Page 28 – Practical Gastro

PASADENA, CA– Arrowhead Pharmaceuticals Inc. (NASDAQ: ARWR) presented additional positive interim 48-week liver biopsy results from the ongoing AROAAT2002 study, an openlabel Phase 2 clinical study of ARO-AAT, the company’s second generation investigational RNA interference (RNAi) therapeutic being codeveloped with Takeda Pharmaceutical Company Limited (“Takeda”) as a treatment for the rare genetic liver disease associated with alpha-1 antitrypsin deficiency (AATD), at The International Liver Congress – The Annual Meeting of the European Association for the Study of the Liver (EASL).

The results demonstrate that, in the AROAAT2002 study, investigational AROAAT treatment led to improvements in multiple measures of liver health, including fibrosis, with substantial and sustained reductions in the level of mutant AAT protein (Z-AAT). In addition, AROAAT treatment was generally well tolerated after up to 1 year of treatment.

Javier San Martin , M.D., chief medical officer at Arrowhead, said: “We believe the interim results that were presented today at EASL represent an important breakthrough for the field and are encouraging for patients with alpha-1 liver disease, who currently have no available treatment options other than liver transplant. The data indicate that treatment with investigational ARO-AAT, being developed in collaboration with Takeda as TAK-999, resulted in substantial, sustained, and consistent reductions in the production of the toxic mutant Z-AAT protein, which has been identified as the cause of progressive liver disease in patients with alpha-1 antitrypsin deficiency. This reduction over 6 and 12 months led to multiple important signals associated with healing of patients’ liver disease. Importantly, we believe ARO-AAT is the first investigational therapy to show this type of benefit in patients with alpha-1 liver disease. We want to thank all the investigators and patients for their participation in the study, and we look forward to the availability of additional results from this study and from our ongoing SEQUOIA study of ARO-AAT, which we anticipate will reach full enrollment during the third quarter of 2021.”

Pharmacodynamics and Efficacy

After 24 weeks (cohort 1, n=4) and 48 weeks (cohort 2, n=5) of treatment with investigational ARO-AAT in the AROAAT2002 study, the following results were observed:

Serum Z-AAT levels decreased in all patients
Median decrease in intra-hepatic Z-AAT levels were:
- Total Z-AAT -80.1% (range -72 to -97%)
- Monomer -90% (range -79 to -97%)
- Polymer -81% (range* -42 to -97%)
- ■ *Excluding 1 subject in cohort 1 that had very low Z-AAT polymer levels at baseline that increased at week 24
- Histological globule burden was reduced in all nine patients, with two achieving full resolution (total aggregate globule burden score=0)
Six of the nine patients (2/4 after 24 weeks and 4/5 after 48 weeks) achieved a 1 or greater stage improvement in Metavir fibrosis stage, with no worsening of fibrosis in the other three patients
- Two patients had baseline F4 fibrosis (cirrhosis), with one patient achieving a twostage improvement to F2 and the other patient achieving a one-stage improvement to F3
Multiple biomarkers of liver health improved, including liver stiffness (FibroScan), liver enzymes alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT), and PRO-C3, a marker of collagen formation

Safety and Tolerability

In AROAAT2002, investigational ARO-AAT demonstrated an acceptable safety profile and was generally well tolerated after up to 1 year of treatment. There were no treatment-emergent adverse events leading to drug discontinuation, dose interruptions, or study withdrawal. Lung function was assessed throughout the study and there were no clinically meaningful changes in percent predicted forced expiratory volume in 1 second (ppFEV1). Three serious adverse events (SAEs) were reported, but none were considered related to the study drug. All SAEs were moderate in severity and all resolved.

AROAAT2002 (NCT03946449) is a pilot open-label, multi-dose, Phase 2 study to assess the response to investigational ARO-AAT in 16 patients with AATD associated liver disease and baseline liver fibrosis. All eligible participants receive a predose biopsy and an end of study biopsy. Treated participants will also be offered the opportunity to continue treatment in an open-label extension (OLE). Including the OLE, interim assessments will be made after 6 months, 12 months, 18 months, and 24 months of treatment with ARO-AAT.

Presentation Details

Title: ARO-AAT an investigational RNAi therapeutic demonstrates improvement in liver fibrosis with reduction in intra-hepatic Z-AAT burden

Authors: Pavel Strnad , et al.

Type: Late-Breaking Oral Presentation

Date and Time: June 26, 2021 at 12:15 CEST A copy of the presentation materials may be accessed on the Events and Presentations page under the Investors section of the Arrowhead website.

About Arrowhead and Takeda Collaboration

In October 2020, Arrowhead and Takeda announced a collaboration and licensing agreement to develop investigational ARO-AAT. Under the terms of the agreement, Arrowhead and Takeda will codevelop ARO-AAT which, if approved, will be cocommercialized in the United States under a 50/50 profit-sharing structure. Outside the U.S., Takeda will lead the global commercialization strategy and receive an exclusive license to commercialize ARO-AAT with Arrowhead eligible to receive tiered royalties of 20-25% on net sales. Arrowhead received an upfront payment of $300 million and is eligible to receive potential development, regulatory and commercial milestones of up to $740 million.

About Alpha-1 Antitrypsin-Associated Liver Disease

Alpha-1 Antitrypsin-Associated Deficiency (AATD) is a rare genetic disorder associated with liver disease in children and adults and pulmonary disease in adults. AATD is estimated to affect 1 per 3,000-5,000 people in the United States and 1 per 2,500 in Europe. The protein AAT is primarily synthesized and secreted by hepatocytes. Its function is to inhibit enzymes that can break down normal connective tissue. The most common disease variant, the Z mutant, has a single amino acid substitution that results in improper folding of the protein. The mutant protein cannot be effectively secreted and accumulates in globules inside the hepatocytes. This triggers continuous hepatocyte injury, leading to fibrosis, cirrhosis, and increased risk of hepatocellular carcinoma.

Individuals with the homozygous PiZZ genotype have severe deficiency of functional AAT leading to pulmonary disease and liver disease. Lung disease is frequently treated with AAT augmentation therapy. However, augmentation therapy does nothing to treat liver disease, and there is no specific therapy for hepatic manifestations. There is a significant unmet need as liver transplant, with its attendant morbidity and mortality, is currently the only available cure.

About Arrowhead Pharmaceuticals

Arrowhead Pharmaceuticals develops medicines that treat intractable diseases by silencing the genes that cause them. Using a broad portfolio of RNA chemistries and efficient modes of delivery, Arrowhead therapies trigger the RNA interference mechanism to induce rapid, deep, and durable knockdown of target genes. RNA interference, or RNAi, is a mechanism present in living cells that inhibits the expression of a specific gene, thereby affecting the production of a specific protein. Arrowhead’s RNAi-based therapeutics leverage this natural pathway of gene silencing.

For more information, please visit: www.arrowheadpharma.com or follow us on Twitter: @ArrowheadPharma

To be added to the Company’s email list and receive news directly, please visit: http://ir.arrowheadpharma.com/email-alerts

NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #212

Auto-Brewery Syndrome: A Schematic for Diagnosis and Appropriate Treatment

Fahad Malik,

Prasanna Wickremesinghe,

Atif Saleem

Auto-Brewery Syndrome (ABS), also called Gut Fermentation Syndrome, is a rare, underdiagnosed medical condition. This is caused by fermentation of ingested carbohydrate by gut fungi resulting in endogenous production of ethanol. Though this syndrome has been described in the medical literature for over 50 years, it still remains misunderstood with limited information regarding diagnosis and treatment. The presenting symptoms and signs of ABS can be protean and mimic other clinical entities. This can make diagnosing this condition challenging. We propose the following schematic for diagnosing and treating this unusual entity based on our ongoing study of ABS patients. The initial step in confirming this diagnosis is a standardized carbohydrate challenge test which we have devised and studied in our ongoing cohort of ABS patients.

Introduction

Auto-Brewery Syndrome (ABS), which has also been described as Gut Fermentation Syndrome, is a rare, underdiagnosed medical condition. In this condition, fermentation of ingested carbohydrate results in endogenous production of ethanol. This syndrome was originally described in 1946 in a 5-year-old South African child undergoing emergency laparotomy, during which a 3-inch posterior stomach wall tear was detected and alcohol noted in the stomach.1 Multiple cases of ABS were subsequently described in Japan during the 1970s. In these cases, identified yeast forms were mostly Candida species as the causative agent.2 ABS is more common in patients with chronic medical conditions such as diabetes, inflammatory bowel disease (Crohn’s disease patients with strictures), short bowel syndrome or immunosuppressed subjects. Since then, there have been sporadic case reports of ABS worldwide.3-7 ABS can also occur in healthy individuals. In our cohort of ABS patients prior exposure to antibiotics was universal. Antibotics can alter the gut microbiome allowing fungal elements to proliferate.8,9 Nonetheless, this condition has continued to be regarded as a myth due to limited knowledge on the subject. Initially, only fungi were implicated in the conversion of carbohydrate to alcohol, but a recent large Chinese study also identified certain species of high alcoholproducing bacteria (e.g., Klebsiella species).10

Pathophysiology

Although the initiating or triggering factors resulting in ABS remain uncertain, we propose the following in its causation:
1. Alteration of the gut microbiome: The disruption of gut homeostasis resulting in overgrowth of fungi, and in rare cases, high alcohol-producing bacteria (e.g., Klebsiella species).1,10 All of our patients had prior exposure to antibiotics before developing ABS symptoms.

2. Fungal fermentation: Commercially, Saccharomyces cerevisiae (i.e., brewer’s yeast) has been used for manufacturing beer for centuries.11

Risk Factors

In our ABS cohort of patients, the most common risk factor for its causation has been prior use of antibiotics. Antibiotics may have disrupted the fine homeostatic balance and symbiotic relationship between the different types of gut microbiota causing yeast overgrowth. Several patients with diabetes, short bowel syndrome, intestinal bacterial overgrowth, and inflammatory bowel disease (Crohn’s disease with strictures), have also been described with ABS. Healthy patients may also suffer from ABS if exposed to a precipitating cause.1,4,5-7,12 It is uncertain if any genetic components could have predisposed these patients to ABS.

Symptoms

Patients with ABS are known to present with signs and symptoms of inebriation. Some with psychiatric symptoms (i.e. altered mood, anxiety, dysphoria, changes in affect and depression) or neurological symptoms (i.e. changes in mental status, drowsiness, brain fog, seizures, and ataxia). The patients can also have the smell of alcohol on their breath. The effects of alcohol are the same regardless of whether it is endogenously or exogenously derived, and can increase the risk of fatty liver, cirrhosis of the liver and acute or chronic pancreatitis.10 The legal limit for driving while intoxicated (DWI) is 0.08% in New York and many other states. We have encountered many patients with ABS with 3-4 times this level. These symptoms could also overlap with those of chronic fatigue syndrome, depression, and alcoholism itself.

Diagnosis

Usually, these patients are either identified by a concerned family member or had been arrested for alleged “DWI”. Identifying these patients is difficult as ABS symptoms could masquerade as other entities. The medico-legal implications of DWI are self-evident. When investigating a patient with possible ABS, a complete medical history and a physical examination should be augmented with interrogation of family and friends as they may provide additional vital information. The patient can develop “memory fog” and therefore might have poor recall of past events. Particular attention should be paid to the onset of the condition, inciting factors, prior antibiotic use, mold exposure, and any other useful information available from their previous evaluations. Needless to say, the present or past detailed history of alcohol intake is mandatory, including asking when the patient last drank alcohol, if at all.

