ther. 2021 Dec;10(4):777-813. doi: 10.1007/s40123-021-00393-8. Epub 2021 Sep 2. PMID: 34476773; PMCID: PMC8589879

17. Mugheddu C, Atzori L, Del Piano M, et al. Successful ustekinumab treatment of noninfectious uveitis and concomitant severe psoriatic arthritis and plaque psoriasis. Dermatol Ther 2017; 30.

18. Chateau T, Angioi K, Peyrin-Biroulet L. Two cases of successful ustekinumab treatment for non-infectious uveitis associated with Crohn’s disease. J Crohns Colitis 2020; 14:571.

19. Miserocchi E, Giuffrè C, Cornalba M, et al. JAK inhibitors in refractory juvenile idiopathic arthritis-associated uveitis. Clin Rheumatol 2020; 39:847–851.

20. Bauermann P, Heiligenhaus A, Heinz C. Effect of Janus kinase inhibitor treatment on anterior uveitis and associated macular edema in an adult patient with juvenile idiopathic arthritis. Ocul Immunol Inflamm 2019; 27:1232–1234.

21. Rogler G, Singh A, Kavanaugh A, Rubin DT. Extraintestinal Manifestations of Inflammatory Bowel Disease: Current Concepts, Treatment, and Implications for Disease Management. Gastroenterology. 2021 Oct;161(4):1118-1132. doi: 10.1053/j.gastro.2021.07.042. Epub 2021 Aug 3. PMID: 34358489; PMCID: PMC8564770.

22. Leung AKC, Leong KF, Lam JM. Erythema nodosum. World J Pediatr. 2018 Dec;14(6):548-554. doi: 10.1007/s12519-018-0191-1. Epub 2018 Sep 29. PMID: 30269303.

23. Weizman AV, Huang B, Targan S, Dubinsky M, Fleshner P, Kaur M, Ippoliti A, Panikkath D, Vasiliauskas E, Shih D, McGovern DP, Melmed GY. Pyoderma Gangrenosum among Patients with Inflammatory Bowel Disease: A Descriptive Cohort Study. J Cutan Med Surg. 2015 Mar-Apr;19(2):125-31. doi: 10.2310/7750.2014.14053. Epub 2015 Mar 11. PMID: 25775631.

24. De Francesco MA, Caruso A. The Gut Microbiome in Psoriasis and Crohn’s Disease: Is Its Perturbation a Common Denominator for Their Pathogenesis? Vaccines (Basel). 2022 Feb 5;10(2):244. doi: 10.3390/vaccines10020244. PMID: 35214702; PMCID: PMC8877283.

25. Maronese CA, Pimentel MA, Li MM, Genovese G, Ortega-Loayza AG, Marzano AV. Pyoderma Gangrenosum: An Updated Literature Review on Established and Emerging Pharmacological Treatments. Am J Clin Dermatol. 2022 Sep;23(5):615-634. doi: 10.1007/s40257-022-00699-8. Epub 2022 May 24. PMID: 35606650; PMCID: PMC9464730.

26. Liu T, Li S, Ying S, Tang S, Ding Y, Li Y, Qiao J, Fang H. The IL-23/IL-17 Pathway in Inflammatory Skin Diseases: From Bench to Bedside. Front Immunol. 2020 Nov 17;11:594735. doi: 10.3389/fimmu.2020.594735. PMID: 33281823; PMCID: PMC7705238.

27. Prevalence and mechanism of nonsteroidal anti-inflammatory drug-induced clinical relapse in patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2006; 4: 196-202

28. Safety of celecoxib in patients with ulcerative colitis in remission: a randomized, placebo-controlled, pilot study. Clin Gastroenterol Hepatol. 2006; 4: 203-211

29. Zochling J, van der Heijde D, Dougados M, Braun J. Current evidence for the management of ankylosing spondylitis: a systematic literature review for the ASAS/EULAR management recommendations in ankylosing spondylitis. Ann Rheum Dis. 2006 Apr;65(4):423-32. doi: 10.1136/ard.2005.041129. Epub 2005 Aug 26. PMID: 16126792; PMCID: PMC1798100.

30. Ulusoy BÖ, Erden A, Güven SC, Armağan B, Yürekli ÖT, Özin YÖ, Omma A, Küçükşahin O. Ustekinumab in enteropathic arthritis. Immunotherapy. 2023 Jun;15(8):583-592. doi: 10.2217/imt-2022-0197. Epub 2023 Apr 5. PMID: 37020400.

31. Fonseca D, Nogueira M, Torres T. Upadacitinib for the treatment of psoriatic arthritis. Drugs Context. 2023 Feb 28;12:2022-11-6. doi: 10.7573/dic.2022-11-6. PMID: 36876156; PMCID: PMC9983629.

32. Wang, Wenfei MD1; Cleveland, Noa Krugliak MD2; Ollech, Jacob MD2; Rubin, David T. MD2. Use of Tofacitinib for the Treatment of Arthritis Associated with Ulcerative Colitis. ACG Case Reports Journal 6(9):p e00226, September 2019. | DOI: 10.14309/crj.0000000000000226

33. Momen Majumder MS, Haq SA, Rasker JJ. Tofacitinib for the treatment of inflammatory bowel disease-associated arthritis: two case reports. J Med Case Rep. 2023 Mar 1;17(1):71. doi: 10.1186/s13256-023-03796-2. PMID: 36855206; PMCID: PMC9976468.

34. Deng Z, Wang S, Wu C, Wang C. IL-17 inhibitor-associated inflammatory bowel disease: A study based on literature and database analysis. Front Pharmacol. 2023 Mar 23;14:1124628. doi: 10.3389/fphar.2023.1124628. PMID: 37033665; PMCID: PMC10076642.

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Nutrition Reviews in Gastroenterology, SERIES #14

Nutrition Therapies for Patients with an Ileoanal Pouch: A Moving Target?

June 2024 • Volume XLVIII, Issue 4
Elizabeth Wall

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An ileal pouch-anal anastomosis (IPAA) is the preferred surgical reconstruction for restoration of intestinal continuity after a total proctocolectomy; it obviates the need for a permanent ileostomy. The pouch, or continuity reservoir, is anastomosed to the sphincter-spared anus allowing for controlled passage of bowel movements (BMs). Patients with mature, properly functioning pouches can expect to pass 6-8 BMs every 24 hours. Diet after IPAA is empiric and patient-specific with the overarching goals to optimize pouch continence and nutrient/fluid absorption. Pouch inflammation is common and thought to be primarily related to an abnormal immune response to pouch dysbiosis.1 Diet may play an important role in mediating the dysbiosis and influence pouch function, though evidence of this is lacking. This article will review basic information regarding IPAA, pouch complications, diet for patients with IPAA, and recommendations for long-term micronutrient supplementation.

Introduction

Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the surgical procedure of choice for patients with refractory ulcerative colitis (UC) and familial adenomatous polyposis (FAP) who desire intestinal continuity after colectomy. The pouch is an alternative to a permanent end ileostomy. The most common pouch configuration is the J-shape (constructed from two limbs of distal ileum, Figure 1), though other configurations are possible based on the surgeon’s determination. To date there is a dearth of evidence to support specific dietary recommendations for patients with IPAA. Frequently, results of small studies with heterogeneous populations and endpoints, or recommendations based on patients’ observations of their responses to certain foods/food components, are used to make generalized dietary recommendations. This review will summarize the limited data and key expert recommendations to support nutrition therapies for patients with IPAA.

IPAA Construction and Function

The IPAA procedure is typically performed in two or three phases depending on the condition of the colon, specifically, and patient’s overall condition.2,3 Approximately 30-40 centimeters of the distal ileum is used to fashion the pouch that is then anastomosed to the sphincter-spared anus.4 The two-step procedure is most commonly performed; the first phase is the proctocolectomy and IPAA construction with a diverting ileostomy (DI) followed 6-8 weeks later by the second step of DI takedown.3 The three-step procedure is often reserved for patients with severe colitis, perforation, bleeding, or dysplasia; the first step is a subtotal colectomy with  end ileostomy, the second step is the completion proctectomy, IPAA construction with DI and takedown of the end ileostomy, and the third step is the takedown of the DI. 

Once bowel continuity is restored, patients will experience a period of intestinal adaptation during which their bowel habits and dietary tolerance evolve. The adaptation process can take 6-18 months following colectomy.6,7 After complete adaptation, patients can expect to pass an average of 6 bowel movements (BMs) per 24 hours; often 1 BM will occur overnight.6 Physical and emotional adjustments to the new pouch habits will vary between patients. Those with a history of severe colitis often pass fewer BMs and feel better with the pouch, however, patients with FAP typically do not have pre-operative gastrointestinal symptoms and must learn to cope with frequent BMs, reduced continence, and fecal urgency after the proctocolectomy. In either scenario, support from an experienced gastrointestinal registered dietitian nutritionist (RDN) will help patients to understand the relationships between diet, hydration, and pouch function to optimize their health and quality of life (QoL). 

IPAA Complications

The IPAA procedure is not without risk of complications; Table 1 lists the phenotypes of pouch disorders. In the acute post-operative phase infection/pelvic abscess, anastomotic leak, and small bowel (SB) obstruction/ileus are most commonly observed; complication rates are higher for patients who received systemic corticosteroids or smoked at the time of surgery.8 Long term complications are characterized by urgency/high frequency of BMs, continence problems (both seepage and difficult evacuation), fatigue, pouch failure, and reduced QoL.3 

Pouch inflammation (pouchitis) is the most common complication associated with an IPAA and affects 30–50% of patients.9 Acute pouchitis is defined as symptoms lasting < 4 weeks and is usually responsive to antibiotic therapy whereas chronic pouchitis lasts > 4 weeks. An approach to diagnosis and management of pouchitis was recently published in this journal.10 

The etiology of pouchitis is not fully understood and is likely multifactorial but thought to be primarily related to an abnormal immune response to pouch dysbiosis; though secondary factors such as Crohn’s disease, infection, ischemia, or radiation can also cause inflammation.1

Diet After IPAA 

The goals of nutrition therapy for patients with IPAA are to optimize SB absorption and to regulate passage of BMs. Patients may report that their pouch function and defecation frequency are directly related to meals and post-prandial gastrointestinal motility; though evidence is lacking with regard to specific dietary elements that directly affect pouch function.7,11 Therefore, patients and clinicians alike must take a flexible and empiric approach when developing meal plans because a patient’s food tolerances will likely change with pouch adaptation and in cases of dysfunction. 

PhenotypeClinical Features
StructuralAnastomotic leak Fistula Pelvic infection/abscess Obstruction Dilation Bezoar
InflammationPouchitis
(acute, chronic antibiotic-responsive, chronic antibiotic-refractory) Crohn’s disease-like pouch inflammation Cuffitis
FunctionalIrritable pouch syndrome Dysmotility Anopouch pain syndrome
Nutrition/metabolicAnemia Metabolic bone disease Micronutrient deficiencies
Table 1. Pouch Disorders Phenotypes1

Immediately after DI takedown, depending upon the surgeon’s opinion of the competence of the pouch and pouch-anal anastomosis, it may be recommended for the patient to follow a low fiber diet. Although evidence lacks for fiber restriction, of particular concern to surgeons are insoluble fibers (e.g., wheat or oat bran, vegetable/legume peels/shells, nuts, and seeds) that accelerate transit, increase stool bulk, and exert pressure on suture lines. Fiber restrictions should be limited to the least number of weeks necessary to prevent patients from indefinite adherence to a low fiber diet. 

Beyond the initial postoperative period, IPAA patients should advance their diet as tolerated to one that is balanced between all food groups. General guidelines for an “IPAA Diet” are lacking given significant variations in patients’ perceived tolerance to foods (see Table 2 for foods observed to effect pouch output; patients can include or limit foods based on their pouch function).7,12,13 After total colectomy absorption of nutrients and fluid is limited to the SB, thus application of the following generally accepted recommendations for those with an ileostomy may help to slow postprandial gastric emptying and intestinal transit for optimal absorption:14,15

Eat multiple (5-6) small meals daily to avoid excessive gastric and pouch distention

Include slowly fermented, gel-forming fiber (e.g., psyllium) with each meal

Avoid simple sugars in foods and beverages to reduce rapid gastric emptying of hypertonic fluid

May limit intake of lactose containing foods and beverages

Separate solid foods and liquids to optimize gastric digestion

Post-prandial rest for 20-30 minutes to increase gastric digestion and to reduce intestinal motility

Sip isotonic or hypotonic fluids between meals

Oral rehydration solutions (ORS) can promote SB absorption of sodium and water

Avoid eating 2-3 hours before bed to reduce nocturnal defecation 

If needed, take antimotility medications 20-30 minutes before meals and at bedtime

See Table 3 for more detailed interventions to improve absorption after IPAA.

Over time, patients with a well-functioning pouch may be able to tolerate larger, less frequent meals. Although evidence is limited, ingestion of foods with gel-forming fibers (psyllium, pectin, gums) may help to increase the consistency of stool and provide important substrate for microbial fermentation and production of important metabolites.14,16 A recent study looked at fruit consumption after IPAA and found that consumption of > 1.5 fruit servings daily reduced the risk of developing pouchitis,17 supporting the importance of dietary fiber consumption after IPAA.

The Mediterranean diet (MD) is known for its emphasis on plant-based foods, fish and olive oil while limiting intake of red meats, saturated fats, sweets, and sugary beverages. Research has demonstrated that the MD can reduce inflammation in chronic disease states.18 More recently, a study demonstrated that patients with IPAA (for UC) who followed the MD for 8 years had reduced fecal calprotectin levels and adherence was inversely associated with episodes of pouchitis.19 Although the exact mechanism is not understood, this data supports the recommendation that IPAA patients follow a MD pattern (Figure 2) to maintain optimal pouch function. 