Basic laboratory tests, i.e. complete blood count, comprehensive metabolic panel, and stool testing should be performed to rule out other medical conditions (e.g. diabetes, immunosuppression, leukopenia). It is also important to ascertain that the patient is not surreptitiously drinking. Therefore, ideally the validity of the patient’s denial of alcohol consumption has to be corroborated by a family member or a friend. The diagnosis of ABS can only be considered after other conditions which may present with similar symptoms have been ruled out. These patients are advised to purchase a breathalyzer and keep a log of their breathalyzermeasured breath alcohol content (BAC) morning and evening, and at any time when they are symptomatic. Any positive level of breathalyzer BAC measurement needs to be confirmed with a concomitant blood alcohol level and the patient’s physician should also be immediately informed.

Just prior to the carbohydrate challenge test, we initially perform upper and lower endoscopy to obtain gastric, upper small bowel, terminal ileal, and colon secretions. These samples are then tested for pH, gram strain, culture, and antibiotic and antifungal sensitivity in a commercial laboratory. Once a particular fungal species is identified, further antifungal sensitivity testing is conducted to determine the appropriate choice of subsequent therapy. The stepwise process for ABS diagnosis is summarized in Figure 1.

The carbohydrate challenge test should be performed when the patient’s breath and blood alcohol levels are zero. If elevated, the patient will have to wait until it becomes zero prior to testing. Patients have to be under complete observation with no access to alcohol along with zero initial blood alcohol level in order for this test to be performed. A diagnostic standardized carbohydrate challenge test was performed after upper and lower endoscopic evaluation. This test consisted of administering 200g of glucose orally in a supervised setting in an isolation room and testing both breath and blood alcohol levels at baseline (0) and at 0.5, 1, 2, 4, 8 hours after glucose administration. Patient were allowed to eat any meal of their choice after the ingestion of 200g of oral glucose. If alcohol levels are elevated at any time during this evaluation, the test is aborted and considered to be positive. Patients who are still negative at 8 hours are given the option to return for a collection of a 16- and 24-hour sample as some fungi can take longer than 8 hours to ferment carbohydrate. Therefore, a negative 8 hour test cannot exclude this diagnosis due to some fermentation occurring even after 24 hours.

Testing a stool sample can assist in the screening process, but the lower gastrointestinal tract can contain small amounts of fungal colonization which would be considered normal and fermentation here would have little clinical significance. Upper gastrointestinal tract fungal colonization is significant, as the presence of fungi is considered pathological in this location. All of the patients who are currently under treatment for ABS had a positive carbohydrate challenge test and positive stool mycological studies on gut secretions.

Until now there had been no known standardized screening test for ABS. Therefore sensitivity and/ or specificity of this test is unstudied. We are the first to propose a carbohydrate challenge test to identity ABS patients. If BAC or blood alcohol is negative, it is unlikely to see a positive carbohydrate challenge test, even if there is a strong suspicion for ABS. When this carbohydrate challenge test is accepted and used more widely, we would have a better idea of the sensitivity, specificity and validity of this test. In our literature review, we have found less than 100 cases since 1952. We are now studying these patients and might be able provide more statistical information in the future.

Treatment

The same initial treatment protocol used for exogenous alcohol intoxication should be used to treat ABS patients as well. This would include administering appropriate intravenous fluids for hydration, maintaining a clear airway, and correcting calorie and nutritional deficiencies (folate and thiamine). Alcohol withdrawal symptoms if present should also be managed with benzodiazepines. After the resolution of the patient’s acute symptoms and stabilization of the patient’s condition, targeted treatment for the patient’s ABS can be initiated. An interdisciplinary approach is strongly recommended in these situations with the assistance of a Gastroenterologist, Psychiatrist and Nutritionist for optimal care. The mainstay of our dietary treatment should be to keep the patient initially on a carbohydrate free diet for 6 weeks as carbohydrate is the only substrate that is converted to alcohol by fungi. Otherwise, these patients are at liberty to ingest any non-carbohydrate meal. A total elimination of carbohydrate is difficult to to practice. We allowed small amounts of carbohydrate found in fruits or vegetables to be acceptable. Antifungal sensitivity testing should be done on any fungal strains isolated from the gastrointestinal secretions to determine the appropriate choice of antifungal treatment. We used nystatin as a firstline treatment when appropriate, as it has the least amount of side effects and an established safety record. Oral azole compounds (e.g., fluconazole and itraconazole) are our next drugs of choice if the patient is still symptomatic with elevated breath and blood alcohol levels while on nystatin therapy. Finally, intravenous micafungin is used for treatment failure.

In addition to antifungal therapy, these patients are started on a single strain probiotic (Lactobacillus acidophilus). Patients should continue to check their BAC twice a day during, and after the 6 weeks of antifungal treatment, and inform their physicians of any positive results. After successfully completing the 6-week therapy if the patient is asymptomatic with negative BAC, the antifungal therapy is gradually tapered during the next 6 weeks and then discontinued. We continued treatment with the probiotic long-term. It would be ideal to have the patient repeat the carbohydrate challenge test prior to reintroducing carbohydrate in their diet if feasible. If this test is positive then the patient would require further antifungal therapy.

Additionally, the role of probiotic use in ABS needs to be fully investigated. Probiotic strains of Lactobacillus have been studied and found to have inhibitory effects on biofilm formation and filamentation in Candida albicans species. This probiotic has also previously been shown to competitively inhibit gut fungal growth in patients.8,13-15 We had previously postulated that fecal microbiome transplant might be valuable in ABS patients. There has only been a single successful report of using fecal microbiome transplant for the treatment of ABS in Belgium. We await further studies on this treatment modality.17 See Figure 2 for proposed treatment algorithm.

Conclusion

ABS is a rare and underdiagnosed medical condition where ingested carbohydrate is converted to alcohol by fermentation in the gut. This condition should be considered in any patient who has signs and symptoms of inebriation despite denying alcohol intake. This syndrome has been described in the medical literature for over 50 years, but it still remains a condition with limited information regarding diagnosis and treatment. If a physician suspects that a patient has ABS, breathalyzer analysis during the symptomatic episodes could help the clinician determine if this condition might be present. We propose a standardized carbohydrate challenge test to screen patients with suspected diagnosis of ABS. While a positive test is very useful in detecting patients with ABS, a negative test does not definitively rule out ABS, as fungi could take longer than 24 hours to convert carbohydrate to alcohol. The seminal NIH microbiome study from 2007 using genetic methodology has found many fungi are undetected by our usual commercial laboratory culture techniques.15,17 As more research emerges on the gut microbiome, it is hoped that a better understanding of this medical condition will ensue.

References

Ladkin RG, Davies JNP. Rupture of the stomach in an African child. Br Med J. Br Med J. 1948 Apr 3;1(4552):644.
Iwata K. A review of the literature on drunken syndromes due to yeasts in the gastrointestinal tract. Tokyo, Japan: University of Tokyo Press; 1972.
Hafez EM, Hamad MA, Fouad M, et al. Auto-brewery syndrome: ethanol pseudo-toxicity in diabetic and hepatic patients. Hum Exp Toxicol. 2017;36:445–50.
Welch BT, Coelho Prabhu N, Walkoff L, et al. Auto-brewery syndrome in the setting of long-standing Crohn’s disease: a case report and review of the literature. J Crohns Colitis. 2016;10:1448–50.
Spinucci G, Guidetti M, Lanzoni E, et al. Endogenous ethanol production in a patient with chronic intestinal pseudoobstruction and small intestinal bacterial overgrowth. Eur J Gastroenterol Hepatol. 2006;18:799–802.
Green AD, Antonson DL, Simonsen KA. Twelve-year-old female with short bowel syndrome presents with dizziness and confusion. Pediatr Infect Dis J. 2012;31(4):425.
Jansson-Nettelbladt E, Meurling S, Petrini B, et al. Endogenous ethanol fermentation in a child with short bowel syndrome. Acta Paediatr. 2006;95:502–4.
Malik F, Wickremesinghe P, Saverimuttu J. Case report and literature review of auto-brewery syndrome: probably an underdiagnosed medical condition. BMJ Open Gastroenterol. 2019;6:e000325.
Painter K, Cordell BJ, Sticco KL. Auto-brewery syndrome (Gut fermentation) [updated 2020 Jun 26]. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/ NBK513346/
Yuan J, Chen C, Cui J et al. Fatty liver disease caused by high-alcohol-producing Klebsiella pneumoniae. Cell Metabolism. 2019;30:675–88.e7.
Walker GM, Stewart GG. Saccharomyces cerevisiae in the production of fermented beverages. Beverages. 2016;2:30.
Tameez Ud Din A, Alam F, Tameez-Ud-Din A, et al. Auto-brewery syndrome: a clinical dilemma. Cureus. 2020;12:e10983.
Cordell B, McCarthy J. A case study of gut fermentation syndrome (auto-brewery) with Saccharomyces cerevisiae as the causative organism. Int J Clin Med. 2013;04:309–12.
Suez J, Zmora N, Zilberman-Schapira G, et al. Postantibiotic gut mucosal microbiome reconstitution is impaired by probiotics and improved by autologous FMT. Cell. 2018;174(6):1406-1423.e16.
Vilela SFG, Barbosa J, Rossoni R, et al. Lactobacillus acidophilus ATCC 4356 inhibits biofilm formation by C. albicans and attenuates the experimental candidiasis in Galleria mellonella. Virulence. 2016;6:29–39.
Vandekerckhove E, Janssens F, Tate D, et al. Treatment of gut fermentation syndrome with fecal microbiota transplantation. Ann Intern Med. 2020;173(10):855.
Sam QH, Chang M, Chai L, et al. The fungal mycobiome and its interaction with gut bacteria in the host. Int J Mol Sci. 2017;18(2):330.

Medical Bulletin Board

Mirikizumab Up-regulates Genes Associated with Mucosal Healing in Ulcerative Colitis for up to One Year in Phase 2 Study

INDIANAPOLIS, July 9, 2021 /PRNewswire / – Eli Lilly and Company (NYSE: LLY) announced new Phase 2 data showing that gene expression changes induced by mirikizumab in patients with ulcerative colitis (UC) over a 12-week induction treatment were maintained for up to one year. These gene transcript changes, which were unique among those who responded to mirikizumab compared to placebo, were associated with mucosal healing, indicating that mirikizumab affects a distinct molecular healing pathway, compared to the spontaneous healing that occurred among those who responded to placebo.

Mirikizumab is being studied in Phase 3 trials for UC and Crohn’s disease (CD), two forms of inflammatory bowel disease that can cause serious and debilitating symptoms, and disruptions in daily life.

A separate analysis of patients with moderate to severe UC evaluated meaningful improvement of bowel urgency, a common symptom of UC that is associated with higher levels of disease activity, decreased work productivity and worse quality of life. These results were presented virtually at the Congress of the European Crohn’s and Colitis Organisation (ECCO), July 8-10, 2021.

Mirikizumab Showed Early and Sustained Gene Expression Changes Associated with Mucosal Healing in UC for Up to One Year

In a previously-published Phase 2 study evaluating patients with UC, mirikizumab down-regulated several gene transcripts associated with inflamed mucosa and up-regulated gene transcripts correlated with healthy mucosa and markers of functional healing after 12 weeks, as defined by clinical disease indices of endoscopy and histology.

In this analysis, a set of differentially-expressed gene transcripts were identified in patients who responded to mirikizumab that were not found in those who responded to placebo at 12 weeks. Of the modulated genes, 71% (n=63) were present only in patients who responded to mirikizumab, 5.6% (n=5) were present only in those who responded to placebo, and 23.6% (n=21) were present in both groups. Effect size estimates were also examined to account for differences in sample size and associated power between treatment groups. The set of gene transcripts regulated by mirikizumab correlated with UC disease activity indices, demonstrating consistency of these molecular changes across symptomatic, clinical, endoscopic and histologic indices of UC disease activity.