Diet and Pouch Dysfunction

Pouch dysfunction can derail any progress a patient has made towards attaining a stable, healthy diet. In the case of pouchitis the combination of medical therapies (typically antibiotics are the first line of therapy as pouchitis is thought to result from microbial dysbiosis) and a shift of diet composition may provide patients symptomatic relief.1 A recent pilot study of 15 adults with active pouchitis identified a positive effect of the Crohn’s Disease Exclusion Diet (excludes processed and refined foods, includes resistant starch and fiber) in patients with strict adherence.20 Although the study was small, non-randomized, and uncontrolled, it seems hopeful that some cases of pouch inflammation may respond to diet therapy. As more is understood about the phenotypes of dysfunction, and the association between pouch function and the microbiome, it is likely that there will be opportunities for 1:1 counseling with a RDN to tailor the diet based on the nature of the pouch dysfunction and create more evidence-based recommendations for dietary therapies to alter active inflammation.7,14 

In patients with pouch dysfunction  that is more irritable in nature (frequent and/or urgent BMs, abdominal cramps, pelvic discomfort, and absence of inflammation),21 it may be reasonable to restrict highly fermentable and osmotically active carbohydrates with a low FODMAP diet (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols).14 Limitation of FODMAP consumption may reduce bacterial fermentation (gas production) of undigested carbohydrates, as well as decrease water delivery to the pouch, both of which can reduce symptoms of gas, bloating, and diarrhea/urgency. Patients with a positive response to the initial exclusion of FODMAPs should work intensively with a RDN to identify trigger foods and to re-introduce those foods that are tolerable. There is minimal evidence though to support FODMAP restriction in the management of pouchitis.22

Observed
Effects of Food		Foods and Beverages 
Stool thickeningApplesauce Banana Bread Pasta Potatoes Oatmeal Rice Peanut butter Soluble, low fermentable fiber (e.g., psyllium)
Stool thinningSpicy foods (capsaicin) Fruit and fruit juice Cabbage
Increased stool outputNuts Corn Chocolate Lettuce Fresh oranges Tomatoes Cow’s milk Alcohol Fried foods Spicy foods
Increased flatusFood with high FODMAPs  Onions, cabbage, and cow’s milk Spicy foods 
Perianal irritationCitrus fruits Spicy foods Nuts and seeds
Table 2. Foods Observed to Effect Stool Output and IPAA13,14

Fluids and Hydration

Hydration status after IPAA is often overlooked. Chronic low-level dehydration (characterized by low 24-hour urine volume, hypotension, chronic fatigue, dry mucous membranes, etc.) can affect a patient’s overall feeling of wellness and their ability to participate in life activities, not to mention the risk of nephrolithiasis and chronic kidney injury. It is recommended for adults with normal kidney function to produce at least 1,000-1,200 mL urine per day and kidney stone formers should make at least 1,500 mL per day.23,24 Attention to both fluid intake and urine output is imperative to gauge hydration and ensure long-term maintenance of normal kidney function. Without the colon to absorb sodium and water, those with an IPAA must rely mainly on SB sodium-glucose co-transporters to drag water across the mucosa.25 Consumption of isotonic fluids such as ORS and avoidance of hypertonic, sugary beverages should improve water absorption and hydration status.

ORS contain specific concentrations of sodium and sugar in water and are known to facilitate SB water absorption. Beverages that contain both sodium (50-70 mEq/L) and glucose (20-40g/L) are palatable options (Table 3).26 IPAA patients who pass high volume stool may find that sipping ORS between meals can help to achieve hydration goals.

Micronutrients

The IPAA consensus guidelines recommend lifelong monitoring of several micronutrients as well as for anemia and metabolic bone disease.1 Most notably, vitamin B12, vitamin D, and iron, are identified as micronutrients of potential concern (particularly in the early phase of IPAA and in the setting of pouch inflammation),1 although other fat soluble vitamins and divalent cations may become deficient in the IPAA population (see Table 4).4 Deficiencies can result from insufficient intake and with altered absorption in the setting of rapid transit or of villous atrophy associated with pouch inflammation.4 In particular, vitamin B12 deficiency can develop from reduced absorption and increased utilization by bacteria if pouch overgrowth/dysbiosis exists.4 Vitamin B12 deficiency can lead to permanent neurological deficits and therefore lifelong therapeutic dosing of cyanocobalamin (1,000 mcg by mouth daily or monthly subcutaneous injection) is safe and recommended. 

Evidence for monitoring and supplementation of micronutrients after IPAA does not exist. Data and guidelines for patients with inflammatory bowel disease and post-surgical malabsorption can guide clinicians when prescribing supplementation regimens. One important factor with respect to interpretation of serum/plasma micronutrient levels when inflammation exists is that reported levels are often perturbed making interpretation difficult.27 A RDN with experience in micronutrient repletion therapy, who is able to perform sequential nutrition focused physical exams, is the ideal team member to develop, institute, and monitor responses to micronutrient supplementation. Short of this, it is prudent for anyone unable to consume a balanced diet to take a daily multivitamin with mineral supplement that meets 100% of the Reference Dietary Intake (RDIs).

TherapyIntervention
DietEat 5-6 small meals Avoid overeating/drinking to prevent excessive pouch distention Use the Mediterranean diet pattern to structure meals Include plenty of plant foods with soluble fiber Oats, peas, carrots, beans, citrus fruits, apple, banana Slows gastric emptying, thickens stool, supports microbiome Eat at least  two fruit servings daily Limit foods with simple sugars  Cakes, cookies, pastries, ice cream, Italian ice Limit greasy foods Limit insoluble fiber, caffeine, and alcohol May increase BM frequency and cause watery stool
FluidsLimit fluids at meals to 4-8 ounces Sip remaining fluids between meals, throughout the day Focus in hypotonic and isotonic fluids for SB water absorption Hypotonic beverages – water, dilute juices, tea, coffee, diet drinks Isotonic beverages – ORS, e.g., Ceralyte®, Pedialyte®, DripDrop®, Trioral® Limit hypertonic beverages Cause osmotic shift of water into the intestinal lumen resulting in more volume to reabsorb Fruit juice, sweet tea, lemonade, sweetened beverages, and cocktails Oral nutrition supplements (Ensure®, Boost®)
Medications and supplementsUse antimotility agents such as loperamide to slow gastrointestinal transit Time antimotility medications 30-60 minutes before meals and bedtime Fiber supplements such as Metamucil® or Benefiber® may help thicken stool for improved continence
ActivitySit for 20-30 minutes after meals to allow for digestion and reduce intestinal motility Avoid eating 2-3 hours before bed to reduce nocturnal defecation
Table 3. Interventions to Optimize Food and Fluid Absorption After IPAA
MicronutrientMonitoring ParametersDaily Maintenance Dose¥ (Oral)Repletion Dose*
Vitamin B12Serum vitamin B12 Serum folate Plasma homocysteine Plasma methylmalonic acid1,000 mcg1,000 mcg subcutaneous injection for 5-7 days
Vitamin DSerum 25-hydroxy vitamin D18 – 70 yrs 15 mcg > 70 yrs 20 mcg100-125 mcg oral daily
Vitamin EPlasma α-tocopherol15 mg90 – 180 mg oral daily
Vitamin ASerum RetinolMen 900 mcg Women 700 mcg Pregnant 770 mcg Lactating 1300 mcg1,500 – 3,000 mcg
oral daily
IronHemoglobin Serum iron Total iron binding capacity Transferrin saturation Serum ferritinMen  8 mcg Women Premenopausal 18 mg Postmenopausal 8 mg50 – 200 mg oral daily (divided doses)
ZincPlasma zincMen – 11 mg Women – 8 mg50 mg oral daily
CalciumBone densityMen 19 – 70 yrs 1,000 mg >70 yrs 1,200 mg Women 19-50 yrs 1,000 mg >50 1,200 mgVariable based on
bone health
Table 4. Micronutrient Monitoring and Dosing Recommendations After IPAA

Conclusion

For patients with severe colitis or FAP the IPAA is a means to restore bowel continuity and avoid a permanent end ileostomy after total proctocolectomy. The procedure requires patients to adopt balanced dietary patterns, such as the MD, that include fruits, vegetables, and fiber to optimize pouch function, absorption, the microbiome, and overall health. Avoidance of excessive pouch distention from over-eating/drinking may help to control the frequency of BMs. Symptoms of irritable pouch syndrome (diarrhea dominant), rather than inflammation, may be controlled with elimination of some highly fermentable carbohydrates. Collaboration between the patient and a RDN is necessary to identify poorly tolerated foods and design the most balanced diet possible. Routine supplementation with vitamin B12 and close monitoring for micronutrient deficiencies, anemia, bone health, and hydration status is essential to ensuring optimal health and well-being. In summary, the IPAA can significantly improve the health and QoL for some patients but may require ongoing RDN support for optimization of nutrient uptake, hydration, and pouch function. 

References

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22. Rabbenou W, Chang S. Medical treatment of pouchitis: a guide for the clinician. Ther Adv Gastroenterol. 2021;14:1-15.

23. Parrish CR, Wall EA. The clinician’s toolkit for the adult short bowel patient Part 1: nutrition and hydration therapy. Pract Gastroenterol. 2022;6:32-53.

24. Borghi L, Meschi T, Amato F, et al. Urinary volume, water, and recurrences in idiopathic calcium nephrolithiasis: a 5-year randomized prospective study. J Urol 1996;155(3):839-843.

25. Barrett KE. Water and Electrolyte Absorption and Secretion. In: Barrett KE. Ed. Gastrointestinal Physiology, 2e. New York, NY: McGraw-Hill; 2014. http://access-medicine.mhmedical.com/content.aspx?bookid=691&sectionid=45431404. Accessed February 25, 2024.

26. Wall E. ORS: The Solutions to Optimize Hydration in Short Bowel Syndrome. Practical Gastroenterology. 2020;3:24-31.

27. Berger MM, Shenkin A, Schweinlin A, et al. ESPEN micronutrient guideline. Clin Nutr. 2022;41:1357-1424.

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FRONTIERS IN ENDOSCOPY, SERIES #91

Endoscopic Management of Laparoscopic Gastric Sleeve Leaks

June 2024 • Volume XLVIII, Issue 4
Kelita Singh,Douglas G. Adler,Abinash Subedi,Fathima Keshia Suhail

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INTRODUCTION

Bariatric surgery is a well-established option for patients with obesity, with over 200,000 procedures performed annually in the United States. Sleeve gastrectomy comprises 58% of these surgeries.1 Gastric sleeve leaks (GSL) can occur in 1-2% of patients following laparoscopic sleeve gastrectomy.2 Leaks occur when tissue breakdown, most commonly near the anastomosis and/or suture or staple lines and can evolve into a fistula with an epithelialized tract if they do not heal in a timely manner.3 GSL are the second most common cause of mortality in patients undergoing sleeve gastrectomy, following pulmonary embolism.4

A multidisciplinary approach is important when managing these patients and should involve surgery, gastroenterology, and interventional radiology. Prompt diagnosis, classification, and treatment of GSL is essential. Techniques for managing GSL can vary based on the patient’s clinical condition, leak classification, expert experience, and availability of resources. In the presence of hemodynamic compromise, septic shock or peritonitis, further surgical management is needed. Otherwise, endoscopic treatment is preferred, due to high perioperative morbidity with surgery.5

Classification

Classification of GSL can guide management decisions. There are several proposed classification systems that are based on timing of presentation and findings on computed tomography (CT) scan. 

The Rosenthal sleeve gastrectomy leak classification system organizes leaks based on timing of presentation.6 Acute leaks are diagnosed and treated before 7 days from the operative procedure, early leaks between 1-6 weeks, late leaks between 6-12 weeks, and chronic leaks after 12 weeks. 

Sleeve leaks can also be classified according to a CT scan classification system7 which is organized by the type of collection on CT and leak visualization. (Table 1) Johari et al. proposed a validated classification system, based on CT imaging that predicts a stepwise increased risk of complication severity, increased hospital stay and salvage resection using a 2-phase modified Delphi process.8
(Table 1)

Csendes et al.Johari et al.
Type Collection on CTClass 1 Phlegmon associated with staple line
I< 5cm in LUQClass 1aPhlegmon 
II> 5cm in LUQClass 1bPhlegmon with small localized locules of gas
IIIDiffuse abdominal collectionsClass 2Fluid collection
IV Pleural (thoracic) collectionsClass 2aFluid collection with localized locules of gas
Type Staple line localization Class 2b Extensive mixed fluid and gas collection
SSuperior part of sleeve Class 3Contrast leak 
MMiddle part of sleeveClass 3aContained contrast leak 
IInferior part of sleeveClass 3bFree intraperitoneal contrast leak 

Leak VisualizationClass 4Chronic fistula 
aNo leak

bPositive leak 

Etiology

The etiologies of GSL can be due to mechanical/tissue causes or ischemic causes. It is related to an increase in intraluminal pressure which exceeds the strength of the tissue and/or staple line.9 When creating a gastric sleeve, a long staple line anastomosis is created which extends from the antrum of the stomach to the gastroesophageal junction. Leaks can form anywhere along the staple line, although most leaks occur near the angle of His, where the gastric wall is susceptible to ischemia. Relative ischemia tends to occur in this area secondary to surgical ligation of gastric arteries, relative dysmotility and increased intragastric pressure. Distal obstructions, such as concomitant gastric sleeve stenosis, can further increase intraluminal pressure and contribute to the development of leaks. 

Risk Factors

Surgical and nonsurgical risk factors contribute to the development of GSLs. Several studies have demonstrated that male gender and higher BMI, especially in super-obese patients (BMI >50 kg/m2), increase the risk of developing a GSL.2,10

Surgical risk factors relate to stapling, ischemia, gastric stenosis, and the experience of the surgeon. Meticulous tissue handling, consideration of tissue thickness, conscious stapling, avoidance of inadvertent narrowing are methods to decrease surgical risk factors.9 Additionally, surgeons performing >43 cases per year can achieve a <1% leak rate.11

Clinical Manifestations 

Clinical manifestation of GSL can range from asymptomatic leaks diagnosed with routine imaging to signs and symptoms of perforation, peritonitis, and septic shock. Fever and tachycardia are two of the most important clinical factors in the diagnosis of GSL.5 Other clinical manifestations include abdominal pain, pain radiating to the left shoulder, vomiting and tachypnea.12

Diagnosis 

Upper gastrointestinal (UGI) fluoroscopy and CT scan of the abdomen with oral contrast are the most common tests used to diagnose GSL. In a head-to-head study comparing UGI contrast studies and CT scan with oral contrast, CT was found to be superior to UGI series in the diagnosis of GSL with a sensitivity of 95% vs. 74.9% respectively.13 Endoscopy is also useful when trying to establish the characteristics of the leak such as size of the orifice.14

Endoscopic Management 

Endoscopic treatment is feasible in most patients with GSL and have been shown to facilitate healing of GSL in 74-81%14,15 of patients, with early intervention increasing the likelihood of success.15 Predictors of successful healing with endoscopic management include acute leaks that developed ≤ 3 days from the operative procedure, early endoscopic treatment < 21 days after leak diagnosis, leak size < 1 cm, and no prior history of banded gastroplasty.15 

There are various treatment options for endoscopic management of GSL. Treatment strategy depends on the characteristics of the defect and center level of experience. The size, viability of surrounding tissue, and location of the defect can be defined endoscopically to determine which closure strategy might be best to perform. Additionally, treatment of distal stenoses and removal of foreign material is important for successful treatment of GSL.16

A retrospective review of 37 patients with GSL demonstrated that 30/37 (81%) were successfully managed endoscopically. Endoscopic techniques performed included: 44% fully covered bariatric gastric stents, 34% internal pigtail plastic stents, 11% septoplasty, 5% endoluminal vacuum therapy, and 3% over-the-scope clip (OTSC).14 Other endoscopic approaches include use of tissue sealants, endoscopic suturing, and novel techniques such as use of cardiac septal occluders. Patients may require combined endoscopic modalities for successful closure, especially in patients with refractory leaks who failed initial endoscopic intervention.17

Endoscopic Internal Drainage

The presence of an intra-abdominal collection (IAC) requires drainage as they tend to be the source of sepsis. Adequate drainage can be performed internally by endoscopy, via percutaneous drains, or, less frequently, via surgery.18,19 The reported efficacy rate when EID is used as a primary intervention is 74-86%.18-20 

Endoscopic internal drainage (EID) is accomplished under general anesthesia with fluoroscopy to identify the defect within the staple line.18 One or more double pigtail stents (DPS) with a diameter of 7 or 10 French are left in place, with one end of the pigtail in the collection and the other end of the pigtail in the stomach, for several months.18-20 Follow up endoscopy with fluoroscopy can be performed after one month for stent retrieval and to determine the presence of any residual leak. In patients with persistent leaks, stents are re-inserted.18 Adverse events of EID include stent migration, seen in 46% of cases, minor gastric mucosal trauma, minor bleeding related to stent erosion, and major bleeding from nearby vessel (i.e., splenic vessels).18,20 

Endoscopic ultrasound (EUS) can also be utilized for endoscopic drainage of IAC. EUS allows determination of collection size, location, and avoidance of any intervening vessels. Drainage is accomplished by using a 19G needle, guidewire, over the wire puncture and deployment of multiple DPS or lumen-apposing metal stents (LAMS) or can simply be done via freehand technique.21  LAMS can be exchanged at 1 month with DPS, if needed.18

Self-Expanding Metal Stents 

SEMS placed is the most common endoscopic interventions used to manage GSL.22 The objective of endoluminal stenting is to divert gastric contents from the leak site and to bypass any distal stenosis if present. The ideal stent should be long enough to cover the distal end of the sleeve, including the incisura. Predictors for success include male gender, higher pre-bariatric surgery BMI, and early stenting. (25 vs. 49 days).23 (Figure 1)

The success of endoluminal stenting for GSL is between 70%-88%.22,24,25 Additionally, successful treatment of GSL with SEMS can occur in 50% of patients after a single endoscopic session.22 The most undesired adverse effect of SEMS for treatment of GSL is migration which has been demonstrated in 30-47% cases.22,24 Anti-migratory mechanisms that can be utilized include endoscopic suturing of stents, longer stent length, and the use of endoscopic clips.22 Other adverse events include stent intolerance, bleeding, foreign body obstruction, strictures, and mucosal hypertrophy. According to one group, the optimal time for stent removal is after six to eight weeks, and they proposed that shorter intervals may lead to incomplete leak closure and longer intervals may result in stent migration or mucosal hypertrophy leading to difficulty with stent extraction.25 Still, in practice many different physicians have different opinions on the optimal stent indwell time and most patients receive individualized care. 

Fully covered self-expanding metal stents (fcSEMS) have the advantage of being easily removable compared to partially covered self-expanding metal stents (pcSEMS).26 However, fcSEMS have a high migration rate, reaching up to 26-67%.27,28 The Mega stent (Taewoong Medical, Seoul, Korea) was designed as a proposed solution to overcome the problem of migration.28 It is an ultra-large fully covered stent with braided mesh and increased flexibility which allows it to conform to post-bariatric anatomy. Its design can increase compression and coaptation against the luminal wall.  Shehab et. al has demonstrated the success rate of Mega stents to be 82% with a migration rate of 18%.28 Stenting can be combined with other treatment modalities, such as over-the-scope clips, which can directly close the wall defect.29 

Through-the-Scope-Clips 

Through the scope clips (TTSC) were initially designed for the treatment of gastrointestinal bleeding. These clips can approximate the edges of a lesion and produce mechanical compression/hemostasis without creating tissue injury seen with thermal hemostatic devices.30 TTSC have been reported as a modality for management of GSL.31,32  Once the edges of the defect are approximated, one or more clips are deployed to close the defect. In a meta-analysis of 17 studies including a total of 98 patients treated with clips for GSL, 4 studies (13 patients) utilized TTSC and successful treatment was reported in 9 of 13 patients (69.2%).32 This study is limited by the inclusion of very small number of patients. The use of TTSC can be considered in stable patients with small leaks, if the leak has failed endoscopic stenting, or is not amenable to stent placement.31  

Over-the-Scope Clips 

The over-the-scope clip (OTSC) is a mechanical clipping device designed to encircle, lift, and close endoscopic defects. These clips can achieve full thickness closure of luminal defects.29 Suction or grasping can be utilized to help ensure proper placement over the entire defect. OTSC is a wall defect closure strategy for the management of GSL.  A meta-analysis reported the use of OTSC in 85 patients across seventeen papers (98 patients) with a successful closure rate of 67.1%.32 The use of OTSC is more efficient if IAC are drained prior.33 OTSC-related adverse events occur in approximately 1.7% of cases.34 These include jejunal stenosis, clip mis-deployment, and micro-perforation or free perforation if there is an underlying ulcer.33,34

As most GSL are located at the proximal end of the staple line, using an OTSC and its mounting system to maneuver and position the clip may be difficult, due to limited space. Successful deployment of an OTSC depends on the working space, size, orientation of the defect and surrounding tissue quality.35 Using OTSC as a closure device to treat GSL should be considered for small- to medium-sized defects that can easily be accessed endoscopically. (Figure 2)

Tissue Sealants

Tissue sealants are adhesives that can be used to treat gastrointestinal leaks with initial data arising predominantly from use in Roux-en-Y gastric bypass (RYGB) patients. Such products are not readily available for endoscopists, which limit its use. The most commonly used sealant used for GSL closure is fibrin glue.32 Fibrin glue mechanically occludes the stomach wall defect and aids in wound healing. It induces a cellular response to tissue damage by forming matrix-building strands which promotes neovascularization and fibroblast proliferation.36 In a 2021 systematic review and meta-analysis, 10 case series comprising 63 patients with GSL were treated with fibrin glue. In 25 patients, the sealant was delivered endoscopically with a 100% success rate. The amount of glue ranged from 2-10 cc (median 4cc). Adverse events were reported in one study and included pain and fever in 3/24 patients.32

Another example of a tissue sealant glue is cyanoacrylate. Cyanoacrylate is a highly adhesive synthetic glue with antibacterial properties that can be utilized as a tissue sealant for GSL closure.37 Only a small amount (0.5-4cc) is needed and it can be utilized in a wet environment. Despite its advantages, it’s rapid polymerization results in poor mechanical properties such as low tensile strength and brittle nature, as well as risking damage to the endoscope.37 

SurgiSIS (Cook Biotech Inc., West Lafayette, IA) is an acellular matrix biomaterial comprising porcine small intestine submucosa. It stimulates proliferation and formation of fibroblasts in the regions of wounds.38 Strips of soaked SurgiSIS material are captured within a specially designed polypectomy snare and loaded into the endoscope outside of the patient. The scope is re-inserted after which the snare is used to place the material on the defect.38 In a 2009 clinical trial, the rate of closure of 5 to 10mm wide fistulas in patients who had undergone prior gastric bypass was achieved in 20/25  patients (80%) after 3 sessions.38 Further studies are necessary to determine the efficacy of SurgiSIS in patients with leaks from sleeve gastrectomy. 

Endoscopic Suturing 

Endoscopic suturing may be considered for closure of GSL when the defect size is large and other methods are less likely successful or have failed.39 The OverStitch (Apollo Endosurgery Inc., Austin, TX) is an endoscopic suturing system, mounted over the scope, that places full-thickness sutures endoscopically. Choosing to perform endoscopic suturing for gastrointestinal leaks depends on the condition/viability/friability/etc. of the target tissue, the feasibility of placing the suture according to the shape of the defect, distance of the margins, and absence of IAC.40  

The success of closing gastrointestinal leaks with endoscopic sutures was initially reported among RYGB patients.41 Mukewar et al. reported 100% immediate clinical success rate for gastrointestinal fistula closure with endoscopic suturing, however only 40% sustained clinical success at 4 weeks after the index procedure.39 There has been limited data which observed the use of endoscopic suturing in the management of GSL. Granata et al. reported 100% clinical success rate for gastric sleeve leak patients treated with OverStitch™ endoscopic suturing (6/6 patients).40 In a 2022 randomized controlled trial, 5/15 patients with gastric sleeve leaks were managed with endoscopic suturing alone with 100% clinical success and no cases of recurrent gastric fistula during the 18 month follow up period.3 

Septotomy 

Septotomy is a relatively new procedure which allows for fluid drainage from an abscess cavity, formed secondary to a leak, into the stomach by dividing the septum that separates the abscess from the gastric lumen.42 This division equalizes the intraluminal pressures by addressing the pressure gradient that drives gastric contents from the gastric lumen into the peri gastric collection.43 These changes can result in abscess cavity collapse and healing can occur through secondary intention and epithelialization.42,43 

This procedure is performed with a forward viewing gastroscope and the leak orifice is identified. If feasible, the abscess cavity is inspected and entered for irrigation.42 Division of the septum can be performed using a needle knife, cutting knife, or other endoscopic tools.43-45 Division of the septum is complete when the entire abscess cavity communicates with the gastric lumen, allowing drainage into the lumen of the stomach.  In a small multicenter study of 9 patients with GSL treated via septotomy, the peri-gastric collections ranged in size from 3-10cm. The mean procedure time was 87 minutes and a mean of 2.3 procedures were required to achieve radiologic resolution.43 Bleeding occurred in 3 patients and was managed successfully with TTSC. All patients achieved radiologic resolution. Diaz et al. demonstrated 5 patients with GSL who were treated with septotomy combined with sleeve dilation. Clinical success was achieved in 80% of patients (4/5), and no adverse events to the procedure were identified.42 

Endoscopic Vacuum Assisted Closure 

Endoscopic vacuum assisted closure (EVAC) is a negative pressure closure technique involving the placement of a porous polyurethane sponge in the abscess cavity at the leak site. In addition to drainage, it also increases local blood flow and promotes granulation tissue formation.46,47 The Endo-SPONGE system (B. Braun, Melsungen, Germany) allows for the insertion of an open-pored sponge into the leakage cavity using an endoscope. A drainage tube is connected to the sponge and suction is applied between 75 – 120 mm Hg depending on the size of the leak.48 The sponge can be inserted in cavities from leaks with large openings (≥ 9mm). The sponge can be exchanged every 3 days via endoscopy.48 

Studies have demonstrated 85-100% success with use of EVAC for treatment of GSL.47-49 Markus et al. demonstrated a 90% healing rate with Endo-SPONGE with a mean treatment time of 17 days. GSL healing with use of a sponge was defined as wound cavity size smaller than 1 cm in radius and 2 cm in depth, after which EVAC was terminated.48 

Cardiac Septal Occluders 

Cardiac septal occluder devices (CSDO) are a novel, off-label, treatment option for the management of GSL. CSDO Amplatzer™ (St. Jude Medical, Plymouth, Minn) is a self-expandable double disk (double umbrella) closure device, made of nitinol and interwoven polyester, which promotes tissue in-growth while sealing fistulous tracts.50 In a 2020 systematic review of 22 patients with GI fistulas, in 2 patients with GSL, technical success was 100% and clinical success (after one year of follow-up) was seen in 77%. Adverse events were reported in 5 patients and included migration and fistula enlargement. Further studies are needed prior to consideration of CSDO as the first line for treatment of GSL.50

Conclusion 

Gastric sleeve leaks are common adverse events following sleeve gastrectomy. Management of these leaks should ideally occur in a multidisciplinary setting.  An endoscopic approach should be considered as a less invasive option to surgery in patients without hemodynamic compromise, septic shock or peritonitis. The endoscopic armamentarium currently provides various options, and continues to expand, serving as a minimally invasive treatment avenue for the management of GSL. 