The results observed at 12 weeks were maintained for up to one year in patients receiving mirikizumab. For methodology, see the “About the Studies” section below.

“In the first clinical study of an anti-IL- 23p19 therapy in ulcerative colitis to evaluate gene expression on this large scale, mirikizumab demonstrated an ability to down-regulate the gene transcripts associated with inflammation and upregulate transcripts associated with mucosal healing in ulcerative colitis, with changes maintained for up to one year,” said Walter Reinisch, Director of the Clinical IBD Study Group, Department of Gastroenterology and Hepatology, Medical University of Vienna. “These results support the continued development of mirikizumab as a potential treatment option for ulcerative colitis, given the importance of mucosal healing and functional healing as key treatment goals for this difficult-to-treat disease.”

Patients with UC Reported on Definition of Meaningful Change in Bowel Urgency

Bowel urgency, the sudden or immediate need for a bowel movement, is one of the most distressing symptoms experienced by patients with UC. In this qualitative study of patients with moderate to severe UC, patients defined both bowel urgency severity and what would be a meaningful improvement in bowel urgency based on an 11-point numeric rating scale (NRS).

In this study, half of patients with UC (50%, n=10) reported that a 1-point change on the urgency NRS would be a meaningful change, indicating improved emotional well-being and greater confidence to leave the home or do their work.

A quarter of respondents (25%, n=5) indicated that a 2-point improvement in the urgency NRS was required to be considered meaningful, and another 25% of respondents (n=5) noted that a 3-point change or more was needed to achieve improvements in quality of life.

Importantly, among the 75% of patients who endorsed a 1 to 2-point change in urgency NRS, initial scores on the urgency NRS ranged from 2 to 9, indicating that this amount of change was meaningful regardless of the severity of an individual’s bowel urgency. For methodology, see the “About the Studies” section below.

“We are very excited to present these findings at ECCO, which provide one of the first analyses from the patient perspective on the impact of bowel urgency and what would constitute a meaningful change,” said Prentice Stovall, Jr., Global Development Leader, Immunology at Lilly. “Given the impact that bowel urgency has on an individual’s ability to work and overall quality of life, this analysis will help us further understand the experience of people with UC and the potential impact of our treatments on this burdensome and debilitating symptom.”

About the Studies

Mirikizumab-Induced Transcriptome Changes in Patient Biopsies at Week 12 are Maintained Through Week 52 in Patients with Ulcerative Colitis

Patients who achieved clinical response at 12 weeks, as measured by a decrease in 9-point Mayo subscore (rectal bleeding, stool frequency, endoscopy) of ≥2 points and ≥35% from baseline, with either a decrease of rectal bleeding subscore of ≥1 or an RB subscore of 0 or 1 continued onto maintenance mirikizumab treatment. Patients given placebo in induction who achieved clinical response continued on placebo in the maintenance period. In this study, colonic biopsies from 52 patients were obtained at Weeks 0, 12 and 52 from the most affected area ≥30 cm from the anal verge (mirikizumab, n=31, placebo, n=7). Of those patients, 31 were 200 mg mirikizumab responders and seven responded to placebo. Transcript changes at Week 12 from baseline in the placebo and mirikizumab arms were clustered into differentially expressed genes using the Bayesian Limma R-package. Differentially expressed genes which maintained their Week 12 expression level through Week 52 in both the placebo and mirikizumab arms were identified and designated as similarly expressed genes. Overall, the safety profile at 52 weeks was consistent with that of mirikizumab in studies of UC and with the class.

A Qualitative Study Exploring Meaningful Improvement in Bowel Urgency among Adults with Moderate to Severe Ulcerative Colitis

In this qualitative study assessing meaningful improvement in bowel urgency based on a NRS, in-depth interviews were conducted in the United States with 20 adults with clinician-confirmed moderate to severe UC. Using an 11-point NRS developed specifically to assess bowel urgency severity, participants were asked to define levels of bowel urgency (where 0=no urgency and 10=worst possible urgency). Participants were also asked to describe what would be a meaningful improvement based on how this change would impact their daily life.

About Mirikizumab

Mirikizumab is a humanized IgG4 monoclonal antibody that binds to the p19 subunit of interleukin 23. Mirikizumab is being studied for the treatment of immune diseases, including ulcerative colitis and Crohn’s disease.

About Ulcerative Colitis

Ulcerative colitis is a chronic inflammatory bowel disease that affects the colon. UC occurs when the immune system sends white blood cells into the lining of the intestines, where they produce chronic inflammation and ulcerations. There is an unmet need for additional treatment options for UC that provide meaningful symptom relief, including bowel urgency, and deliver sustained clinical remission.

About Eli Lilly and Company

Lilly is a global health care leader that unites caring with discovery to create medicines that make life better for people around the world. We were founded more than a century ago by a man committed to creating high-quality medicines that meet real needs, and today we remain true to that mission in all our work. Across the globe, Lilly employees work to discover and bring life-changing medicines to those who need them, improve the understanding and management of disease, and give back to communities through philanthropy and volunteerism.

To learn more about Lilly, please visit us at: lilly.com and lilly.com/newsroom

Lilly Forward-Looking Statement

This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about mirikizumab as a potential treatment for patients with ulcerative colitis and/or Crohn’s disease and reflects Lilly’s current beliefs and expectations. However, as with any pharmaceutical product, there are substantial risks and uncertainties in the process of drug research, development, and commercialization. Among other things, there can be no guarantee that future study results will be consistent with study results to date, that mirikizumab will prove to be a safe and effective treatment or that mirikizumab will receive regulatory approvals or be commercially successful. For further discussion of these and other risks and uncertainties, see Lilly’s most recent Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission. Except as required by law, Lilly undertakes no duty to update forward-looking statements to reflect events after the date of this release.

DISPATCHES FROM THE GUILD CONFERENCE, SERIES #39

Management of Intestinal Metaplasia and Gastric Cancer

Shradha Gupta,

Aasma Shaukat

Epidemiology of Gastric Cancer

Gastric cancer is the fifth most common and fourth most deadly cancers worldwide.¹ The World Health Organization estimates that in 2018, gastric cancer accounted for 783,000 deaths globally.² Gastric cancer incidence and mortality varies geographically.

Gastric cancers can be divided based on anatomic location into cardia and non-cardia gastric cancers. The non-cardia gastric cancers, arising from the antrum, incisura, body, and/or fundus are associated with Helicobacter pylori (H.pylori) infection.

Adenocarcinoma is the most common type (90- 95%) of gastric cancer followed by some other types including gastrointestinal stromal tumors (GIST), neuroendocrine tumors like carcinoids, lymphoma, leiomyosarcoma and lipomas. Adenocarcinoma are further divided into intestinal and diffuse type.

Asian countries like Japan, Mongolia and Korea have high incidence whereas lower incidence is observed in United States and Northern Europe. In men of South-Central Asian countries, including Iran, Afghanistan, Turkmenistan, and Kyrgyzstan it is the most commonly diagnosed cancer and leading cause of death. According to Global cancer statistics 2020 (GLOBACON), one million new cases were added in 2020.¹ Incidence in males is twice as compared to females. Its incidence is decreasing worldwide but it is still associated with high mortality making it a significant public health concern.

In the United States, gastric cancer ranks 15th in incidence among the major types of cancer.³ The majority of gastric cancers in the United States are non-cardia gastric cancers. In the United States only 10% to 20% of all cases diagnosed are early-stage diagnosis. The remaining patients present with metastatic disease. The median age of diagnosis is 68 years. Over the past 50 years the incidence of gastric cancer has decreased from 33 to 10 cases in males and 30 to 5 cases in female per 100,000. In the United States, 1 in 103 men and women will be diagnosed with gastric cancer in their lifetime.

Overall, 5-year survival rate of gastric cancer is estimated to be 32% (including all stages of cancer). For localized disease this survival rate is 70% whereas for distant metastatic disease the rate is 6%.3 In early limited cancer the 5-year survival rate is more than 95% in Japan. In Japan, endoscopic resection techniques have been refined and is probably related to reduced mortality despite overall high incidence.

Risk Factors for Gastric Cancer

The incidence and mortality of gastric cancer are highly variable geographically. Certain risk factors have been identified which contribute to increase in the incidence of gastric cancer. These are summarized in table.1

Diet is a modifiable risk factor for gastric cancer. Multiple studies including case-control and cohort studies have suggested high risk associated with salt rich diet including pickle, decreased intake of high fiber diet, particularly fruits.⁴ Low Vitamin C consumption might play a role in prevalence of gastric cancer. Consumption of processed meat, dairy foods and N-nitroso compounds are associated with higher rates of gastric cancer. Ingestion of green tea is associated with lower risk. Due to modernization and availability of refrigeration the cooked food is safer for longer duration thereby reducing the risk.

Obesity and lack of physical activity has been recognized as a risk factor in gastric cancer. Cigarette smoking is also related to increase incidence. Moderate amount of physical activity is protective.

The risk of gastric cancer in immigrants is similar to the population of their original country. The birth-place is a stronger risk predictor than the current residential location. Thus, showing the importance of childhood exposure in the etiology of gastric cancer. Migrants do not lose their risk in the first-generation migrants or their young children. Generally, after two generations the risk in immigrant population becomes similar to adopted country. Positive family is a strong predictor of gastric cancer.

Approximately one to three percent of gastric cancer is hereditary in nature. Hereditary diffuse gastric cancer is less than one percent of total gastric cancer cases. It is associated with increased incidence of gastric and breast cancer. Other familial syndromes associated are familial adenomatous polyposis (FAP) and Peutz–Jeghers syndrome (PJS).⁵ In both the above-mentioned disease polyp and dysplasia lead to development of cancer.

Atrophic gastritis and intestinal metaplasia are precancerous lesions for gastric cancer. Certain studies have linked Helicobacter pylori infection with the above. Eradication of Helicbacter pylori leads to reduce incidence of gastric cancer.⁶ Pernicious anemia due to vitamin B12 deficiency secondary to autoimmune gastritis, affects 2%– 5% of the elderly population. Studies have shown that patients with pernicious anemia could have an increased risk of cancer. Vitamin B12 will improve the anemia but have no effect on autoimmune gastritis.

H.pylori infection has been linked to non cardia gastric cancer which is the most prevalent gastric cancer in the United States. Multiple studies have shown that testing and eradication of H. pylori worldwide has resulted in reduced incidence of gastric cancer.

Its prevalence is higher in older males. As the prevalence also increases with safe drinking water and food, logically it is more rampant in lower socio-economic groups. Foundry workers are at risk for developing gastric cancer with dust iron being an important cause. It has also noted to be present in Hiroshima and Nagasaki survivors.