References

References

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39. Mukewar S, Kumar N, Catalano M, et al. Safety and efficacy of fistula closure by endoscopic suturing: a multi-center study. Endoscopy. Nov 2016;48(11):1023-1028. doi:10.1055/s-0042-114036

40. Granata A, Amata M, Ligresti D, et al. Endoscopic management of post-surgical GI wall defects with the overstitch endosuturing system: a single-center experience. Surg Endosc. Sep 2020;34(9):3805-3817. doi:10.1007/s00464-019-07145-7

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42. Diaz R, Welsh LK, Perez JE, et al. Endoscopic septotomy as a treatment for leaks after sleeve gastrectomy: Meeting presentations: Digestive Disease Week 2019. Endosc Int Open. Jan 2020;8(1):E70-E75. doi:10.1055/a-1027-6888

43. Mahadev S, Kumbhari V, Campos JM, et al. Endoscopic septotomy: an effective approach for internal drainage of sleeve gastrectomy-associated collections. Endoscopy. May 2017;49(5):504-508. doi:10.1055/s-0042-122012

44. Kim KH, Jung K, Kim YH, Seo KW. Endoscopic Septotomy as a Treatment for Chronic Leak after Laparoscopic Sleeve Gastrectomy. J Metab Bariatr Surg. Jun 2021;10(1):42-45. doi:10.17476/jmbs.2021.10.1.42

45. Shnell M, Gluck N, Abu-Abeid S, Santo E, Fishman S. Use of endoscopic septotomy for the treatment of late staple-line leaks after laparoscopic sleeve gastrectomy. Endoscopy. Jan 2017;49(1):59-63. doi:10.1055/s-0042-117109

46. Joo MK. Endoscopic Approach for Major Complications of Bariatric Surgery. Clin Endosc. Jan 2017;50(1):31-41. doi:10.5946/ce.2016.140

47. Leeds SG, Burdick JS, Fleshman JW. Endoluminal Vacuum Therapy for Esophageal and Upper Intestinal Anastomotic Leaks. JAMA Surg. Jun 1 2016;151(6):573-4. doi:10.1001/jamasurg.2016.0255

48. Markus A, Henrik BJ, Benedikt R, et al. Endoscopic vacuum therapy in salvage and standalone treatment of gastric leaks after bariatric surgery. Langenbecks Arch Surg. May 2022;407(3):1039-1046. doi:10.1007/s00423-021-02365-9

49. Archid R, Wichmann D, Klingert W, et al. Endoscopic Vacuum Therapy for Staple Line Leaks after Sleeve Gastrectomy. Obes Surg. Apr 2020;30(4):1310-1315. doi:10.1007/s11695-019-04269-6

50. De Moura DTH, Baptista A, Jirapinyo P, De Moura EGH, Thompson C. Role of Cardiac Septal Occluders in the Treatment of Gastrointestinal Fistulas: A Systematic Review. Clin Endosc. Jan 2020;53(1):37-48. doi:10.5946/ce.2019.030

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Feeding Tube Response in Esophagitis

May 2024 • Volume XLVIII, Issue 5

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Eosinophilic esophagitis (EoE) in young children can be associated with poor feeding as well as associated failure to thrive/failure to gain weight. Thus, use of nasogastric (NG) tube feeds as well as surgical gastrostomy tube (G-tube) feeds may be recommended to improve caloric intake as well as to provide elemental nutrition in this age group with EoE. There is minimal long-term data available regarding which pediatric patients with EoE would benefit most from NG/G-tube feeds.  

This retrospective study occurred at a tertiary children’s hospital in the United States. All pediatric patients with EoE and with a history of enteral tube feeds used as treatment for EoE from 2002 to 2021 were included. Basic patient demographics were obtained on all patients, and all patients were evaluated for both endoscopic and histologic response to enteral feeds. A total of 457 pediatric patients with EoE were identified, of which 39 pediatric patients with EoE required enteral tube feeds. The mean age of initial diagnosis of EoE for patients requiring enteral tube feeds was 6.3 ± 7.6 years, and the mean age for patients requiring enteral tube placement was 6.3 ± 9.3 years. The most common symptoms in this patient group were emesis and dysphagia. When compared to children with EoE who did not require enteral tube feeds, the patients with EoE and enteral tube feeds were significantly younger, had a significantly lower body mass index (BMI), and had a significantly lower initial Eosinophilic Esophagitis Endoscopic Reference Score (used to determine treatment response to EoE) and Endoscopic Severity Score.  

Most patients had enteral tube placement for failure to gain weight, and 19 patients (49%) required a transition from NG tube feeds to G-tube feeds. The vast amount of enteral nutrition provided to this patient group consisted of elemental formula (87%). Other therapeutics provided for this group included proton pump inhibitors, system steroids, and dupilumab. Enteral tubes remained in place for a mean of 6.8 ± 6.2 years. Most patients (92%) had enteral tube complications which were relatively mild, including tube displacement or granulation tissue formation. Most patients (71%) with enteral support achieved histologic EoE response. There was a significant increase in BMI-for-age z-scores in those patients with EoE requiring enteral feeds. Patients requiring enteral feeds prior to a diagnosis of EoE were significantly more likely to have autism or developmental delay, be non-white, and have no food allergies compared to patients with enteral feeding starting after a diagnosis of EoE. However, there was no difference in patient age, sex, or year in which EoE was diagnosed. Patients requiring initial enteral feeds due to a feeding problem had a delay of 2.2 ± 0.6 years prior to EoE eventually being diagnosed.

Although this is a small retrospective study, it does provide some interesting information to pursue further. For example, the finding that pediatric patients with EoE requiring enteral tube feeds having lower associated Eosinophilic Esophagitis Endoscopic Reference Scores and Endoscopic Severity Scores need further study as such patients may require more intensive feeding therapy and perhaps medical therapy. The delay in EoE diagnosis in patients with enteral feedings already in place suggests that a heightened awareness of the possibility of EoE is needed when evaluating children with feeding problems.

Borinsky S, Cameron B, Xue Z, LaFata S, Kiran A, Ocampo A, McCallen J, Lee C, Redd W, Cotton C, Eluri S, Reed C, Dellon E. Feeding Tube Placement, Complications, and Treatment Responses in a Large Eosinophilic Esophagitis.  J Pediatr Gastroenterol Nutr 2023; 77: 753-759.

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Nutritional Considerations for Hypermobile Ehlers-Danlos Syndrome

May 2024 • Volume XLVIII, Issue 5
Cheryl Iny Harris,Dacre R.T. Knight,Lisa A. Mejia,Laurie Bilyeu

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While the hallmarks of hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum
disorders (HSD) are pain, joint instability, and injuries to soft tissues, most patients with hEDS and
HSD have a myriad of manifestations within the gastrointestinal tract that affect dietary tolerance
and quality of life. These include irritable bowel syndrome, functional dyspepsia, gastroparesis,
constipation, and celiac disease. Other common comorbidities include postural orthostatic tachycardia
syndrome and mast cell activation disorders, which may impact fluid and electrolyte balance, food
intolerances, and contribute to anxiety around food. Nutritional supplements are commonly used,
though research is needed to clarify their potential role in hEDS/HSD management. Patients with hEDS/
HSD benefit from the support of a multidisciplinary healthcare team. This review discusses nutritional
implications and provides practical recommendations to address the manifestations of hEDS/HSD.

Introduction

 Ehlers-Danlos syndromes (EDS) encompass a group of 14 heritable connective tissue disorders.1 The most prevalent form of EDS is hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) with hEDS/HSD appearing to be female-predominant inherited disorders.2 All types of EDS except hEDS/ HSD have identified genetic markers. HSD is also known as joint hypermobility syndrome (JHS), an older term that still appears in research. Key characteristics of hEDS/HSD are pain, fatigue, joint instability, and its consequential injuries to soft tissues.3 Patients with HSD share most of the features of hEDS, with similar symptoms, disease severity, and treatment strategies.3 Clinical features are widespread, affecting neurologic, cardiovascular, gastrointestinal, and urogynaecological systems. 

The largest prevalence study is from Wales, UK, indicating 1:500 (2%) of the general population received a formal diagnosis of hEDS or JHS.4 Both hEDS/HSD are currently underdiagnosed, with diagnosis typically taking 10+ years.5 According to an EDS worldwide survey, 97% of people with EDS report that prior to diagnosis, their healthcare team attributed their symptoms to psychological causes.6 Studies suggest the actual prevalence of hEDS/ HSD is closer to 3% of the general population.4,7 

Management of hEDS/HSD involves relieving symptoms and ensuring sufficient nutrient intake. This review focuses on gastrointestinal (GI) disorders, such as irritable bowel syndrome (IBS), functional dyspepsia (FD), gastroparesis, celiac disease, and other nutrition-related disorders, such as temporomandibular joint (TMJ) dysfunction, eating disorders (EDs), autonomic disorders such as postural orthostatic tachycardia syndrome (POTS) and mast cell activation disorder (MCAD).8 Practical applications will be emphasized (see Table 1). 

Gastrointestinal Manifestations of hEDS/HSD 

Gastrointestinal disorders are among the most common manifestations of hEDS/HSD, with studies reporting ~90% of patients experience symptoms of diseases of gut-brain interaction (DGBIs).8 GI symptoms may include dysphagia, reflux, postprandial fullness, bloating, abdominal pain, nausea, vomiting, diarrhea, and constipation. Patients often attribute symptoms to eating, which can generate food fears and changes in appetite that impact nutritional intake and contribute to disordered eating patterns.8 

Irritable Bowel Syndrome 

Research suggests that up to 62% of people with hEDS/HSD are diagnosed with a subtype of IBS (IBS-diarrhea, IBS-constipation, IBS-mixed, IBS-undefined).9 Using the ROME IV criteria, IBS is characterized by the presence of recurrent abdominal pain one day a week or more for at least 3 months and the presence of at least two symptoms related to defecation, a change in stool frequency and/or form. Visceral hypersensitivity, central sensitization, autonomic dysfunction, mast cell activation, and/or biopsychosocial factors may also contribute to symptoms of IBS. Symptomatic patients often seek nutrition guidance initially; however, organic disease must be ruled out first if there is unintentional weight loss, anemia, elevated inflammatory markers, or signs of a potential GI bleed. 

A first-line approach for IBS management is to implement the NICE (National Institutes for Health and Care Excellence) guidelines, which include:10,11 

eating regular, small meals 

eating slowly 

hydrating adequately 

avoiding excessive caffeine, alcohol, or carbonation 

avoiding more than 3 portions of fruit or juice daily 

avoiding polyols for people with loose stools 

reducing fatty foods 

limiting insoluble high fiber foods 

Research is limited on the efficacy of the NICE guidelines; however, they are often the initial strategy because of the relative ease of implementation. 

If symptoms do not improve, a secondary approach is the low FODMAP diet (LFD) (fermentable oligo, di, monosaccharides, and polyols). The LFD involves a 2–6 week guided elimination diet of osmotically active short-chain carbohydrates, followed by a structured reintroduction phase to learn potential triggers while adding in high FODMAPs, and finally, a personalization phase to maintain intake of FODMAPs that are tolerated well.10,11 Studies show the LFD reduces GI symptoms, such as bloating, abdominal pain, and diarrhea, in 57-82% of people with IBS.10 An LFD should only be undertaken with the guidance of a trained Registered Dietitian Nutritionist (RDN). 

In a study of 165 patients diagnosed with both IBS and JHS, and controls with IBS only, all subjects followed the LFD.12 Patients with JHS had greater decreases in abdominal pain and bloating. The patients who had both JHS and IBS-C showed the largest improvement on an LFD compared to IBS-C controls.12 Further studies are needed to confirm these results and understand the biological mechanism for decreased pain in patients with JHS. 

 

Irritable Bowel Syndrome
Start with the National Institutes for Health and Care Excellence (NICE) guidelines
If the NICE guidelines are not successful in alleviating symptoms, consider the low FODMAP diet with the elimination, reintroduction, and personalization phases
Functional Dyspepsia
Consider a trial limiting fatty or spicy foods, wheat, caffeine, and alcohol
Consider a Mediterranean Diet pattern to reduce intake of animal protein and increase intake of fruits and vegetables
Consider a trial of the low FODMAP diet
Have small meals throughout the day
Eat slowly and chew well
Gastroparesis 
Incorporate a small particle size diet with a focus on blending, mashing, or mincing foods
Adjust fiber intake if necessary
Increase movement after meals if possible
Have small meals throughout the day
Consume foods with fat as tolerated. Fat is sometimes tolerated best in liquid form.
Constipation
Eat two kiwifruit a day
Increase intake of soluble fiber which binds water (e.g., oats, flax) with increased fluid intake
Add foods with natural sorbitol content (e.g., prunes, dried apricots)
For IBS-C, consider a short-term trial of the NICE guidelines or the low FODMAP diet
Celiac Disease
Adopt a lifelong gluten-free diet
Monitor for nutrient deficiencies
Temporomandibular Disorders
Switch to pureed foods or soft textures if needed
Cut food into smaller pieces to ease chewing
Postural Orthostatic Tachycardia Syndrome 
Increase fluid consumption to 2-3 liters daily and increase salt up to 6-10 grams unless contraindicated
Consider a lower glycemic diet if appropriate
Monitor symptoms and tailor specific recommendations based on the patient’s needs
Mast Cell Activation Disorders
An experienced RDN should evaluate a diet journal for potential MC triggers
Consider a low histamine diet elimination and reintroduction if indicated
Table 1. Diet Recommendations for Manifestations of hEDS/HSD

Functional Dyspepsia 

The hallmarks of functional dyspepsia (FD) include decreased appetite, postprandial distress, early satiety, nausea, belching, and epigastric pain.13 Studies found that between 37-86% of patients with hEDS/HSD experience FD symptoms.13 FD often impairs dietary intake. Limited research supports small, frequent, regular meals, eating slowly, and chewing well. There is potential benefit to limiting fatty or spicy foods, wheat, caffeine or alcohol.14 Lower adherence to the Mediterranean diet pattern has been associated with worsening of symptoms in FD, thus there may be utility to adopting the Mediterranean diet, which reduces intake of animal protein and increases intake of fruits and vegetables. Also, implementing the LFD has been shown to reduce symptoms.14 

Gastroparesis 

Common gastroparesis symptoms include changes in appetite, nausea, vomiting, early satiety, and unintentional weight loss. A large case-control study compared hospitalized patients with and without EDS and found patients with EDS exhibited a 12.26 higher odds ratio of a concurrent diagnosis of gastroparesis.15 These results are supported by another study which found 52% of patients with GI symptoms and JHS were diagnosed with gastroparesis.16 Nutrition interventions to manage gastroparesis include smaller meals, modification of fiber intake, and post-prandial 

movement as tolerated to enhance motility. A small particle size diet, or altering food consistency by blending, processing or mashing food may help expand dietary tolerance (e.g., smoothies, mashed potatoes).17 

Constipation 

Constipation is common; a recent study found 73% of patients with hEDS/HSD had constipation versus 16% of controls.3 The underlying etiology of constipation in hEDS/HSD is multifactorial and includes DGBIs, delayed motility, small intestinal methane overgrowth, pelvic floor dyssynergia, medication induced constipation, and rectal hyposensitivity.8,18 Treatment should be individualized, and dietary adjustments may include eating two kiwifruit daily, gradually increasing higher fiber foods, like oats, prunes, or flaxseed, or adding soluble fiber supplements, such as psyllium husk or partially hydrolyzed guar gum.11,19 Excess fiber intake can potentially aggravate constipation, especially without concurrent adequate water intake. Patients with comorbid rectal hyposensitivity may benefit from biofeedback, which has been studied in hEDS/ HSD.18 

Celiac Disease 

One small study found that 16% of people with hEDS/HSD also had celiac disease.8 A large case control study determined the rate of celiac disease was 5.5 times higher in people with EDS than the average hospitalized patient.15 Swedish patients with EDS/JHS had an odds ratio of 2.3 of a subsequent celiac diagnosis.20 A study in children with joint hypermobility (excessively lax joints, without associated pathology) found an odds ratio of 10.9% for positive celiac serology.21 Further studies are needed; however, celiac testing is prudent for patients with symptoms or a family history. 

People diagnosed with celiac disease need to follow a lifelong, strict gluten-free diet and benefit from consultation with an RDN. Newly diagnosed patients tend to be low in vitamins A, D, E, B12, copper, zinc, folate, and iron, and anyone following a gluten-free diet may be deficient in B vitamins, folate, iron, and calcium due to lack of enrichment and fortification of gluten-free products.22 Nutrient levels should be monitored, with diet modifications and/or supplementation as indicated. 

Other Nutrition-Related Manifestations of hEDS/HSD 

A range of conditions, including TMJ, POTS, MCAD, and EDs, are frequently found in people with hEDS/HSD. These conditions contribute to the patient’s symptom burden and add an additional layer of complexity to eating. 

Temporomandibular Joint Disorders 

While the literature is limited, 40-100% of people with EDS report headache and jaw pain.23 A recent case-control study found that TMJ symptoms, including myofascial pain, headache, jaw pain, and disc displacement occurred more in people with hEDS than controls.23 Dislocations or subluxations may make chewing difficult and compromise nutritional status. Pain with oral care may exacerbate dental problems. Patients with TMJ and hEDS/HSD should be referred to an RDN to ensure adequate oral intake and appropriate food consistencies, and to knowledgeable dentists and physical therapists (PTs) as needed. 

Postural Orthostatic Tachycardia Syndrome 

POTS is a form of dysautonomia affecting approximately 30% of people with hEDS/HSD.7 It is characterized by an increase in heart rate of 30 beats per minute (bpm) in adults (40 bpm for adolescents) in the first 10 minutes when moving from a recumbent to a standing position. Patients must have symptoms of orthostatic intolerance, such as palpitations, concentration difficulties, abnormal fatigue, presyncope, or headache for 3 or more months without another explanation.24 

Nutrition changes are the cornerstones of treatment for POTS, although medication is often needed. POTS involves hypovolemia; treatment expands blood volume via increased fluids, salt, exercise, and decreased fluid pooling with compression garments.24 Over 90% of people with POTS experience GI symptoms. Most symptoms improve when sitting or recumbent; bloating, constipation and diarrhea generally do not.7,25 People with concurrent hEDS/HSD and POTS may experience a higher burden of GI symptoms compared to those with hEDS/HSD without POTS.25 

Recommendations should be tailored based on physician guidance and co-morbid illnesses, such as cardiac diseases.26,27 Unless contraindicated, the initial recommendations are 6 grams of salt and 2-3 liters of fluid.27 Patients can gradually increase salt intake up to 10 grams, with close monitoring of symptoms, and adjustments based on clinical response.24 Alcohol, caffeine, and dehydration typically worsen symptoms.26 

Two small studies investigated dietary interventions in people with POTS. In one study, 20 females with POTS (8 also had hEDS) experienced significant improvements in orthostatic and GI symptoms with a 4-week, self-reported gluten-free diet.28 Another case-control study examined 12 women with POTS who had a history of orthostatic symptoms with high glycemic foods; information on comorbid conditions such as hEDS/HSD was not provided. The study participants experienced a significant increase in tachycardia after consuming 75 grams of glucose, compared to the 13 controls.29 This preliminary research suggests a gluten-free and/or a low glycemic diet deserve further study. They may be worth exploring for motivated patients who have been screened for celiac disease and are not at risk of an ED. 

Mast Cell Activation Disorders 

Mast cells (MCs) are white blood cells found in the mucosa and throughout connective tissue and skin. MC diseases include clonal diseases, which are rare and associated with genetic mutations, and non-clonal MCADs, which include mast cell activation syndrome (MCAS).30 Typically, MCs respond to pathogens; however, in MCADs, MCs may respond to benign stimuli, such as temperature, food, chemicals, medications, physical exertion, stress, etc. and degranulate, causing an inflammatory cascade by releasing histamine, heparin, prostaglandins, and other mediators. MCAD symptoms affect multiple organ systems: gastrointestinal, neurologic, cardiovascular, dermatologic, and respiratory. Symptoms range from mild to anaphylaxis.30 

Ehlers-Danlos Syndromes 
Ehlers-Danlos Society: ehlers-danlos.com 
Ehlers-Danlos Syndrome (EDS) GP Toolkit: gptoolkit.ehlers-danlos.org 
Ehlers-Danlos Support UK: ehlers-danlos.org 
Hypermobility Syndrome Association (HMSA): hypermobility.org 
SEDS Connective: sedsconnective.org 
hEDS/HSD Diagnostic Checklist: ehlers-danlos.com/heds-diagnostic-checklist 
EDS Diet & Nutrition: ehlers-danlos.com/international-consortium-working-groups 

Physical Therapy 
Clarkson University Technologia/Leslie Russek PT, DPT, PhD: webspace.clarkson.edu/~lrussek/research.html 
Jeannie di Bon, PT: youtube.com/c/JeannieDiBonHypermobility 

Other 
Dysautonomia International: dysautonomiainternational.org 
The Mast Cell Disease Society: tmsforacure.org

The only well-researched treatment for MCADs is avoidance of known MC triggers, especially in the case of anaphylaxis, and MC stabilizing medications, such as cromolyn sodium, ketotifen, or histamine blocking medications.30 

Controversy exists over diagnostic algorithms for MCADs; however, overall, studies estimate a 24-31% overlap between MCADs and hEDS.31 MCADs have potential nutritional implications, including risks for bone loss and food restriction. A low histamine diet (LHD) is commonly 

recommended, despite a lack of research.32 Aged and fermented foods are higher in histamine, but there is no universally accepted list of low histamine foods, and no experimental studies examining the clinical impact of an LHD in people with MCAD. One survey of self-reported experiences on an undefined LHD had 51.1% reporting improvement, 19.1% reporting no change and 29.8% of people who were unsure.33 An experienced RDN should work with patients to identify patterns of foods triggering MC reactions, and advocate for the widest range of foods tolerated.34 

Eating Disorders 

Patients with GI disorders are at increased risk for developing ED and patterns of disordered eating. There is a bi-directional relationship where GI symptoms can lead to food restriction and restriction exacerbates GI symptoms. Avoidant-restrictive food intake disorder (ARFID) is an ED unrelated to weight involving fear of symptoms from eating, such as choking, pain, or nausea.35 In a 2023 study, 37.9% of people with hEDS/HSD had a positive ARFID screen using the Nine Item Avoidant/Restrictive Food Intake Disorder Screen (NIAS).36 A positive screen was associated with changing diets, skipping meals, eliminating foods, and seeking or receiving nutritional support, such as enteral feeding.36 

Patients should be screened to identify an ED, although the NIAS has not been validated for people with GI disorders.37 An experienced ED specialist can discern the difference between necessary vigilance due to pain, disease management or disordered eating. A multi-disciplinary approach is necessary, including an RDN, psychological support, and medical interventions when appropriate. 

Supplement Use in hEDS/HSD 

Supplements are widely used; however, research on utility for hEDS/HSD is lacking. Supplements should be discussed with patients reporting use or expressing interest. There are currently no evidence-based recommendations for dietary supplementation to treat hEDS/HSD, nor supplements that will benefit all patients. Supplementation regimens should be based on nutrition assessments of individual patients. Research specific to hEDS/ HSD is needed, particularly on the supplements mentioned below. 

Antioxidants 

Mantle et al. proposed a 12-nutrient and antioxidant protocol intended to address various forms of EDS in 2004.38 No trials have been published on this. Three studies explored supplement use, and 61- 81% of patients with hEDS/HSD report taking supplements.36,39,40 Patients frequently reported using vitamins C, D and magnesium in all studies and B vitamins and multivitamins in two studies.39,40 

Collagen 

Abnormal synthesis and processing of collagen proteins and the extracellular matrix (ECM) are recognized in EDS, with some of the specific proteins and genetic variants identified.41 The collagen or ECM variants associated with hEDS/ HSD have not yet been identified.2 Collagen synthesis always requires adequate dietary intake of amino acids and cofactors. However, no data suggests excess collagen from any source or type provides additional benefit for hEDS/HSD. 

Folate 

A recent review postulates that hEDS/HSD might be due to a common polymorphism known as a methylenetetrahydrofolate reductase (MTHFR) deficiency that prevents the proper usage of vitamin B9, or folate. The solution would be providing the supplemental 5-methyltetrahydrofolate and/ or decreasing folic acid supplementation.42 The authors allude to trials of folate supplementation in patients with hEDS/HSD but did not share the number of patients, the dose used, or if they confirmed that those patients had MTHFR mutations, or the wider context of interactions with the methionine cycle. There are no published trials in patients with hEDS/HSD. Further research is warranted, and more information is needed before practice guidelines can be developed. 

CONCLUSION 

Patients with hEDS/HSD experience a wide range of manifestations that impact nutrient intake, digestion, and food tolerance and will benefit from specialized nutrition guidance and having access to resources (See Table 2). Common comorbidities, such as DGBIs, other GI disorders, EDs, MCAD, and POTS add additional layers of complexity. Each patient with hEDS/HSD will need a plan tailored to their individual circumstances. Supplement usage is common, and clinicians should query about usage and evaluate its appropriateness. Clinicians should anticipate that patients will benefit from coordinated support from a multi-disciplinary team including RDNs. 

References

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tachycardia syndrome. Neurogastroenterol Motil.

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The Basics of Liver Transplantation for the Primary Care Provider and the General Gastroenterologist 

May 2024 • Volume XLVIII, Issue 5
Phoenix Fung,Michael Babich

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Liver transplant remains a well-established treatment that can drastically improve the survival and quality of life for patients with end-stage liver disease and certain hepatic malignancies. It is crucial for the primary care provider (PCP) and/or general gastroenterologist to understand the basics of liver transplantation as they play an important role in the management of patients with liver disease. Timely identification and referral to a transplant center is key. We are providing the PCP with an overview of liver transplantation indications, evaluation process, and management factors to consider prior to transplant. We want to highlight the importance of identification of potential liver transplant candidates who may benefit from early referral as well as provide information on evolving trends and advances in the liver transplant process. By raising liver transplantation knowledge, we can improve patient outcomes, facilitate timely referral, and ensure comprehensive care for patients throughout the transplantation process.

Introduction 

Despite the advances in the management of chronic liver disease, liver transplantation remains a definitive life sustaining treatment for patients with severe acute or advanced chronic liver disease despite best medical therapy. It is important for the provider to be aware of the basics of the liver transplant process as they are often the gatekeepers to help screen patients requiring referral for liver transplantation. The process of liver transplantation is often both complex and multifaceted requiring a multidisciplinary approach between multiple healthcare professionals, including the PCP. This article aims to educate providers who treat patients with liver disease with an overview of the indications for liver transplantation, the evaluation process, and the pre-transplant management of patients during the waiting list period. Learning the principles of liver transplantation and management of patients with chronic liver disease can facilitate improved outcomes of patients. In addition, this paper serves to provide basic clinical updates within the last decade on liver transplantation for practitioners who manage cirrhosis. 

Liver Transplant Statistics

The first successful human liver transplant was performed in 1963 by Dr. Thomas Starzl. Since then, over 200,000 liver transplants have been performed in the United States (US) in the past 35 years. According to the Organ Procurement and Transplantation Network (OPTN), the liver is the second most transplanted organ. Between 2019-2022, the average number of liver transplants per year in the US was between 7,000-8,000 for deceased donors and 400-500 for living donors. Despite the COVID-19 pandemic, 8,906 liver transplants were performed in the United States in 2020, which was more than in any previous year.1 The average wait time for liver transplant can range widely, from a few days to up to 5 years depending on the urgency. As of April 2023, there were approximately 10,000 patients listed for liver transplant. Liver transplant recipients had a five-year survival rate of >70%, compared to 15% for patients receiving medical therapy alone, emphasizing the life-saving impact of transplantation.2

Chronic non cholestatic liver disorders
Chronic hepatitis C
Chronic hepatitis B
Autoimmune hepatitis
Alcohol-related liver disease
Cholestatic liver disorders
Primary biliary cirrhosis
Primary sclerosing cholangitis
Biliary atresia
Alagille syndrome
Nonsyndromic paucity
  of the intrahepatic bile ducts
Cystic fibrosis
Progressive familial intrahepatic cholestasis
Metabolic disorders causing cirrhosis
Alpha-1-antitrypsin deficiency
Wilson disease
Nonalcoholic steatohepatitis
  and cryptogenic cirrhosis
Hereditary hemochromatosis
Tyrosinemia
Glycogen storage disease type IV
Neonatal hemochromatosis
Metabolic disorders causing severe
  extrahepatic morbidity
Familial amyloid polyneuropathy
Primary Hyperoxaluria
Urea cycle defects
Disorders of branched chain amino acids
Hepatocellular carcinoma
Hepatoblastoma
Fibrolamellar hepatocellular carcinoma
Hemangioendothelioma
Fulminant hepatic failure
Budd-Chiari syndrome
Metastatic neuroendocrine tumors
Polycystic disease
Retransplantation

Alcohol associated liver disease was the leading indication for transplant in 2020. Other common categories for adult liver transplantation are hepatitis C virus infection, hepatocellular carcinoma (HCC), acute liver failure, and non-alcoholic steatohepatitis (NASH) according to the 2019 OPTN.3

Research has revealed disparities in liver transplant access and outcomes based on ethnicity. A study published in the American Journal of Transplantation found that Hispanic and African American patients faced a higher risk of waitlist mortality and lower chances of receiving a liver transplant compared to Caucasian patients.4 A significant gender disparity also exists in the donor pool. In the United States, approximately 62% of deceased liver donors are male, while only 38% are female. 

Timing of Referral for Liver Transplant Evaluation

Who is a Candidate for Liver Transplantation?