H.PYLORI: DISCOVERY TO CARCINOGEN STATUS

H. pylori was discovered first in 1982 by Australian physicians Drs. Barry Marshall and Robin Warren. It is a gram negative, spiral shaped bacterium living in the stomach. It is transmitted through the feco-oral routes. Studies have shown that this accounts for 50-70 % of gastric ulcers. It is also associated with gastric adenocarcinoma. In 1975 Correa et al. outlined a cascade leading to development of gastric adenocarcinoma.⁷ They suggested the following sequence of events normal gastric mucosa / nonatrophic gastritis / multifocal atrophic gastritis without intestinal metaplasia / intestinal metaplasia of the complete (small intestine) type / intestinal metaplasia of the incomplete (colonic) type / low-grade dysplasia / high-grade dysplasia / invasive adenocarcinoma. H. pylori infection causes gastritis and then in some patients follows the above cascade to eventually gastric adenocarcinoma. (Figure 1)

Patients with peptic ulcer disease (PUD), a past history of PUD (with no documented treatment), low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma, or a history of endoscopic resection of early gastric cancer (EGC) should be tested for H. pylori infection. Strong consideration is made for people younger than 60 years with dyspepsia with no alarming can be tested and if positive treated to postpone the EGD. In patients undergoing EGD for dyspepsia biopsies should be taken and tested for H. pylori. Antimicrobial treatment of chronically infected people might trigger antimicrobial resistance as almost half of the world population is infected with H. pylori infection.⁸ Vaccination against has been shown effective in experimental animal models, but so far, such efficacy has not been studied in humans. Studies have shown that among patients with H. pylori infection with or without intestinal metaplasia, H. pylori treatment was associated with a lower risk of incident gastric cancer compared to placebo.

Proton pump inhibitor (PPI) use is associated with worsening of gastric atrophy, particularly in H. pylori–infected individuals. One study analyzed 63,397 patients who had been treated for H. pylori and who had appeared to be cleared of the infection.⁹ The results suggested that people who used PPI after treatment of H. pylori were twice at risk of gastric cancer as compared to people who did not use PPI.

First-line treatment of H. pylori is bismuth quadruple therapy or concomitant therapy consisting of a PPI, clarithromycin, amoxicillin, and metronidazole. Certain factors like previous antibiotic exposure and previous treatments should be put in perspective. If first line therapy fails, a salvage regimen avoids antibiotics previously used and can use other drugs like levofloxacin.

Intestinal Metaplasia and Proposed Progression to Gastric Cancer

Gastric intestinal metaplasia (GIM), defined as the replacement of normal healthy gastric mucosa by epithelium resembling intestinal cells. It is associated with an increased risk for intestinal-type gastric adenocarcinoma. There is increased discussion about further endoscopic testing or surveillance for the same reason. In 1975, Correa et al. described the cascade of steps leading to the development of intestinaltype gastric adenocarcinoma. Less than 0.25% of patients with GIM every year progress to gastric cancer. It has been recognized as a pre malignant condition, when exposed to environmental stimuli like H. pylori, smoking and high salt intake may result to advancement of gastric cancer.

Certain indicators like location, extent and severity of GIM will influence the transformation of GIM to gastric cancer. Lesions found in gastric body are more likely to advance into gastric cancer. One-fourth of the patients diagnosed with high grade dysplasia (HGD) will advance to adenocarcinoma. Once H.pylori infection is diagnosed it should be treated in these patients.

There is no common guideline for surveillance of GIM. In high-grade dysplasia with no endoscopically defined lesions, surveillance at six months or one year is recommended. In low-grade dysplasia with no endoscopically defined lesion, patients should receive follow up within a year after diagnosis.10 In the presence of an endoscopically defined lesion, resection should be considered to obtain a more accurate diagnosis.

A standard surveillance protocol is needed which should focus on the patients at greatest risk. In countries with lower incidence, high risk individuals should be identified. Multiple factors such as genetic risk, epidemiological factors and status of H. pylori infection should be considered. After the initial screening, high-risk patients with intestinal metaplasia should enter surveillance protocols for uniformity of care and future trends.

Recommendations For Screening for Gastric Cancer

As evident from the discussion above, there is a high-risk population which is known for gastric cancer. Guidelines to identify precursor lesions and then appropriate screening and surveillance will help in early detection and prevention of gastric cancer. In countries like Japan which are considered high-risk, high false positive results have been identified as a consequence of screening. In the United States, screening high risk populations like older males with pernicious anemia, atrophic gastritis and familial syndromes like FAP, could be a clinically justified method of screening.

ASGE guidelines suggests that patients with GIM at high-risk of gastric cancer due to ethnic background or family history should undergo surveillance endoscopy. Future surveillance endoscopies can be discontinued if two consecutive endoscopies have been negative for dysplasia and eradication of H. pylori has been achieved.

AGA guideline by Gupta S et al. and Gawron AJ et al. are recommended reading for recommendations for surveillance endoscopy in patients with GIM and high-risk individuals.^10,12

Future Research Areas

Despite decreasing incidence of gastric cancer, its mortality is still very high and diagnosis is made at a later stage of the disease. Screening methods available for even high-risk populations do not yield good positive predictive value. Multiple studies aim to identify non-invasive biomarkers from other bodily fluid like urine, saliva, gastric juice or blood.

On routine endoscopy we can miss almost ten percent of the lesions. High-definition endoscopy with virtual chromoendoscopy is superior to white light endoscopy alone. The endoscopist can identify high-risk lesions better with these enhanced imaging modalities. Biopsy of these targeted lesions increases the positive predictive value.

References

Ferlay J, Ervik M, Lam F, et al, eds. Global Cancer Observatory: Cancer Today. International Agency for Research on Cancer; 2020. Accessed November 25, 2020. gco.iarc.fr/today
World Health Organization. Cancer. WHO. Available at http://www.who.int/mediacentre/factsheets/fs297/en/. 12 September 2018; Accessed: February 5, 2020.
Surveillance, Epidemiology, and End Results Program. SEER Stat Fact Sheets: Stomach Cancer. National Cancer Institute. Available at http://seer.cancer.gov/statfacts/html/ stomach.html. Accessed: February 5, 2020.
Karimi P, Islami F, Anandasabapathy S, Freedman ND, Kamangar F. Gastric cancer: descriptive epidemiology, risk factors, screening, and prevention. Cancer Epidemiol Biomarkers Prev. 2014 May;23(5):700-13. doi: 10.1158/1055-9965.EPI-13-1057. Epub 2014 Mar 11. PMID: 24618998; PMCID: PMC4019373.
Liu KS, Wong IO, Leung WK. Helicobacter pylori associated gastric intestinal metaplasia: Treatment and surveillance. World J Gastroenterol. 2016 Jan 21;22(3):1311-20. doi: 10.3748/wjg.v22.i3.1311. PMID: 26811668; PMCID: PMC4716041.
Lee YC, Chiang TH, Chou CK, Tu YK, Liao WC, Wu MS, Graham DY. Association Between Helicobacter pylori Eradication and Gastric Cancer Incidence: A Systematic Review and Meta-analysis. Gastroenterology. 2016 May;150(5):1113-1124.e5. doi: 10.1053/j.gastro. 2016.01.028. Epub 2016 Feb 2. PMID: 26836587.
Kinoshita H, Hayakawa Y, Koike K. Metaplasia in the Stomach-Precursor of Gastric Cancer? Int J Mol Sci. 2017 Sep 27;18(10):2063. doi: 10.3390/ijms18102063. PMID: 28953255; PMCID: PMC5666745.
Altayar O, Davitkov P, Shah SC, Gawron AJ, Morgan DR, Turner K, Mustafa RA. AGA Technical Review on Gastric Intestinal Metaplasia-Epidemiology and Risk Factors. Gastroenterology. 2020 Feb;158(3):732-744.e16. doi: 10.1053/j.gastro.2019.12.002. Epub 2019 Dec 6. PMID: 31816301; PMCID: PMC7425600.
Cheung KS, Chan EW, Wong AYS, et al.: Long-term proton pump inhibitors and risk of gastric cancer development after treatment for Helicobacter pylori: a population-based study. Gut 67 (1): 28-35, 2018.
Gupta S, Li D, El Serag HB, Davitkov P, Altayar O, Sultan S, Falck-Ytter Y, Mustafa RA. AGA Clinical Practice Guidelines on Management of Gastric Intestinal Metaplasia. Gastroenterology. 2020 Feb;158(3):693-702. doi: 10.1053/j.gastro.2019.12.003. Epub 2019 Dec 6. PMID: 31816298; PMCID: PMC7340330.

CASE REPORT GUIDELINES FOR AUTHORS

Practical Gastroenterology Case Report Guidelines for Authors

• The aim of Case Reports is to provide challenging yet clinically relevant and informative cases to primary care physicians.

• The Case should center around one (1) to three (3) high quality images that are completely described in the report. Images should be endoscopic, pathologic, and/or radiographic (without any patient identifiers) with clear labeling as appropriate.

• The Case must be a concise report submitted as a Word document consisting of no more than 1250 words.

• The images must be submitted as .jpg files separate from the Word document.

• There should be a brief introduction/abstract, relevant presentation of the case, relevant case discussion and conclusion.

• The conclusion should include one or two clinical pearls that the reader may apply to their practice or add to their knowledge set.

• References should be limited to 8. References should follow AMA style and journal names should be abbreviated according to Index Medicus practice. Inclusive page ranges should be indicated.

• Authors should be limited to 3 on each submission. No author photographs are necessary. All authors must provide their names, addresses, phone numbers, complete titles and affiliations.

• Case Reports must not have been published previously. Each Case Report is subject to review by members of our Editorial Board. Case Reports are subject to final editing. Upon publication, Case Reports will be copyrighted by Practical Gastroenterology Publishing, Inc.

• Please submit your Case Report to: Adrien Mahl, Editor Practical Gastroenterology practicalgastro@aol.com

FROM THE LITERATURE

EGD Observation Time and Neoplasm Detection

To evaluate an institutional policy of EGD observation time and the detection rate of upper gastrointestinal neoplasm (UGI), all endoscopists from July 2010 to March 2019 were requested to follow institutional policy extending more than 3 minutes of observation time in every screening EGD. Observation time was defined as the time from when the endoscope reached the duodenum to when it was withdrawn and neoplasm detection rate (NDR) was obtained during this period and was compared with a baseline period from 2009 to 2015.

During the study period, 30,506 EGDs were performed. The mean subject age was 49.9 and 56.5% were men. All endoscopists achieved an average EGD observation time of more than 3 minutes during the period. Mean observation time was 3.35 and was significantly longer than the baseline at was 2.38. NDR was 33%, which was higher than the baseline (23%). Even after adjusting for subjects’ age and gender, smoking history and endoscopists’ biopsy sampling rate, prolonged EGD observation time of more than 3 minutes increased the NDR of UGI neoplasms (odds ratio 1.51).

It was concluded there was evidence that implementing a period of prolonged observation time could increase NDR and that should be an important quality indicator of the EGD examination.

FROM THE LITERATURE

Gastrointestinal Infection and the Risk of Microscopic Colitis

To examine the relationship between gastroenteritis and the risk of microscopic colitis (MC), a casecontrolled study was carried out of 5 adult patients with MC diagnosed between 1990 and 2016 in Sweden, matched up to 5 general population controls according to age, sex, calendar year and county. Cases of MC were identified using systematized nomenclature of medicine codes from the ESPRESSO study, a cohort of gastrointestinal pathology reports from all 28 pathology centers in Sweden. Logistic regression modeling that was used to estimate adjusted odds ratio (aORs), and 95% confidence intervals (CIs).

Through December 2016, 13,466 MC cases were matched to 64,479 controls. The prevalence of previous diagnosed gastrointestinal infection was 7.5% among patients with MC, which was significantly higher than controls (3%). After adjustment, gastroenteritis was associated with an increased risk of MC (aOR 2.63). Among specific pathogens, Clostridioides difficile (aOR 4.39), Norovirus (aOR 2.87), and Escherichia species (aOR 3.82), but not Salmonella species, were associated with an increased risk of MC.

The association between gastrointestinal infections and risk of MC was stronger for the collagenous subtype (aOR 3.23), as compared with lymphocytic colitis (aOR 2.51). The associations remain significant after adjustment for immunemediated conditions and polypharmacy than when compared with unaffected siblings.

It was concluded in a nationwide study that gastrointestinal infection, particularly C. difficile, is associated with an increased risk of subsequent MC.

DISPATCHES FROM THE GUILD CONFERENCE, SERIES #37

A Practical Approach to Managing Immune Checkpoint Inhibitor-Induced Colitis

Michael G. Kattah

INTRODUCTION

As indications for immune checkpoint inhibitors (ICIs) expand, it is critical that gastroenterologists and primary care physicians be aware of how to identify and manage associated side effects. ICIs have dramatically altered the treatment landscape and outcomes for a wide variety of cancers since they were were first approved by the Food and Drug Administration (FDA) a decade ago. ICIs are monoclonal antibodies that augment the anti-tumor immune response by blocking the immune checkpoints cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein-1 (PD-1) or its ligand PD-L1. Initially approved for the treatment of advanced melanoma, their mechanism of action targets a fundamental aspect of tumor immunology, leading to FDA approval in multiple other tumors (particularly for anti-PD-1/PD-L1).1–6 While ICIs are effective, the resulting immune activation can lead to immune-mediated tissue damage in multiple organs. This review will cover the practical aspects of diagnosing and managing patients with ICIinduced diarrhea and colitis.

Immune Checkpoint Inhibitors, Adverse Events and Colitis

Immune self-tolerance is regulated in part by “immune checkpoints” that restrict exaggerated immune responses and prevent autoimmune disease. Immune checkpoint inhibitors (ICIs) inhibit these immune checkpoints and allow tumor infiltrating lymphocytes to target malignant cells. There are two major classes of ICIs targeting distinct priming and effector phases of the immune response, anti-CTLA-4 and anti-PD-1/PD-L1.^1–6 In current oncologic practice, anti-PD-1/PD-L1 constitute the majority of approved tumor types for ICIs, and anti-CTLA-4 is approved as combination therapy with anti-PD-1/PD-L1 only in specific indications.^1–6

While ICIs have revolutionized cancer treatment, the inhibition of checkpoint proteins can lead to immune-related adverse events (irAEs). IrAEs are thought to result from autoreactive T-cells disinhibited from attacking normal host cells. IrAEs can target multiple organs, and the gastrointestinal (GI) tract can be the target of severe or life-threatening events.4,5 Diarrhea is the most commonly reported gastrointestinal symptom of ICIs, occurring in 30-60% of patients.7 In oncologic practice, ICI-induced colitis is often defined clinically by symptoms of diarrhea without an infectious cause, as well as abdominal pain, mucus, tenesmus, hematochezia, or fever.8 In general, anti-CTLA-4 is associated with earlier-onset and more severe irAEs than PD-1/PD-L1 inhibitors, and the combination increases the incidence and severity further still.9–11 Interestingly, patients who experience an irAE of any organ system have improved overall survival compared to those without irAEs, with a specific survival benefit for GI-related irAEs.12 Data from advanced melanoma showed that patients who discontinued ICIs due to treatment-related adverse events had similar overall survival at five years compared to the overall population.1 Taken together, this implies that irAEs like ICI-induced colitis, if tolerable and responsive to treatment, are not necessarily associated with worse survival, and may in some circumstances correlate with more robust antitumor activity and a higher likelihood of favorable treatment response.

Initial Evaluation of Patients with ICI-Induced Diarrhea and Colitis

Evaluation and management of these patients have been outlined by multiple clinical practice updates, guidelines, and recommendations based on expert opinion and retrospective studies.13–19 The diagnosis of ICI-induced colitis should be considered in any patient with diarrhea and colitis symptoms occurring after ICI-initiation. ICI-induced colitis occurs with a median onset of 5-7 weeks after ICI initiation, though it can start as early as one week or over six months later.¹

The first step in evaluation is to assess severity and rule out infectious causes, including Clostridiodies difficile (C.Diff) and common bacterial, viral, and parasitic pathogens. Lactoferrin and fecal calprotectin have been studied in ICIinduced colitis as non-invasive markers to help differentiate between inflammatory versus noninflammatory diarrhea.^20,21 Routine labs including complete blood count, complete metabolic panel, sedimentation rate, and C-reactive protein are recommended, although their diagnostic and prognostic utility are less clear in this setting than in inflammatory bowel disease (IBD). Testing for noninfectious, non-inflammatory causes of diarrhea may include checking thyroid stimulating hormone to rule out hyperthyroidism, tissue transglutaminase (TTG)-IgA and total IgA to rule out celiac disease, and lipase and fecal elastase to rule out pancreatic insufficiency, since all have been described as rare irAEs.22 For patients with grade ≥ 2 disease who may require biologics, it is important to check for latent tuberculosis, viral hepatitis (A, B and C) and HIV. Computed tomography (CT) scans are not routinely recommended, but if there is concern for perforation or other acute pathology then a contrast-enhanced CT scan is a fast and highly informative test.^13-20

Endoscopy with biopsy remains the gold standard for the diagnosis and risk-stratification of patients with suspected moderate-to-severe ICIinduced colitis. Patients with mild ICI-induced colitis may be diagnosed and treated empirically without endoscopic evaluation, especially if the non-invasive evaluation suggests a mild inflammatory non-infectious colitis (i.e., elevated fecal calprotectin and negative infectious stool studies). Endoscopic evaluation serves several purposes. First, the recommendations for moderateto- severe ICI-induced colitis involve holding immunotherapy and treating with prednisone, interventions which could unnecessarily harm patients with alternative etiologies of diarrhea. Moreover, the presence of CMV or other infectious colitis can be assessed with higher sensitivity and specificity on histology. Finally, endoscopic evaluation aids in risk stratification. High-risk features such as large ulcers >1cm, deep ulcers, and pancolitis are associated with steroid treatment failure, identifying patients who would benefit from early induction with biologics.^20,23,24 ICI-induced intestinal inflammation can affect any part of the GI tract, so upper endoscopy and colonoscopy are ideal. However, retrospective studies have demonstrated that >98% of patients with ICI-induced colitis had involvement of the left (distal) colon, supporting a practice of flexible sigmoidoscopy for expedited initial evaluation.^25,26

In select patients with a negative sigmoidoscopy or persistent or refractory symptoms, subsequent upper endoscopy and colonoscopy could be considered to look for more proximal colitis, gastritis, or enteritis.

ICI-induced colitis can be confirmed by histology. Common features include neutrophilic cryptitis, crypt abscesses, epithelial apoptosis, and increased intraepithelial lymphocytes. Anti-PD-1 is more likely than anti-CTLA-4 to exhibit features of lymphocytic or collagenous colitis, with some reports of chronic mucosal injury.^27,28 Given the possibility of microscopic colitis, it is important to perform biopsies in multiple colonic segments even if the mucosa appears endoscopically normal.

Management of ICI-Induced Diarrhea and Colitis Based on Severity

Grade 1

Grade 1 diarrhea is defined as <4 daily stools above the patient’s baseline or mildly increased ostomy output, while grade 1 colitis is asymptomatic.8 Most society practice guidelines do not recommend GI consultation for grade 1 symptoms, although fecal calprotectin and infectious stool studies should be obtained in patients with symptoms lasting for 3 days.19 Patients with grade 1 diarrhea should be monitored closely because they may quickly progress to higher grades of diarrhea and colitis. ICIs may be held but are usually continued for mild grade 1 ICI-induced colitis.^13–19 Treatment is supportive and may include loperamide and hydration, although we typically rule out infections like C.Diff before prescribing anti-diarrheal agents. If the patient’s symptoms do not improve after 3-14 days of conservative management, it is recommended to start enteric budesonide at 9mg per day for four weeks followed by a taper by 3mg every two weeks.^13,18 If patients do not respond to budesonide, they should be escalated to systemic steroids with prednisone 1mg/kg per grade 2 management.^13,14,16

Grade 2

Grade 2 diarrhea is defined as 4-6 stools over baseline, or moderately increased ostomy output, while grade 2 colitis is defined by abdominal pain, mucus and hematochezia.8 At this stage, ICIs are held, and GI should be consulted with consideration for flexible sigmoidoscopy in addition to noninvasive testing outlined above. Patients with grade 2 diarrhea and colitis are treated with prednisone 1mg/kg, followed by a taper over 4-8 weeks.13,18 If patients do not respond within three days of starting oral prednisone, they should be escalated to IV methylprednisolone or a biologic, either infliximab (IFX) or vedolizumab (VDZ). If patients fail to respond to IV steroids within three days, then they should be treated with a biologic. Some Grade 2 patients may respond to a single dose of a biologic followed by a steroid taper, but some may require additional induction doses.¹³

Grade 3 or 4

Grade 3 diarrhea is defined as ≥ 7 stools above baseline or severe increase in ostomy output, while grade 3 colitis is defined by severe pain, fever, or peritoneal signs requiring intervention, or interference with activities of daily living.8 Grade 4 diarrhea and colitis are defined by all the criteria of grade 3 but are also life-threatening.8 Most grade 3 and all grade 4 patients should be hospitalized with GI consultation, and ICIs are held. The laboratory evaluation is outlined above, including necessary tests in anticipation of biologic therapy. If there is concern for perforation or other acute pathology, a contrast-enhanced CT scan should be obtained. Patients should undergo endoscopic evaluation to assess for high-risk features. Hospitalized grade 3/4 patients are started on IV methylprednisolone 1-2mg/kg. If they fail to respond to IV steroids within 72h then they should start a biologic. Patients with grade 3/4 disease will typically require three doses of IFX or VDZ, often dosed at 0, 2, and 6 weeks.^13,29,30

For grade ≥ 2 ICI-induced colitis, ICIs are held at least until patients recover and successfully taper down to a prednisone dose of ≤10mg/day.^13,14,18 Repeat endoscopy is beneficial for patients with persistent symptoms, but also for risk stratifying patients who are being considered for restarting ICIs after recovering from ICI-induced colitis. While most experts recommend considering permanent discontinuation of anti-CTLA-4 for grade ≥ 2 ICI-induced colitis,13,14,18 the risks and benefits should be weighed in conjunction with the treating oncologist. PD-1/PD-L1 inhibitors are generally associated with milder ICI-induced colitis and may be restarted if patients successfully wean to ≤10mg of prednisone daily.13–16,18 Concurrent administration of maintenance IFX while resuming ICIs was reported to prevent recurrent ICI-induced colitis in a small number of patients.^13,31 Therefore, treatment with IFX, or by extension VDZ, may allow ICIs to be restarted in some patients with prior ICI-induced colitis.

Evidence Supporting Various Therapies for Treating ICI-Induced Colitis

Glucocorticoids are the mainstay of treatment for patients with grade ≥ 2 ICI-induced colitis. A systematic review and meta-analysis of 1210 patients found that corticosteroids were effective in 59%.32 Several studies have identified endoscopic features associated with steroid-refractory disease, including large >1cm ulcers, deep ulcers, pancolitis, and high colitis severity scores.20,23,24 Therefore, in moderate cases without high-risk features, steroids are typically first-line. Enteric budesonide was not more effective than placebo in a randomized controlled trial for primary prophylaxis against anti-CTLA-4 induced colitis33 but is effective for patients who have features of microscopic colitis on histology or patients with persistent mild grade 1 diarrhea.13

The anti-tumor necrosis factor (TNF) IFX is one of the most commonly prescribed agents for IBD and the best characterized biologic for treating ICI-induced colitis. While it is generally safe and well-tolerated, relative contraindications include active or recurrent infections, untreated tuberculosis or HBV, moderate-to-severe heart failure, or demyelinating conditions. With regard to the risk of malignancy with anti-TNF agents, a recent metaanalysis found that the risk of new cancer or cancer recurrence in patients with a history of cancer was similar to non-biologic therapies.34 The risk may be even lower in ICI-induced colitis patients who commonly receive limited induction doses rather than long-term anti-TNF maintenance therapy. IFX appears to be effective in approximately 80% of steroid-refractory patients.24,32 There are mixed data regarding whether IFX treatment affects the efficacy of ICIs by interfering with the antitumor immune response. One retrospective study found similar overall survival in patients treated with the combination of steroids and IFX versus steroids alone,12 while another retrospective study reported that patients treated with IFX and steroids exhibited reduced overall survival compared to steroids alone.35 Nevertheless, IFX appears to be generally safe and effective in this setting.