Patients with severe acute or advanced chronic liver disease for which medical therapy has reached maximization should be evaluated for liver transplantation.5 The main population that the PCP should focus on referring for liver transplantation are patients with decompensated cirrhosis, cirrhotic patients with MELD (Model for End Stage Liver Disease) score ≥ 15, and patients with significant quality of life issues secondary to their end stage liver disease. Hepatic decompensation develops due to progressive portal hypertension from cirrhosis, with varying presentations, such as hepatic encephalopathy, ascites, variceal bleeding, spontaneous bacterial peritonitis, hepatorenal syndrome, hepatic hydrothorax, hepatopulmonary syndrome, and portopulmonary hypertension. Patients who develop hepatic decompensation in the form of variceal bleeding, hepatic encephalopathy, or ascites have significantly reduced survival compared to cirrhotic patients who are well-compensated. The median survival of persons with compensated cirrhosis is 9-12 years compared to 2 years in persons with decompensated forms of liver disease. In a patient with compensated cirrhosis, the rate of decompensation is 5-7% per year.6 Providers should be screening for hepatic decompensations in a routine and systematic fashion. 

The PCP should be aware of the definition of fulminant or acute liver failure and recognize the need for expedited inpatient evaluation in a liver transplantation center. Fulminant liver failure is the rapid hepatic deterioration with development of hepatic encephalopathy and coagulopathy in patients who do not have underlying liver disease. If the adult patient has fulminant liver failure, and anticipated life expectancy of less than 7 days without liver transplant, in an intensive care unit, and acute onset of hepatic encephalopathy with one of the following criteria: (1) ventilator dependence (2) required dialysis or (3) INR >2, then the patient qualifies for Status 1A. When listed as Status 1A, the OPTN prioritizes the search for first available liver donors by expanding the criteria from regional to national. For the purposes of this paper, we would like to focus on recognition of indications for liver transplant referral for patients with chronic liver disease in the outpatient setting.

There are clinical considerations to help determine successful liver transplant candidacy. Oftentimes, the patient has to be sick enough, where transplant would increase survival odds, but not too ill where they would not be expected to survive the operation and the immediate postoperative period. Patients must be able to demonstrate the insight and willingness to comply with a complex medical regimen required post-transplantation, particularly the need to take chronic immunosuppressive medications to prevent allograft rejection and prophylactic antibiotics/antivirals to prevent infection. Patients cannot have other severe comorbid conditions that could potentially compromise the graft or patient survival. These evaluations will occur in the transplant center through a comprehensive multidisciplinary team approach. 

Understanding the Basics

Classification of Liver Disease Severity

The Child-Turcotte-Pugh Score and the MELD-3.0 scoring system help classify the liver disease severity and need for liver transplantation evaluation. The Child-Turcotte classification system was developed in 1964 to risk-stratify patients undergoing shunt surgery for portal hypertensive decompression. In 1972, Pugh modified the Child-Turcotte system, and it became known as the Child-Turcotte-Pugh (CTP) score. Components of the CTP score include the serum total bilirubin, serum albumin, INR, presence/quantity of ascites, and presence/grade of encephalopathy. CTP score has been shown to accurately predict surgical outcomes in patients with cirrhosis and portal hypertension. In addition, clinicians have widely used this tool to assess the risk of short-term mortality in cirrhotic patients. Overall, the 30-day post operative mortality following abdominal surgery of a cirrhotic patient with CTP score A is 10%, CTP score B is 30% and CTP score C is 76–82%. One year survival is 45% in CTP score C, compared to 95% and 80% in CTP score A and CTP score B, respectively.7 Patients with CTP-C scores are the sickest, and special attention should be focused on this group. 

Model of End Stage Liver Disease (MELD) Score is another prognostic scoring system which estimates the survival probability of a patient with end-stage liver disease. It is calculated using the serum bilirubin, serum creatinine, and INR. United Network for Organ Sharing (UNOS) manages the United States transplant allocation system and uses the MELD score for organ recipient priority. In 2002, the MELD score was adopted by UNOS for deceased liver organ allocation. The MELD scores range from 6 to 40, which correspond to 3-month survival odds of 90% and 7%, respectively. In January 2016, the MELD score was further modified to incorporate serum sodium to create the MELD-Na equation as hyponatremia in cirrhosis is a marker of increased liver transplant waitlist mortality.8 Further adaptations of the MELD score have been utilized to reduce wait time death of patients on the transplant list and make listing more equitable. In July 2023, the MELD 3.0 score was implemented to reduce liver transplant wait list mortality by accounting for female sex, serum albumin, and a lowered serum creatinine cut-off from 4.0 mg/dL to 3.0 mg/dL. The new scoring system addresses the disparity that females have had consistently lower transplant rates historically.9

The PCP should use prognostic score systems of CTP score and MELD-3.0 score to risk stratify cirrhotic patients. Patients with decompensated cirrhosis or MELD-3.0 ≥ 15 are recommended to be referred to a liver transplant center for evaluation due to their high risk of morbidity and mortality. 

Indications for Liver Transplant Evaluation

Liver transplantation can restore quality of life and prolong patient survival. Progressive advancements in care of liver transplant patients show favorable short and long term outcomes. Graft survival is 91.2% at 1 year, 76.5% at 5 years, and 56.4% at 10 years.10 The main indications for liver transplantation are decompensated liver disease, acute liver failure, primary unresectable hepatic malignancy, inherited metabolic liver disease, and retransplantation. Chart 1 provides an inclusive list of indications for liver transplantation. 

The Evolving Liver Transplantation Population

The most recent American Association of the Study of Liver Disease (AASLD) Guidelines has modified nomenclature to change “alcoholic” to “alcohol-associated” cirrhosis to help reduce the stigma associated with the disease faced by patients and family members.11 Alcohol-associated liver disease is the most common indication for liver transplant in the United States at present. Alcohol-associated liver disease has surpassed hepatitis C as the leading indication for liver transplant in the United States in the last several years. Since the introduction of well tolerated direct acting antivirals with substantial rates of hepatitis C eradication, there is a reduction in the need for liver transplantation and development of hepatocellular carcinoma in this subset of patients.12

Alcohol-associated liver disease and metabolic dysfunction-associated steatohepatitis (MASH), previously referred to as non-alcoholic steatohepatitis (NASH) are projected to be the leading indications for liver transplantation in the near-future.13 Obesity and metabolic syndrome are risk factors for development of metabolic dysfunction associated liver disease (MASLD), which can progress to MASH and cirrhosis. The rate of obesity has doubled in the last 30 years worldwide, with the growth rate within the United States being one of the highest. Patients added to the transplant wait list with NASH as an indication increased by 170% between 2004 and 2013.14 It is predicted that MASH will be the leading indication for liver transplant in the U.S. over the next 10 to 20 years.15 Up to 25% of patients with MASH will progress to cirrhosis with increased risk of hepatocellular carcinoma development, therefore early diagnosis and management may curb the need for liver transplantation. Patients with MASH-induced cirrhosis can be a challenging population to manage due to comorbid conditions such as severe cardiovascular disease, which can preclude transplantability. Metabolic clinics for weight loss and early referral for bariatric surgery may be an option to help reduce MASLD-associated fibrosis but is not recommended in decompensated liver disease. Potential pharmacologic treatments for MASH are being studied. Resmetirom, an oral liver-directed thyroid hormone receptor beta–selective agonist, has been recently FDA approved for patients with stage 2-3 fibrosis secondary to MASH, which has been shown to be helpful in hepatic fibrosis regression.16

Alcohol-induced hepatitis is one of the most severe manifestations of alcohol-associated liver disease, with high morbidity and mortality. Liver transplantation may be considered as a last option for patients with alcohol-induced hepatitis when medical treatment has failed or is contraindicated. Many liver transplant centers require six months of alcohol abstinence prior to evaluation for liver transplantation. Due to the risk of significant morbidity and mortality without transplantation during that 6-month period, predictors have been studied in the US and Europe to identify a subset of patients with low risk of recidivism. Select patients with severe alcohol-induced hepatitis who fail to respond to medical therapy should be considered for liver transplant.17 The most favorable factors associated with low risk of recidivism include: alcohol induced hepatitis as initial hepatic decompensating event, good social support, insight to severity of disease, absence of severe psychiatric disorders, recent life stressor, prolonged duration of abstinence prior to transplantation, stable employment, and a covenant to adhere to life-long alcohol abstinence.18 Although there are similar favorable one and three years survival outcomes in patients transplanted for alcohol induced hepatitis compared to other indications for liver transplant, the cumulative incidence of persistent alcohol use post-transplant was 10% in the first year and 17% by the third year, with increasing alcohol use associated with increased mortality over time, based on recent studies.19 Further longitudinal studies need to be performed to elucidate the generalizability of these outcomes. 

MELD Exception Points

OPTN prioritizes organ allocation based on medical necessity using the MELD-3.0 score, with higher scores given higher priority access to the donated organs. MELD exception points are granted in certain liver diseases when the severity of the liver disease is not reflected by the calculated MELD score. Typically, the morbidity and mortality is higher in this population subset and the patient is “sicker than the MELD” score. These indications include hepatocellular carcinoma, hilar cholangiocarcinoma, primary hyperoxaluria, metabolic disorders of the urea cycle, hepatopulmonary syndrome, portopulmonary hypertension, cystic fibrosis, and familial amyloid polyneuropathy. If the patient meets specific inclusion criteria, they are OPTN waitlisted with a MELD score equivalent to the median MELD at transplant within the surrounding transplant centers minus 3 points (MMaT-3). The median MELD is calculated from within 150 nautical miles surrounding each donor hospital in the country and is applied to the exception point score for any transplant candidate receiving liver offers from that donor hospital. Patients with primary hyperoxaluria and metabolic diseases, such as urea cycle disorders or organic acidemia, meeting criteria receive MELD exception equivalent to the MMaT.20,21

Hepatocellular Carcinoma

Hepatocellular carcinoma in a cirrhotic patient is an important indication for liver transplant. A landmark trial by Mazzaferro showed a 4-year post-liver transplant survival benefit of 75% with recurrence-free survival of 83% when the liver cancer was confined to the “Milan criteria”.22  Hepatocellular carcinoma within “Milan criteria” includes one lesion ≤ 5 cm, or three lesions < 3 cm without metastasis. Hepatocellular carcinoma is diagnosed based on cross sectional CT or MRI with confirmation of tumor dimensions by a radiologist in an OPTN approved transplant center. These patients are eligible for MELD exception points if they meet criteria. HCC can be treated with locoregional therapy while awaiting transplantation. Hepatocellular carcinoma that is beyond the Milan criteria limits can be attempted to be down-staged by loco-regional treatment so as to be brought within Milan criteria, and then can be reconsidered for transplantation without sacrificing post-transplant survival.23

Cholangiocarcinoma

Cholangiocarcinoma is a bile duct cancer with increased risk of development in patients with underlying primary sclerosing cholangitis (PSC). In general, intrahepatic cholangiocarcinoma is a relative contraindication to liver transplant due to the aggressive nature of the malignancy with poor post-transplant survival. For patients undergoing curative surgical resection, there are high rates of recurrence up to 60-70%. Five-year survival for patients with resectable disease is 20-40%.24 Patients with hilar cholangiocarcinoma are likely not candidates for resection due to the anatomical location of tumor being in the area of the hepatic duct and its bifurcation. The Mayo Clinic has created a highly selective protocol using neoadjuvant chemotherapy prior to liver transplant for early stage unresectable, non-metastatic perihilar cholangiocarcinoma. The five-year survival after liver transplant is 73%, based on their protocol.25 For consideration of liver transplant for perihilar cholangiocarcinoma, UNOS requires the transplant institution to have an approved written treatment protocol, and grants MELD exception points if the patient is suitable. 

HRS – New Nomenclature

Hepatorenal syndrome (HRS) is defined as renal failure in a person with cirrhosis in the absence of intrinsic renal disease. Previous nomenclature of Type 1 HRS is now termed HRS-acute kidney injury (HRS-AKI). Patients with HRS-AKI have a rapid deterioration in renal function with very high morbidity and mortality. AKI is defined as an increase in serum creatinine ≥ 0.3 mg/dL from baseline within 48 hours or a ≥ 50% increase in serum creatinine within the last 7 days.26 After ruling out intrinsic renal disease and post-renal obstruction as a cause, and after failing to improve with 48 hours of intravascular volume repletion, this entity would be considered HRS-AKI. Patients with HRS-AKI should have an expedited referral for liver transplantation. HRS-AKI is usually reversible after liver transplantation. HRS Type 2, now termed HRS-chronic kidney disease (HRS-CKD), is a more gradual impairment in renal function that is less severe than type 1 HRS and is seen typically in patients with refractory ascites, which are resistant to diuretics. The definition of HRS-CKD requires the patient to meet HRS criteria and have eGFR < 60 ml/min per 1.73 m2 for ≥ 3 months, in absence of other structural causes. Select patients with chronic kidney disease and liver disease should be considered for combined liver-kidney transplantation. 

Contraindications for Liver Transplantation

An important concept of liver transplantation is to recognize contraindications to liver transplantation. Universal absolute contraindications include severe cardiopulmonary disease, active extrahepatic malignancy, metastatic hepatocellular carcinoma, uncontrolled sepsis, brain death, AIDS, active alcohol or illicit substance abuse, persistent noncompliance or lack of social support, and anastomotic barriers to liver transplantation.27 Many transplant centers require a minimum alcohol abstinence of 6 months with substance dependence program attendance. Literature suggests the risk of recidivism is lower in patients who complete at least 6 months of sobriety compared to those with shorter periods.28 The recommendation remains controversial, as other studies suggest the length of pre-transplantation abstinence is a relatively poor predictor of post-transplantation abstinence.29 An exception to the “six-month rule” may be considered when patients are being transplanted for alcohol-induced hepatitis in a center with a protocol for this situation. Conversely, hepatic function may improve with alcohol abstinence in patients with alcohol-induced cirrhosis to the extent a transplant is less urgent.30

Relative Contraindications

Physiologic, not chronologic, age should be considered in a patient undergoing liver transplant evaluation. There has been an increasing median age of patients being evaluated and waitlisted for transplantation. Registrants for UNOS liver transplant waitlist aged ≥ 65 years increased from 8% in 2002 to 17% in 2014.31 Post transplant survival for patients over age 65, compared to younger cohorts, was overall lower in earlier studies.32,33 More recent studies do not indicate higher rates of mortality or lower graft survival in young compared to elderly liver recipients in early transplant outcomes, however increased malignancy rates are seen in older patients.34

It is also feasible that being transplanted at an older age is associated with increased morbidity and mortality due to natural shorter life expectancy in older patients. A detailed evaluation to assess for functional and nutritional status, as well as medical comorbidities including cardiopulmonary status and malignancy, is highly recommended. In the absence of significant comorbidities, age > 70 years is not a contraindication for liver transplant.