VDZ is another option for patients with steroidor IFX-refractory disease. VDZ targets the integrin α4β7 and inhibits lymphocyte trafficking to the gut with a favorable safety profile. VDZ has been used effectively in steroid and IFX non-responders, but the response rates may be lower in IFX nonresponders as these patients likely represent a more refractory population.³⁰VDZ therefore is an option as both a first-line biologic in steroid-refractory patients as well as rescue therapy for IFX nonresponders.

IFX and VDZ have not been compared headto- head, so choosing between the two can depend on several factors. One retrospective cohort study suggested that patients who received VDZ for ICIinduced colitis had a shorter steroid course, shorter hospital stay, and lower recurrence of diarrhea or colitis compared to patients treated with IFX, although it is unclear if the VDZ-treated patients had less severe disease.³⁶Extrapolating from IBD, IFX is more effective than VDZ for moderate-tosevere disease, but VDZ is associated with fewer infectious complications.37,38 VDZ also induces a response more slowly than IFX in ICI-induced colitis, with a median response time of five days for VDZ versus two days for IFX.^24,30 Given these data, our general practice is to use IFX for hospitalized patients with more severe ICI-induced colitis, and VDZ for more moderate patients, patients with relative contraindications to anti-TNF therapy, or if we anticipate needing a maintenance biologic. Given its favorable side-effect profile, VDZ may have a role for secondary prophylaxis, though more data are needed. Regardless of the agent used, prompt evaluation, diagnosis, and initiation of treatment are critical. In a retrospective study, patients treated with a biologic within 10 days from onset of symptoms were found to have shorter duration of symptoms, fewer hospitalizations, and were weaned off of steroids more easily than patients treated 10 days after symptom-onset.³

Remaining Questions in Clinical Practice

As the indication for ICIs are expanding, there are many questions remaining on how to manage ICI-induced colitis. For example, when and how to safely restart ICI therapy in patients who have recovered from ICI-induced colitis requires further investigation. Treating to complete mucosal healing,40 or concomitant administration of a biologic may reduce the risk of recurrent ICIinduced colitis, but we need more studies to determine the best approach.

Beyond IFX and VDZ, data supporting other therapies are generally limited to small case series and case reports. Tofacitinib (JAK inhibitor), ustekinumab (anti-IL-12/23), and fecal microbial transplant have been described as effective in small numbers of patients who had failed steroids, IFX, and VDZ.^41–45 It will be helpful to have additional data regarding how best to prioritize biologics or other treatments for refractory patients. As we learn more about the underlying microbial, immunologic, and molecular mechanisms of ICI-induced colitis, it would be ideal to identify biomarkers of patients at highest risk for severe disease and initiate primary prophylaxis.^46–49 Patients with pre-existing IBD appear to be at increased risk of developing GI irAE compared to patients without IBD.49 Given that patients with IBD respond well to ICIs,^50–52 immunotherapy should not be withheld,^13,16 but it will be important to determine how best to optimize control of their IBD prior to immunotherapy initiation to prevent treatment-related complications.

In conclusion, ICIs have dramatically altered the treatment of many cancers and have brought hope to many patients. By virtue of their mechanism, ICIs lead to a variety of side-effects that may portend improved efficacy against their underlying malignancy. With close monitoring, prompt diagnosis, appropriate treatment, and multidisciplinary collaboration, the associated adverse effects can generally be managed effectively.

References

Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. New Engl J Med. 2019;381(16):1535-1546. doi:10.1056/nejmoa1910836
Baumeister SH, Freeman GJ, Dranoff G, Sharpe AH. Coinhibitory Pathways in Immunotherapy for Cancer. Annu Rev Immunol. 2014;34(1):1-35. doi:10.1146/annurev-immunol-032414-112049
Bagchi S, Yuan R, Engleman EG. Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance. Annu Rev Pathology Mech Dis. 2020;16(1):1-27. doi:10.1146/annurev-pathol-042020-042741
Michot JM, Bigenwald C, Champiat S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer. 2016;54:139-148. doi:10.1016/j. ejca.2015.11.016
Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and Ipilimumab versus Ipilimumab in Untreated Melanoma. New Engl J Medicine. 2015;372(21):2006-2017. doi:10.1056/nejmoa1414428
Hodi FS, O’Day SJ, McDermott DF, et al. Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. New Engl J Medicine. 2010;363(8):711-723. doi:10.1056/nejmoa1003466
Prieux-Klotz C, Dior M, Damotte D, et al. Immune Checkpoint Inhibitor-Induced Colitis: Diagnosis and Management. Target Oncol. 2017;12(3):301-308. doi:10.1007/s11523-017-0495-4
National Cancer Institute: Common Terminology Criteria for Adverse Events (CTCAE) 5.0. undefined.
Bellaguarda E, Hanauer S. Checkpoint Inhibitor–Induced Colitis. Am J Gastroenterol. 2020;115(2):202-210. doi:10.14309/ ajg.0000000000000497
Som A, Mandaliya R, Alsaadi D, et al. Immune checkpoint inhibitor- induced colitis: A comprehensive review. World J Clin Cases. 2019;7(4):405-418. doi:10.12998/wjcc.v7.i4.405
Collins M, Michot JM, Danlos FX, et al. Inflammatory gastrointestinal diseases associated with PD-1 blockade antibodies. Ann Oncol. 2017;28(11):2860-2865. doi:10.1093/annonc/mdx403
Abu-Sbeih H, Tang T, Ali F, et al. The impact of immune checkpoint inhibitor-related adverse events and their immunosuppressive treatment on patients’ outcomes. J Immunother Precis Oncol. 2018;1(1):7. doi:10.4103/jipo.jipo_12_18
Dougan M, Wang Y, Rubio-Tapia A, Lim JK. AGA Clinical Practice Update on Diagnosis and Management of Immune Checkpoint Inhibitor (ICI) Colitis and Hepatitis: Expert Review. Gastroenterology. Published online 2020. doi:10.1053/j.gastro. 2020.08.063
Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018;36(17):JCO.2017.77.638. doi:10.1200/jco.2017.77.6385
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Haanen JBAG, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl_4):iv119-iv142. doi:10.1093/annonc/mdx225
Grover S, Rahma OE, Hashemi N, Lim RM. Gastrointestinal and Hepatic Toxicities of Checkpoint Inhibitors: Algorithms for Management. Am Soc Clin Oncol Educ Book. 2018;(38):13-19. doi:10.1200/edbk_100013
Thompson JA, Schneider BJ, Brahmer J, et al. NCCN Guidelines Insights: Management of Immunotherapy-Related Toxicities, Version 1.2020. J Natl Compr Canc Ne. 2020;18(3):230-241. doi:10.6004/jnccn.2020.0012
Abu-Sbeih H, Ali FS, Luo W, Qiao W, Raju GS, Wang Y. Importance of endoscopic and histological evaluation in the management of immune checkpoint inhibitor-induced colitis. J Immunother Cancer. 2018;6(1):95. doi:10.1186/s40425-018- 0411-1
Berman D, Parker SM, Siegel J, et al. Blockade of cytotoxic T-lymphocyte antigen-4 by ipilimumab results in dysregulation of gastrointestinal immunity in patients with advanced melanoma. Cancer Immun. 2010;10:11.
Prasanna T, McNeil CM, Nielsen T, Parkin D. Isolated immunerelated pancreatic exocrine insufficiency associated with pembrolizumab therapy. Immunotherapy. 2018;10(3):171-175. doi:10.2217/ imt-2017-0126
Wang Y, Abu-Sbeih H, Mao E, et al. Endoscopic and Histologic Features of Immune Checkpoint Inhibitor-Related Colitis. Inflamm Bowel Dis. 2018;24(8):1695-1705. doi:10.1093/ibd/izy104
Foppen MHG, Rozeman EA, Wilpe S van, et al. Immune checkpoint inhibition-related colitis: symptoms, endoscopic features, histology and response to management. Esmo Open. 2018;3(1):e000278. doi:10.1136/esmoopen-2017-000278
Wright AP, Piper MS, Bishu S, Stidham RW. Systematic review and case series: flexible sigmoidoscopy identifies most cases of checkpoint inhibitor-induced colitis. Aliment Pharm Therap. 2019;49(12):1474-1483. doi:10.1111/apt.15263
Herlihy JD, Beasley S, Simmelink A, et al. Flexible Sigmoidoscopy Rather than Colonoscopy Is Adequate for the Diagnosis of Ipilimumab-Associated Colitis. Southern Med J. 2019;112(3):154- 158. doi:10.14423/smj.0000000000000944
Karamchandani DM, Chetty R. Immune checkpoint inhibitor- induced gastrointestinal and hepatic injury: pathologists’ perspective. J Clin Pathol. 2018;71(8):665. doi:10.1136/jclinpath- 2018-205143
Hammami MB, Gill R, Thiruvengadam N, et al. Balancing the Checkpoint: Managing Colitis Associated with Dual Checkpoint Inhibitors and High-Dose Aspirin. Digest Dis Sci. 2019;64(3):685- 688. doi:10.1007/s10620-019-05534-5
Johnson DH, Zobniw CM, Trinh VA, et al. Infliximab associated with faster symptom resolution compared with corticosteroids alone for the management of immune-related enterocolitis. J Immunother Cancer. 2018;6(1):103. doi:10.1186/s40425-018-0412-0
Abu-Sbeih H, Ali FS, Alsaadi D, et al. Outcomes of vedolizumab therapy in patients with immune checkpoint inhibitor–induced colitis: a multi-center study. J Immunother Cancer. 2018;6(1):142. doi:10.1186/s40425-018-0461-4
Badran YR, Cohen JV, Brastianos PK, Parikh AR, Hong TS, Dougan M. Concurrent therapy with immune checkpoint inhibitors and TNFα blockade in patients with gastrointestinal immunerelated adverse events. J Immunother Cancer. 2019;7(1):226. doi:10.1186/s40425-019-0711-0
Ibraheim H, Baillie S, Samaan MA, et al. Systematic review with meta-analysis: effectiveness of anti-inflammatory therapy in immune checkpoint inhibitor-induced enterocolitis. Aliment Pharm Therap. 2020;52(9):1432-1452. doi:10.1111/apt.15998
Weber J, Thompson JA, Hamid O, et al. A Randomized, Double- Blind, Placebo-Controlled, Phase II Study Comparing the Tolerability and Efficacy of Ipilimumab Administered with or without Prophylactic Budesonide in Patients with Unresectable Stage III or IV Melanoma. Clin Cancer Res. 2009;15(17):5591- 5598. doi:10.1158/1078-0432.ccr-09-1024
Micic D, Komaki Y, Alavanja A, Rubin DT, Sakuraba A. Risk of Cancer Recurrence Among Individuals Exposed to Antitumor Necrosis Factor Therapy. J Clin Gastroenterol. 2017;53(1):e1-e11. doi:10.1097/mcg.0000000000000865
Verheijden RJ, May AM, Blank CU, et al. Association of Anti- TNF with Decreased Survival in Steroid Refractory Ipilimumab and Anti-PD1–Treated Patients in the Dutch Melanoma Treatment Registry. Clin Cancer Res. 2020;26(9):2268-2274. doi:10.1158/1078-0432.ccr-19-3322