Patients will need curative treatment for isolated primary extrahepatic malignancy with oncologic clearance prior to liver transplant. Typically, there is a waiting period to ensure absence of tumor recurrence after definitive treatment prior to transplant listing. There is heightened concern for risk of tumor recurrence for patients with prior malignancy who are on long-standing immunosuppression after transplant. The Israel Penn database is a collection of patients who developed malignancy after organ transplants. Based on the Israel Penn data, malignancies which have a low risk of recurrence are incidental renal tumors, lymphoma, testicular, cervical, and thyroid cancers. Malignancies with intermediate risk of recurrence are uterine, Wilms’ tumor, colon cancer, prostate, and breast cancer. Tumors associated with a high risk of recurrence include bladder cancer, sarcoma, melanoma, symptomatic renal cancer, and myelomas.35 A judicious individualized, multidisciplinary approach by the transplant team is used to decide on optimal candidates and timing of listing. 

Although AIDS is a contraindication for transplant, HIV patients are eligible for transplantation in the presence of adequate immune function with CD4 >100/µL with undetectable viral load at the time of liver transplant. Co-management with an infectious disease specialist is recommended.5

Class III obesity (body mass index (BMI) ≥ 40) is a relative transplant contraindication. It is associated with coronary artery disease, hyperlipidemia, diabetes mellitus, renal dysfunction, and obstructive sleep apnea.5 Obesity increases the risk of perioperative complications and length of post-operative hospital stay and reduces long term survival. Primary graft non function, immediate, 1-year, and 2-year mortality were significantly higher in the morbidly obese group. Five-year mortality was significantly higher both in the severely and morbidly obese subjects, mostly due to cardiovascular events.36 Weight loss is recommended prior to transplant in patients with class III obesity. While patients with severe obesity and/or metabolic-associated fatty liver disease can be considered for bariatric surgery, this is contraindicated in decompensated liver disease due to risk of worsening hepatic dysfunction with surgery. Studies investigating the performance of gastric sleeve placement simultaneously with liver transplant, to assist with weight management, demonstrate safety and may be helpful in long term total body weight loss.37

Patients with severe ascites can be seen as “overweight”, but this should not be confused for obesity as oftentimes that patient has co-existing anasarca and sarcopenia.  The presence of ascites is associated with an increased risk of postoperative morbidity and mortality post-transplant. A study performed by Leonard et al. showed that correction of BMI for ascites volume placed 11-20% of the studied patients who received a liver transplant into a lower BMI classification. It was calculated that each liter of ascites removed during the transplant was associated with a 7% increased relative risk of mortality.38 Special care should be utilized to prevent further malnutrition, as patients with ascites will still require high protein diets as cirrhosis is a catabolic state. 

Underweight patients also pose a concern, as patients at both extremes of BMI have significantly higher wait list mortality and worse liver transplant outcomes as compared with those with normal BMI (18.5 to <25). Underweight patients (BMI < 18.5) have higher risk of hemorrhagic complications and cerebrovascular events. Overweight patients (BMI > 40) have a higher risk of infectious complications and cancer events. Given this disparity, innovative means are required to target high risk groups.39 A comprehensive nutrition assessment and dietary management should be utilized in patients who are at extremes of BMI to help minimize complications. 

Understanding the General
Liver Transplant Evaluation Process 

Patients should be referred to a liver transplant center if there is decompensated liver disease or MELD-3.0  ≥ 15. The PCP should be familiar with their local transplant centers. Oftentimes, there will be local outreach clinics if the nearest center is distant. The patient should understand that a referral does not mean they will be automatically listed for a liver transplant. Generally, the multidisciplinary transplant team consists of the transplant hepatologist and surgeon, nurse coordinator, financial coordinator, social worker, psychiatrist, dietician, physical therapist, anesthesiologist, and pharmacist, all of whom will interact with the patient. During the initial evaluation, the transplant process will be discussed with the patient, and individual evaluations performed. The patient’s motivation and insight to comply with medication therapy and long term follow up, social support, functional and nutritional status, and substance abstinence duration are assessed. The hepatologist ensures medical management has been maximized and appropriate treatments are up to date. The transplant surgeon evaluates surgical contraindications for liver transplant, as well as suitability for living donor evaluation if applicable.  Standard blood tests, including blood type, screening for liver disease, and determining the infection status of HBV, HCV, EBV, CMV, VZV, RPR, and HIV are performed. Status of tuberculosis exposure is typically performed with interferon-gamma release assay (i.e., Quantiferon gold) or tuberculin skin testing. Cardiopulmonary testing may include echocardiogram, cardiac stress test, heart catheterization as needed, and pulmonary function testing. These are used to screen for significant valvular disease, heart failure, coronary artery disease, significant respiratory diseases, hepatopulmonary syndrome, and portopulmonary hypertension. Testing is based on individualized risk. Cross sectional abdominal imaging with CT or MRI are performed to rule out intra- and extra-hepatic malignancy, especially hepatocellular carcinoma, and anatomic contraindications. Standard preventative care measurements such as age- and indication-appropriate malignancy screening with mammogram, colonoscopy, low dose contrast CT chest, and pap smear are reviewed. Screening for osteoporosis with DEXA scan and vitamin D levels are incorporated into the process. Dental exam should be completed to assess for necessary extractions prior to transplant. After an extensive evaluation is completed and the patient/family comprehends the aspects of the transplant process, the multidisciplinary team discusses whether the patient should be waitlisted for organ transplant. 

Understanding Liver Donation

Deceased Donor vs. Living Donor 

Transplanted livers may be received from a living or a deceased donor. Almost 20% of patients on the US waiting list die or become too sick for the transplant. Deceased liver donation remains the primary source of organs for liver transplantation. However, the scarcity of deceased donor organs has led to the utilization of living donors to expand the donor pool to provide timely transplants for recipients. Deceased liver donors are typically individuals who have experienced irreversible brain damage or cardiac arrest and are declared legally brain dead. These donors are often individuals who have registered as organ donors or have consented to donation through their families. The process involves meticulous matching of the donor liver with a suitable recipient based on factors such as blood type, body size, and urgency of need. Organs from deceased donors are carefully preserved and transported to the recipient’s transplant center. 

Living donor liver transplantation (LDLT) occurs when an individual readily volunteers to donate a portion of their liver to someone in need. This is possible because of the liver’s incredible ability to regenerate. Candidates being considered for living donor transplantation will need to meet evaluation criteria set forth by the transplant center. The decision to accept a liver donor is determined by a multidisciplinary team in a transplant center.

Along with the assignment of an Independent Living Donor Advocate (ILDA) by the recovery hospital, the evaluation and selection of an adult liver donor involves a comprehensive assessment of their medical and psychosocial health status to determine eligibility. The ILDA, either an individual or a team, must be qualified and understand the full transplant protocol of the recovery hospital, function independently of the recipient’s team, advocate for the donor, and ensure that the donor has received all information required to make an informed decision. The living donor must undergo psychosocial testing with a team of psychiatrists and psychologists prior to organ recovery to ensure that there are no detrimental psychosocial issues (including high risk behaviors, mental health issues, substance use disorders, etc.) that precludes organ donation or would affect long term recovery. This team also must determine that the donor is free of coercion, can make informed decisions, and understands the long and short term psychological and medical risks.40 Advantages of living donor liver transplantation (LDLT) include reduced wait time for the recipient, use of a graft with minimal ischemic time, and sufficient time to plan for an elective surgery. The evaluation process is otherwise similar to deceased donor.41

Surgical techniques for living donor liver transplantation involve the partial resection of the donor’s liver, either the right or left lobe, which can regenerate to near-normal size and function in both the donor and recipient within a few months. With regards to outcomes, graft failure occurs in 5.9% (6 months), 7.9% (1 year), 14.7% (3 year), 20.7% (5 year), and 40.6% (10 year) of deceased donor recipients. There is a slightly lower graft failure rate for living donor recipients: 4.9% (6 months), 7.4% (1 year), 12.2% (3 year), 23.7% (5 year), and 36.7% (10 year). It is notable that overall recipient mortality has continued to improve over the last decade.42

Given the current allocation policies in the United States, patients with MELD scores <15 on the waiting list rarely receive a liver in a timely fashion. Patients with low MELD scores must rely on either living donors or expanded-criteria deceased donors if they are to receive a transplant. In the landmark Adult-to-Adult Living Donor Liver Transplantation Cohort (A2ALL) study, the survival benefit of an LDLT was demonstrated at MELD-Na scores less than 15.43

An ideal patient for LDLT would be one with a low MELD score but decreased quality of life due to underlying end stage liver disease. Life altering manifestations from end stage liver disease, such as refractory hepatic encephalopathy, ascites/hepatic hydrothorax, sexual dysfunction, sarcopenia, and pruritus can occur, and are not reflected in the MELD 3.0 score. A study performed in the United States by Jackson et al. showed significant survival benefit of LDLT in patients with end-stage liver disease, even at MELD-Na scores as low as 11. For patients with low MELD scores and significant quality of life issues from liver disease, LDLT is a good alternative to waiting for a deceased donor as it will significantly increase survival compared with remaining on the waitlist.44

Although the number of living donor transplants performed annually has increased slowly over the years, it still accounts for only about 5% of liver transplants in the United States.45 Of the 8,906 liver transplants performed in the US in 2020, 7,979 (89%) patients received organs from a deceased donor and 425 (11%) from a living donor.46

Medical Management of Patients
Awaiting Liver Transplantation 

The matching of a donor and recipient is prioritized based on recipient MELD score per UNOS and compatible ABO blood type. As such, the waitlist time for liver transplant is variable. For patients with low MELD scores, waitlist time can be years, between listing and getting called for their transplant. It is therefore essential to continue management of the cirrhotic patient during this time period to help reverse or delay the need for transplant. The management of the cirrhotic patient can be complex. It is recommended to communicate with the transplant team for major medical decisions, however “day to day” management of portal hypertension, HCC surveillance, counseling on substance dependence and tobacco cessation, weight loss counseling for obese patients, screening for malnutrition and monitoring of functional status, vaccination for Hepatitis A and B, and preventative measures such as ensuring PAP smear, mammogram, colonoscopy and DEXA scan are up to date can be performed by the PCP. Early referral for liver transplant is recommended for patients with alcohol-related liver disease to facilitate prompt treatment for substance addiction. 

PCPs should recognize that non-transplant peri-operative risk is substantially increased in patients with decompensated cirrhosis, especially CTP class C. PCPs should consult with the transplant hepatologist/transplant team prior to any, particularly abdominal, surgery to weigh the risks and benefits, as surgery can increase morbidity and mortality. In addition, patients should be counseled on eating a high protein diet to counteract sarcopenia and development of hepatic encephalopathy. Typically, the recommended protein intake is 1.2 to 1.5 g/kg per day, based on ideal body weight, with protein included with each meal and snack. A protein-based bedtime snack can reduce the incidence of sarcopenia.47

Summary

In conclusion, it cannot be overstated that liver transplantation is a life-saving procedure for patients with acute or chronic end-stage liver disease. The evaluation process involves a comprehensive assessment of a patient’s medical history, comorbidities, and psychosocial factors that play a key role in identification of suitable candidates for this life saving procedure. The decision to undergo liver transplantation is complex and requires a collaborative approach involving multiple healthcare professionals. As a PCP, the understanding of key aspects of the evaluation process is crucial for recognizing patients who may benefit from liver transplantation and ensuring their timely referral to transplant centers. Candidates for liver transplant referral include, but are not limited to, patients with acute liver failure, decompensated liver disease, primary unresectable hepatic malignancy, inherited metabolic liver disease, and MELD score ≥ 15. The role of the primary care provider does not end with timely referral to transplant centers, but also involves being knowledgeable about pre-transplant management, including optimizing patient health, managing complications, and providing appropriate long term follow up. PCPs can make a significant difference in improving patient quality of life and long-term survival rates by actively participating in the care of patients with chronic liver disease. By collaborating closely with transplant teams and staying updated on the indications, evaluation criteria, and potential contraindications, PCPs can enhance patient outcomes and contribute to the overall success of liver transplantation. 

References

References

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Moylan CA, Brady C, Johnson J, et al. Disparities in Liver Transplantation Before and After Introduction of the Model for End-Stage Liver Disease Score. JAMA. 2008 Nov 26;300(20):2371-8. 

Martin P, DiMartini A, Feng S, Brown R, Fallon M. Evaluation for Liver Transplantation in Adults: 2013 Practice Guideline by the American Association of the Study of Liver Diseases and the American Society of Transplantation. Hepatology. 2014;59(3):1144-1165.

D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol. 2006;44(1):217-31. 

Wiesner R, Edwards E, Freeman R, et al. Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology. 2003;124:91-6. 

Londono MC, Cardenas A, Guevara M, et al. MELD score and serum sodium in the prediction of survival of patients with cirrhosis awaiting liver transplantation. Gut. 2007;56(9):1283-90. 

Kim WR, Mannalithara A, Heimbach JK, et al. MELD 3.0: The model for end-stage liver disease updated for the modern era. Gastroenterology. 2021;161(6):1887-1895.e4. 

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Endoscopic Therapy for Refractory Benign Esophageal Strictures

May 2024 • Volume XLVIII, Issue 5
Douglas G. Adler,Zheyuan Jenny Wang

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The management of refractory benign esophageal strictures (RBES) presents a formidable clinical challenge, necessitating frequent interventions to ameliorate symptoms and enhance the quality of life for affected individuals. Among the array of available endoscopic therapeutic modalities for RBES, esophageal dilation stands out as the primary treatment approach, with both balloon dilators and bougies demonstrating high rates of technical success and satisfactory clinical resolution. Despite its efficacy, approximately 30-40% of strictures recur following dilation, prompting exploration into adjunctive therapies such as steroid injections, incisional therapy, stent placement, and the application of mitomycin C. Triamcinolone injections have emerged as an option, reducing stricture recurrence rates and improving dysphagia scores, particularly in refractory anastomotic strictures. However, the literature reports conflicting findings regarding their efficacy, underscoring the need for further investigation. Similarly, stent placement, including the use of self-expanding metal stents (SEMS) and lumen-apposing metal stents (LAMS), offers viable alternatives, albeit with concerns regarding migration rates and adverse events. Furthermore, self-dilation, while rarely employed, presents a patient-centered approach that can be both safe and effective when appropriately implemented. Despite these advancements, several knowledge gaps persist, necessitating further research to refine treatment strategies, optimize clinical outcomes, and enhance the overall management of RBES. This literature review aims to synthesize existing evidence, identify areas of agreement and disagreement, and delineate avenues for future investigation to address these critical gaps in understanding and practice.