Zou F, Shah AY, Glitza IC, Richards D, Thomas AS, Wang Y. S0137 Comparative Study of Vedolizumab and Infliximab Treatment in Patients With Immune-Mediated Diarrhea and Colitis. Am J Gastroenterol. 2020;115(1):S68-S68. doi:10.14309/ ajg.0000000000000848
Dulai PS, Singh S, Jiang X, et al. The Real-World Effectiveness and Safety of Vedolizumab for Moderate–Severe Crohn’s Disease: Results From the US VICTORY Consortium. Am J Gastroenterol. 2016;111(8):1147-1155. doi:10.1038/ajg.2016.236
Colombel J-F, Sands BE, Rutgeerts P, et al. The safety of vedolizumab for ulcerative colitis and Crohn’s disease. Gut. 2017;66(5):839. doi:10.1136/gutjnl-2015-311079
Abu-Sbeih H, Ali FS, Wang X, et al. Early introduction of selective immunosuppressive therapy associated with favorable clinical outcomes in patients with immune checkpoint inhibitor–induced colitis. J Immunother Cancer. 2019;7(1):93. doi:10.1186/s40425- 019-0577-1
Turner D, Ricciuto A, Lewis A, et al. STRIDE-II: An Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): Determining Therapeutic Goals for Treat-to- Target strategies in IBD. Gastroenterology. Published online 2021. doi:10.1053/j.gastro.2020.12.031
Esfahani K, Hudson M, Batist G. Tofacitinib for Refractory Immune-Related Colitis from PD-1 Therapy. New Engl J Med. 2020;382(24):2374-2375. doi:10.1056/nejmc2002527
Bishu S, Melia J, Sharfman W, Lao CD, Fecher LA, Higgins PDR. Efficacy and outcome of Tofacitinib in Immune checkpoint inhibitor colitis. Gastroenterology. 2020;160(3):932-934.e3. doi:10.1053/j.gastro.2020.10.029
Thomas AS, Ma W, Wang Y. Ustekinumab for Refractory Colitis Associated with Immune Checkpoint Inhibitors. New Engl J Med. 2021;384(6):581-583. doi:10.1056/nejmc2031717
Wang Y, Ma W, Abu-Sbeih H, Jiang Z-D, DuPont HL. Fecal microbiota transplantation (FMT) for immune checkpoint inhibitor induced–colitis (IMC) refractory to immunosuppressive therapy. J Clin Oncol. 2020;38(15_suppl):3067-3067. doi:10.1200/ jco.2020.38.15_suppl.3067
Wang Y, Wiesnoski DH, Helmink BA, et al. Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis. Nat Med. 2018;24(12):1804-1808. doi:10.1038/s41591- 018-0238-9
Luoma AM, Suo S, Williams HL, et al. Molecular Pathways of Colon Inflammation Induced by Cancer Immunotherapy. Cell. 2020;182(3):655-671.e22. doi:10.1016/j.cell.2020.06.001
Dubin K, Callahan MK, Ren B, et al. Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockadeinduced colitis. Nat Commun. 2016;7(1):10391. doi:10.1038/ ncomms10391
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Gielisse EAR, Boer NKH de. Ipilimumab in a patient with known Crohn’s disease: To give or not to give? J Crohn’s Colitis. 2014;8(12):1742-1742. doi:10.1016/j.crohns.2014.08.002
Bostwick AD, Salama AK, Hanks BA. Rapid complete response of metastatic melanoma in a patient undergoing ipilimumab immunotherapy in the setting of active ulcerative colitis. J Immunother Cancer. 2015;3(1):19. doi:10.1186/s40425-015-0064-2

Medical Bulletin Board

Echosens Launches Smartexam®: Fibroscan® Software Upgrade Unlocks the True Power of Company’s Innovative and Differentiated Technology

New product and software update for existing devices available
May 12, 2021

WALTHAM, MA – Echosens, a high-technology company offering the FibroScan family of products, is pleased to announce the launch of SmartExam®, innovative technology designed to take examinations with FibroScan to an even greater level of accuracy, specificity and reliability as a non-invasive diagnostic solution for measuring liver fat and stiffness. SmartExam unlocks three key benefits for users: improved reliability in the diagnosis and monitoring of steatosis with continuous controlled attenuation parameter (CAP™); extended usage among severely obese patients with deeper assessment of liver fibrosis and steatosis; and optimized patient care with task automation features that enable physicians to dedicate more time to patient care.

“SmartExam is another example of our commitment to innovation pushing the identification and monitoring of liver disease, lifestyle change and therapeutic interventions to the next level,” says Jon Gingrich, CEO, Echosens North America. “SmartExam’s new computation method allows for a continuous measurement of CAP™ during the entire examination, which reduces variability* by 42%.** In addition, SmartExam offers a 28% increase* in probe-to-capsule distance to improve accuracy and reliability among severely obese patients.** Finally, the new task automation features guide operators through exams, making the examination process easier and faster than ever. We are thrilled to provide this innovative software to our customers.”

This critical diagnostic tool enables heath care professionals to make more informed treatment decisions about liver health and may reduce the need for expensive and more invasive testing to detect liver disease. This important upgrade provides key benefits for clinics and the patients they serve.

Estimates show that 357 million people will have nonalcoholic steatohepatitis (NASH) globally by 2030. NASH can often lead to advanced fibrosis and liver cancer, liver transplantation, increased risk of cardiovascular events and all-cause mortality. As the twin epidemics of liver disease and obesity continue to grow, and because of the prevalence and associated costs of underdiagnosed liver disease—which is now linked to over $100 billion in annual direct costs—FibroScan is gaining traction among U.S. physicians and specialists.

A nurse at French Cochin University Hospital states, “The obese population that we receive for FibroScan examinations has increased substantially in recent years. CAP has become essential to our prescribers to precisely monitor patient’s steatosis. SmartExam allows us to address complex patients and provide more reliable results.”

* CAP for pediatric patients with liver disease is only available with SmartExam capability.

** Audière et al. EASL 2020 poster #FRI-073– 42% is the variability decrease computed on a patient’s cohort scanned with the M probe.

*** Without SmartExam, the maximum recommended Probe-to-Capsula distance (PCD) is 35 mm. With SmartExam, it is 45mm, representing an increase of 28%.

**** Only for M and XL probes.

About Echosens

Echosens, the developer of FibroScan®, is an innovative high-technology company offering a full range of products and services supporting physicians in their assessment and management of patients with chronic liver diseases. FibroScan is supported by over 2,500 peer-reviewed publications and examinations are covered by Medicare, Medicaid and many insurance plans.

For more information, please visit: echosens.com

NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #211

Beyond the Banana Bag: Treating Nutritional Deficiencies of Alcohol Withdrawal Syndrome

Brian D. Peterson,

Matthew Stotts

Excessive alcohol consumption can lead to a variety of health complications. With abrupt cessation or reduction in alcohol intake, individuals may experience alcohol withdrawal syndrome (AWS), with symptoms ranging from mild tremors to life-threatening seizures. To prevent well-described symptomatic nutritional deficiencies and severe electrolyte abnormalities, hospitalized patients are often placed on institutional protocols to manage both their withdrawal symptoms and concomitant nutrient deficiencies. These protocols often differ among health systems in their approach to nutrient replacement, primarily due to a lack of high-quality evidence for dosing. This review focuses on nutritional challenges seen in these individuals with AWS, with specific focus on immediate repletion strategies to prevent the neurologic and hematologic sequelae of common micronutrient deficiencies. This review also offers practical strategies to transition to outpatient repletion to minimize chronic nutritional deficiencies.

INTRODUCTION

Alcohol use disorder (AUD) is a common diagnosis encountered by health care providers both in the hospital and outpatient settings. The lifetime prevalence of AUD, as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5), has increased over the last 20 years, with estimates up to 30% of non-institutionalized United States adults, leading to higher incidences of alcoholrelated health problems such as liver dysfunction and alcohol withdrawal syndrome (AWS).^1,2 While patients with AUD are often admitted to hospitals for reasons other than AWS, those at high risk for AWS are often screened with the Prediction of Alcohol Withdrawal Severity Scale (PAWSS) and monitored with the Clinical Institute Withdrawal for Alcohol (CIWA). The latter scoring system correlates symptoms to the required dose of benzodiazepines or barbiturates needed to prevent life threatening symptoms of AWS.

Individuals with AUD are known to be at high risk for nutritional deficiencies and severe electrolyte derangements. Hospital protocols often include supplementing micronutrients such as thiamine, folic acid, and a variety of minerals. To date, there are few high-quality studies investigating the optimal dosing of deficient nutrients for patients treated for AWS. This lack of standardized, evidenced-based dosing strategies increases the potential that patients may receive insufficient repletion, leading to progression of nutritional deficiencies and their sequelae.

Alternatively, they may receive a longer duration of supplementation than required, leading to a high pill burden without significant benefit.

Micronutrients

Individuals with AUD may be deficient in micronutrients for a variety of reasons. In addition to heavy alcohol use often being associated with a poor diet, alcohol ingestion can directly cause malabsorption as well as electrolyte disturbances through alterations in renal tubular function.3 Providers must be aware of strategies for monitoring and replacing these micronutrients.

Thiamine

Thiamine (Vitamin B1) is a common micronutrient deficiency seen in those with AUD. It is a ubiquitous water-soluble vitamin found in whole grains, meats, and fish and is absorbed in the small intestine by both active transport and passive diffusion. Only a small percentage is stored outside of the plasma, primarily in the liver. Due to its short half-life and limited stores (~ 21 days), frequent ingestion of thiamine containing foods or supplements is required.⁴

Thiamine deficiency is uncommon in healthy individuals, as most developed countries fortify their grains and cereals with thiamine to ensure the population meets the adult recommended daily allowance (RDA) of approximately 1.1- 1.2mg per day.5 People with AUD can become thiamine deficient through a combination of decreased intake of thiamine rich foods and decreased hepatic storage. Animal models have shown direct inhibition of duodenal transport by ingested alcohol. However, the clinical relevance is unclear with several clinical studies failing to show decreased duodenal thiamine uptake with active alcohol use.6 There are two available ways to assess thiamine status:

1. Directly measuring thiamine diphosphate serum levels

2. Measuring the function of the thiamine dependent erythrocyte transketolase enzyme7

The clinical utility of either test is unclear due to a lack of experimental data showing an association between low measured thiamine and severity of clinical symptoms. Additionally, the turn-around time is too long (7-10 days) to be useful in urgent clinical decision making.