Dilation

Esophageal dilation remains the primary treatment for RBES as patients with RBES often require multiple dilations.,,  Most strictures are successfully treated with endoscopic dilation, however approximately 30-40% recur. There are several methods of performing esophageal dilation. These vary by the type of dilator used and the way it is passed through the esophagus to the level of the stricture itself. Generally, dilation can be categorized as either balloon or mechanical (bougie-type). Balloon dilators can be passed through-the-scope (TTS) or over a guidewire. Placement can be verified by direct visualization via endoscopy, and/or via fluoroscopy.1,4 TTS balloons come in a variety of sizes and are in widespread use. (Figure 1) The most common type of bougies in current use are Savary-Gilliard (SG) or Maloney dilators. Modern bougies, made of polyvinyl chloride, are generally passed over a wire, frequently with additional fluoroscopic guidance, across a stricture where they exert radial and longitudinal pressure on the stricture. It should be noted that using balloon dilation is technically easier, but the cost is higher as balloons are one time use devices. SG and Maloney dilators are not disposable and can be used repeatedly and are more cost effective over time.4 There is no statistical difference between the balloon dilation and SG dilators in terms of clinical resolution of esophageal strictures., Repeated dilation treatment by balloons and bougies was found to have an overall clinical success rate of 70.9% in a 2019 retrospective analysis.7 Another study found successful dilation, defined as the ability to expand the esophageal lumen to accommodate a 42F (14 mm wide) catheter, was attained in 93.5% of patients undergoing endoscopic dilation.10

Among the adverse events associated with dilation for benign esophageal strictures are perforation, bleeding, bacteremia, and (rarely) esophageal fistula. The perforation rate has been reported between 0.1 – 0.4%, which no clear evidence of different perforation rates for mechanical versus balloon dilators.1 Significant bleeding and bacteremia are rare adverse events. Furthermore, data suggests no significant difference in adverse event rates between the use of balloon dilators and other methods, underscoring the safety and efficacy of both approaches in clinical practice.8 Numerous individuals encounter challenges with traditional interventions such as balloons and bougies in managing refractory strictures, necessitating the exploration of additional and alternative therapeutic modalities.

Steroid Injection

Triamcinolone, a long-acting and semi-viscous corticosteroid agent, has been utilized as an adjunctive therapy to enhance the efficacy of dilation in the treatment of refractory strictures, or as standalone therapy. Most investigators utilize triamcinolone acetate or acetonide at concentrations of 10 mg/mL, although higher concentrations of 40 mg/mL have also been employed. The volume of injection has varied across studies, ranging from 0.5 mL to 2.8 mL. Additionally, betamethasone and dexamethasone preparations have been utilized, with no discernible differences in outcomes reported among different steroid formulations. 

Triamcinolone injections are indicated for refractory strictures where conventional dilation techniques have proven ineffective. The precise mechanism of action of triamcinolone in stricture management remains unclear. However, studies suggest that corticosteroids decrease the fibrotic healing that appears to occur after dilation.9 Triamcinolone injections have shown potential results in reducing stricture recurrence rates and improving dysphagia scores, particularly in patients with refractory anastomotic strictures.9, Meta-analysis has not demonstrated consistent improvement in dysphagia scores among patients receiving steroid injections, but the interpretation of these findings is limited due to the high heterogeneity of the data. Studies have reported a significant decrease in the Periodic Dilation Index (PDI), which is defined as the number of dilations required/duration of time in months, among patients receiving intralesional steroid injections alongside dilation therapy.11 Triamcinolone may prove beneficial in managing RBES, potentially reducing the frequency of necessary dilations. There is currently no standardized protocol for the number of triamcinolone injection sessions. The optimal dosing regimen and injection technique may vary based on the specific characteristics of the stricture and individual patient factors.9 The literature presents conflicting results regarding the efficacy of triamcinolone injection in the management of patients with RBES. Pereira-Lima et al. reported a significant increase in the number of dysphagia-free patients after 6 months and an improvement in dysphagia scores in a double-blind randomized study consisting of 19 patients. In contrast, the double-blind study of 60 patients conducted by Hirdes et al. failed to replicate these results. 

While endoscopic triamcinolone injections are generally well-tolerated, adverse events may include intramural infection, yeast esophagitis, and perforation. Due to the low number of adverse events, statistical analysis was not possible in a 2018 meta-analysis that analyzed the effect of intralesional steroid injections in addition to endoscopic dilation of benign refractory esophageal strictures.11 

Incisional Therapy

Incisional therapy represents an additional option for patients with RBES. This therapeutic approach entails the use of electrocautery or mechanical devices to directly incise or cauterize the fibrotic stricture itself. The fundamental principle underlying this modality mirrors that of dilation, involving the disruption or displacement of circumferential fibrotic tissue and collagen fibers to facilitate the restoration of a satisfactory lumen diameter and prevent reformation of scar tissue. 

Needle knife incision is the most commonly employed technique. This technique employs a needle-knife catheter, widely used for ERCP, to perform electrosurgical incisions in a radial manner around the stricture. (Figure 2) The determination of the length and quantity of incisions is tailored to each specific stricture. Typically, an average of 4-12 radial incisions is required for ideal treatment.13 Optimal outcomes are typically observed with short-segment strictures measuring less than 1 cm such as Schatzki rings or anastomotic strictures. With long segment strictures, complete removal of the stricture rim may not always be feasible. In a prospective outcome study, 87.5% of patients had neither subjective dysphagia nor endoscopic recurrence at a 24 month follow up after incisional therapy.

Potential adverse events associated with incisional therapy include pain, bleeding, and perforation. The perforation or hemorrhage rate associated with balloon or bougie dilation ranges from 0.1% to 0.4%,1 while the perforation rate with endoscopic incision therapy falls within the range of 0% to 3.5%, with no reported evidence of significant bleeding.13

Stents

Self-Expanding Metal Stents

Endoscopic stent placement has emerged as mainstay of treatment for managing RBES. It is widely recognized as a safe procedure and is frequently used as a first-line therapy option. Stents commonly employed in therapy include partially covered self-expanding metal stents (PCSEMS), fully covered self-expanding mental stents (FCSEMS), LAMS, and biodegradable stents (where they are commercially available). Stents are deployed under endoscopic and/or fluoroscopic guidance, depending on the patient and the type of stent used, with placement confirmation via endoscopy. Alternatively, direct visualization can guide stent placement without fluoroscopic assistance.

SEMS were introduced into clinical practice approximately three decades ago. PCSEMS and FCSEMS have both been evaluated for treatment of RBES. Presently, temporary placement of SEMS is commonplace in the management of RBES. (Figure 3) It has been recommended by one study that FCSEMS should be left in place for up to 12 weeks to minimize the risk of hyperplastic tissue and stent embedment, but in practice many patients require longer stent indwell times and treatment should be individualized. Both PCSEMS and FCSEMS were found to have a high technical success rate and short-term clinical efficacy. There was no statistical difference between PCSEMS and FCSEMS. Adverse events linked to PCSEMS encompass stent migration and tissue ingrowth. Conversely, FCSEMS primarily presents stent migration as the main adverse event. Stent migration persists as a significant concern and represents a primary factor prompting re-intervention with SEMS. 

Migration rates were observed to be 17.6% for PCSEMS post-placement and 17.4% for FCSEMS, as reported in a 2015 retrospective case review.18 A different 2016 multicenter study reported stent migration in 44.4% of patients with SEMS. Additionally, a literature review published in 2017 documented stent migration in 11.9% of patients treated with SEMS, while 20.3% experienced tissue in-growth or overgrowth. Another multicenter study conducted in 2016 reported a notable stent migration rate of 44.4% among patients receiving SEMS.  It should be stressed that stent migration is not always an adverse event per se. If the stricture responds to stenting, and the lumen opens up appropriately, there may no longer be a stenosis there to help anchor the stent in place. 

Biodegradable stents have emerged as a potential solution to address adverse events associated with SEMS and self-expandable polymer stents (SEPS), although these devices are not currently available in the United States. Two main types of biodegradable stents have been developed: knitted poly-L-lactic acid monofilaments, although no longer available, and the SX-ELLA BDS composed of semicrystalline biodegradable polymer known as polydioxanone. These stents offer constant radial force over a period of 4-5 weeks, allowing sufficient time for treating underlying esophageal diseases, while their progressive hydrolysis-mediated self-degradation prevents tissue overgrowth.22 Notably, their complete dissolution within 11-12 weeks obviates the need for endoscopic removal. Adverse events such as bleeding and chest pain have been reported. It is worth noting that BDS are associated with a higher incidence of major adverse events (28.6%) compared to FCSEMS and SEPS (10.6% and 14.3% respectively).22 Further prospective randomized trials are warranted to compare the clinical effectiveness of BDSs with FCSEMS. These trials should aim to determine the optimal duration of stent placement, evaluate the value of repeat stenting over extended periods, and assess the cost-effectiveness alongside patient satisfaction. A 2012 prospective multicenter study comparing FCSEMS, SEPS, and BDS revealed no significant differences in the clinical success of all three stent types. However, BDSs and FCSEMS demonstrated superiority over SEPS in several variables, including the dysphagia-free period, long-term improvement, and the number of reinterventions required.16 It should be noted that SEPS are no longer in clinical use. 

Lumen-apposing metal stents (LAMS)

LAMS were initially designed for the management of pancreatic fluid collections, chosen for their anti-migratory property attributed to their saddle-shaped design. Over time, their clinical applications have expanded greatly beyond their initial indications, owing to several benefits such as offering multiple different diameters, short stent lengths, and facilitating simple stepwise deployment, which enhances technical success. These devices can be used effectively to treat short-segment RBES. (Figure 4) Comparative effectiveness studies have demonstrated that LAMS procedures are both feasible and safe, yielding good clinical outcomes. Technical and clinical success rates have been reported at 98.6% and 79.7%, respectively.23 Notably, the migration rate with LAMS stands at 10.6%, significantly lower than that observed with SEMS.24 Moreover, LAMS have exhibited superior clinical outcomes compared to FCSEMS and BDS. However, adverse events associated with LAMS include perforation, discomfort prompting early removal, stent migration, bleeding, and stricture reformation. 

In a 2020 multicenter study comparing 15 mm and 20 mm stents, stent migration (15.6%) was the most common adverse event with 15 mm LAMS, but pain (14.3%) was the most common adverse event with 20 mm LAMS. Moving forward, future research endeavors aim to provide more extensive data on long-term outcomes and explore the utility of LAMS in managing refractory strictures, thereby guiding device refinement, and enhancing clinical practice.

Mitomycin C

Mitomycin C, a chemotherapeutic agent primarily employed in the treatment of malignancies such as esophageal, anal, breast, and bladder cancer, possesses pharmacological properties that make it a potential candidate for scar modulation.3 In the context of esophageal strictures, mitomycin C is administered either topically at the site of the stricture or injected directly into the stricture following dilation. The typical dosing regimen involves diluting 0.4 mg/mL of mitomycin C in 1 mL of saline, which is then divided into aliquots of 0.5 mL each. These aliquots are injected into the four quadrants of the narrowest part of the stricture.3 Despite its potential benefits, the administration of mitomycin C is not without risks, as adverse events such as intense pain, necrosis, and ulceration have been reported. However, while no longer widely practiced, there is published literature reporting the use of this agent in patients with corrosive esophageal strictures refractory to repeated endoscopic dilation.

Self-Dilation

Self-dilation represents a patient-centered approach to the management of strictures, aiming to empower patients with the ability to actively participate in their own care. Self-dilation is offered to patients with esophageal strictures refractory to other treatments such as endoscopic dilation, incisional therapy, or stent placement.28 Techniques for safe and effective self-dilation typically involve educating patients either in the clinic or during their hospital stay, if admitted, within 48 hours following endoscopic dilation. Patients are instructed to begin self-dilation with a Maloney dilator that is either the same size or one size smaller than the dilator used during their typical endoscopic dilation procedure. Patient selection criteria include those with recurrent strictures after dilation, many of which are proximal, and individuals who have failed previous treatments such as Savary or balloon dilation, or those who have undergone dilation combined with intralesional steroid injections or incisional therapy., Despite the potential benefits, patients may exhibit reluctance to engage in self-dilation due to concerns regarding pain or perforation. Nevertheless, self-dilation offers a safe, effective, and cost-efficient treatment option for appropriately selected patients with refractory strictures. In a 2013 small retrospective study, esophageal self-dilation was successful in treatment of 90% of patients. Another 2018 retrospective study showed comparable results, with a technical success rate of 94% and median number of endoscopic dilation procedures dropping from 17 over a median period of 9 months to 1.5 procedures after initiation of self-dilation. Further research is needed to refine patient selection criteria and optimize the implementation of self-dilation protocols in clinical practice.

Conclusion

The management of RBES continues to pose a significant clinical challenge, often requiring repeated interventions to alleviate symptoms and improve quality of life for affected individuals. The array of endoscopic therapeutic modalities available for RBES includes dilation, steroid injections, incisional therapy, stent placement, and the use of mitomycin C. While each approach offers distinct advantages and potential drawbacks, several key agreements and disagreements have emerged from the existing body of literature. Endoscopic dilation, whether performed with balloon dilators or bougies, remains the primary treatment modality for RBES, demonstrating high rates of technical success and an acceptable rate of clinical resolution. Triamcinolone injections have shown promise in reducing stricture recurrence rates and improving dysphagia scores, particularly in refractory anastomotic strictures. However, conflicting findings regarding the efficacy of triamcinolone injection underscore the need for further research to elucidate its true effectiveness. Discrepancies in reported stent migration rates highlight the necessity for standardized protocols and further investigation into optimal stent selection and placement techniques. Self-dilation is rarely undertaken although when appropriately implemented this approach offers a safe, effective, and cost-efficient treatment option for selected patients with refractory strictures. Overall, while significant progress has been made in the endoscopic management of RBES, several knowledge gaps persist, warranting additional research to refine treatment strategies and optimize clinical outcomes in this challenging patient population. 

References

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