Early symptoms of thiamine deficiency include short-term memory loss, weakness, and peripheral neuropathy. While thiamine deficiency induced congestive heart failure (wet beriberi) rarely occurs in developed countries, Wernicke-Korsakoff syndrome (WKS) is a common manifestation of thiamine deficiency in the United States.⁸ WKS initially presents with Wernicke’s Encephalopathy (WE), a reversible clinical syndrome characterized by a triad of altered mental status, gait ataxia, and nystagmus. If untreated, WE can progress to the chronic, irreversible neuronal changes of Korsakoff’s Syndrome (KS), characterized by retrograde and anterograde memory loss. Different studies cite the prevalence of WKS as high as 60% in patients with AUD.⁹ Alarmingly, about 80% of patients with WKS are diagnosed at autopsy, indicating that the syndrome often goes untreated.¹¹ It is difficult to predict which patients are most at risk for developing symptoms of thiamine deficiency due to differences in genetic susceptibilities, alcohol consumption, and diet.Early symptoms of thiamine deficiency include short-term memory loss, weakness, and peripheral neuropathy. While thiamine deficiency induced congestive heart failure (wet beriberi) rarely occurs in developed countries, Wernicke-Korsakoff syndrome (WKS) is a common manifestation of thiamine deficiency in the United States.⁸ WKS initially presents with Wernicke’s Encephalopathy (WE), a reversible clinical syndrome characterized by a triad of altered mental status, gait ataxia, and nystagmus. If untreated, WE can progress to the chronic, irreversible neuronal changes of Korsakoff’s Syndrome (KS), characterized by retrograde and anterograde memory loss. Different studies cite the prevalence of WKS as high as 60% in patients with AUD.⁹ Alarmingly, about 80% of patients with WKS are diagnosed at autopsy, indicating that the syndrome often goes untreated.¹¹ It is difficult to predict which patients are most at risk for developing symptoms of thiamine deficiency due to differences in genetic susceptibilities, alcohol consumption, and diet.

Folic Acid

Folic acid (Vitamin B9) is an essential nutrient obtained from leafy vegetables, broccoli, chickpeas and fortified grains. Folic acid is an important cofactor in DNA synthesis and amino acid production. The liver accounts for 50% of the total body folic acid storage with the remaining 50% stored in the blood and bone marrow. Patients with AUD become deficient through decreased dietary intake, diminished intestinal absorption, increased renal losses, and disrupted hepatobiliary conversion to active metabolites. Fortunately, folic acid deficiency is uncommon in the United States since widespread grain fortification in 1998.³

The most common sign of folic acid deficiency is macrocytic anemia without the neurologic sequelae of B12 deficiency. Replacing folate may improve macrocytic anemia, but could worsen neurologic symptoms such as dementia, depression, peripheral neuropathy, or subacute combined spinal cord degeneration if a B12 deficiency is also present. The mechanism for neurologic worsening after folic acid replacement is poorly understood so it is important to treat concomitant B12 deficiencies prior to giving folic acid.^10,12 Common symptoms of folic acid deficiency include weakness, fatigue, shortness of breath and skin and hair changes.¹³ There is also evidence that folate deficiency and the subsequent hyperhomocysteinemia can increase the risk for alcohol withdrawal seizures.¹⁴

Magnesium

Magnesium is a dietary nutrient found in leafy vegetables, meats, and nuts. Hypomagnesemia occurs in about 30% of patients with AUD due to inadequate dietary intake, poor absorption, and alcohol-induced urinary losses.¹⁵ Importantly, magnesium plays a role in the homeostasis of other important electrolytes; hypomagnesemia can lead to both hypocalcemia by inhibiting parathyroid hormone and to hypokalemia through increased urinary losses15,16 Magnesium also plays a role in thiamine homeostasis by functioning as a cofactor for the enzyme transketolase. Patients with suspected WE who fail to improve after thiamine repletion may have a more robust response after magnesium correction.^17,18 The degree of hypomagnesemia in patients presenting with AWS correlates with more severe symptoms of withdrawal and an increase in 1 year mortality.⁵ Symptoms of hypomagnesemia include neuromuscular manifestations (muscular weakness, tremors, positive Trousseau’s sign) and cardiac complications leading to arrhythmias and possible sudden death.¹⁵

Phosphorus

Phosphorus is an important micronutrient commonly found in meats, nuts and dairy products. Individuals with chronic alcohol use often have deficits in their total body stores of phosphorous due to inadequate dietary intake of foods rich in phosphate and frank malnutrition in some. These patients also have urinary losses from alcoholinduced renal tubular dysfunction.¹⁵A total body deficit of phosphorus often becomes apparent after correction of underlying alcoholic ketoacidosis and glucose administration, leading to phosphate shifting into cells for glucose phosphorylation and ATP production.

Other Micronutrients

A variety of other micronutrient deficiencies have been associated with AUD, including other water-soluble vitamins such as niacin, pyridoxine, cobalamin (B12), riboflavin in addition to fatsoluble vitamins and trace elements like zinc, selenium, and iron.

Initial Acute Management

When individuals with chronic heavy alcohol use present to the hospital, providers should be aware of the potential nutritional deficiencies that are likely present and aim to adequately replete these nutrients to prevent both short and long-term clinical consequences. Malnourished patients can experience refeeding syndrome when starting nutrition repletion, leading to life threatening fluid shifts and depletion in phosphorus, magnesium, and potassium. Severely malnourished patients should be closely monitored for clinical and laboratory signs of refeeding syndrome and treated timely and effectively.¹⁹

Approach to Thiamine Repletion

Thiamine is a universal component of vitamin repletion protocols in AWS. The goal of thiamine repletion is to replenish circulating concentrations as quickly as possible to ensure central nervous system availability and both prevent and treat Wernicke’s long before it develops into Korsakoff syndrome.

The heterogeneity in alcohol consumption, genetic predisposition, and dietary intake makes it difficult to develop general thiamine replacement guidelines in patients presenting with AWS.20 A Cochrane review from 2013 revealed a lack of high-quality evidence to guide clinicians in choosing the proper dose, route, and frequency of thiamine for at risk patients.²¹Currently, dosing strategies for thiamine rely on expert opinion and often differ among institutions and professional societies (Table 1). The historical dose of 100mg IV thiamine daily was arbitrarily chosen in the 1950s because it represented a high dose at that time. This dose has persisted through use of the “banana bag” for AWS, which often contained 100mg IV thiamine per bag, among other vitamins and minerals.²²This thiamine dose is likely insufficient in magnitude and dosing frequency for high-risk individuals. The plasma half-life of thiamine is approximately 1.5 hours, which leads some authors to suggest a required dosing interval of every 8-12 hours in patients at risk for WE.^22,23 Notably, oral preparations should be avoided in patients with AWS due to poor intestinal absorption.²⁴ Data from the UK National Health Service (NHS) has shown that a 5-day course of IV/IM thiamine supplementation was associated with large savings compared to shorter courses, primarily through preventing progression to Korsakoff syndrome and associated costs caring for debilitated patients in long term care facilities.25

While high-quality data on dosing regimens and duration are limited, potential guiding principles for clinicians to consider include (Table 2):

Prophylactically replacing thiamine in all patients presenting with alcohol withdrawal syndrome can prevent permanent symptoms of WKS and reduce associated healthcare costs.
Administering thiamine as soon as possible given evidence for developing WE after prolonged glucose administration without thiamine replacement.²⁶
Oral bioavailability in patients with AWS is poor and initial therapy should favor IV/IM repletion. Often the intravenous therapy is continued for 2-3 days before transitioning to an oral regimen.
The short half-life of thiamine necessitates multiple doses per day in high-risk patients.
Long term oral supplementation should be considered in individuals who remain at nutritional risk with high probability of continued alcohol misuse. Higher doses than the typical RDA are likely needed to compensate for poor absorption during active alcohol consumption (typically 100mg oral thiamine/day).

Approach to Folic Acid Repletion

The upper limit for folic acid supplementation in a healthy adult is approximately 1 mg per day.¹²The bioavailability of oral supplementation approaches 100% when consumed without food or alcohol. In cases of severe, symptomatic megaloblastic anemia when enteral access is lost or difficult to obtain, IV or IM preparations can be used. There are no high-quality studies or guidelines for how long to treat with supplemental folic acid. It is reasonable in patients with mild megaloblastic anemia to supplement 1mg by mouth daily for several months until their anemia has resolved. Higher risk patients may benefit from indefinite 1mg oral folic acid supplementation. Concomitant multivitamin with minerals supplementation should be evaluated for folic acid content to avoid dosing over the recommended daily upper limit. Typical multivitamins contain about 400mcg folic acid.

Unlike thiamine, which does not seem to have adverse physiologic effects from high dosages, folic acid supplementation above the recommended daily allowance (RDA) of 1 mg by mouth daily is controversial and has been linked to increased cancer risk and neurocognitive changes in some populations.²⁷To date, there are no randomized controlled trials evaluating the optimal folic acid dosing strategy for patients at risk for alcohol withdrawal seizures. In 2015, the National Toxicology Program with the US Department of Health and Human Services developed a comprehensive needs assessment for further research into optimal folic acid dosing.²⁸This needs assessment should spur research into optimal folic acid dosing to help guide future patient management.

Approach to Magnesium Repletion

Serum magnesium levels are a poor representation of total body magnesium status because 99% of the body’s magnesium is stored intracellularly.²⁹However, serum magnesium is the most common test used to guide replacement. Clinicians should be aware that a normal serum magnesium level may mask a total body magnesium deficit. See Table 3 for dosing strategies. Patients with reduced renal function should receive approximately 25-50% of the recommended dosages.³⁰Oral dosing can be split into two daily doses to avoid causing diarrhea. Serum magnesium levels should be checked at least daily in patients with AUD or more frequently in patients with symptomatic hypomagnesemia. Of note, patients receiving multiple intravenous doses of magnesium should be monitored for EKG changes. Magnesium replacement and monitoring after hospital discharge should be considered in some patients due to total body storage depletion and continued urinary losses from alcohol induced renal tubular dysfunction.¹⁵

Approach to Phosphorus Repletion

Patients at risk for refeeding syndrome should be treated in the hospital setting due to the need for frequent laboratory monitoring.³¹While ongoing alcohol use will place individuals at risk for ongoing phosphorus loss, abnormalities in the excretion of urinary phosphate typically resolves after a few weeks of ongoing abstinence. Table 3 gives an approach to managing hypophosphatemia in the inpatient and ambulatory settings. Importantly, phosphorus repletion should be enteral except in cases of extreme depletion (<1.0mg/dL) due to the risk of calcium chelation with rapid IV phosphorus administration.³¹

Other Micronutrient Deficiencies

In addition to the previously discussed micronutrients, there are multiple other important nutrient deficiencies in patients presenting with AWS that should be considered. These micronutrients can be replaced using a daily multivitamin with minerals (MVM), often continued indefinitely while actively consuming alcohol. Providers should realize that over the counter multivitamins may not include the essential minerals needed. Patients are encouraged to ask their pharmacist or health care provider for specific MVM recommendations.

Transition to Outpatient Management

After recovering from AWS with an initial period of aggressive micronutrient supplementation, the need for additional nutrient replacement depends on an individual’s nutritional and social needs. Factors such as employment status, social support, food insecurity, and housing status have been shown to correlate with increased alcohol use and worsened nutritional status.³²As an example, a meta-analysis from 2018 investigated the efficacy of nutritional interventions in homeless patients with AUD and found that several interventions (particularly providing meal services) could improve nutrition related behavior, although the data was insufficient in determining long term outcomes in nutrition status and disease progression.³³

It is reasonable to discharge all individuals with recommendations for nutritional supplementation until they can be assessed by their outpatient provider. A complete multivitamin with minerals (MVM) is an efficient and affordable way to deliver essential micronutrients. Notably the dose of thiamine in these may be inadequate in those with ongoing heavy alcohol use.

CONCLUSION

Strategies to replete micronutrient deficiencies in patients presenting with AWS vary among institutions and individual providers due to a lack of prospective or randomized studies. Thiamine deficiency is one of the most concerning and potentially underdiagnosed nutrient deficiencies seen in this population. Thiamine replacement should be given intravenously 2-3 times a day in those who have symptoms of deficiency or are at high risk. Specific attention must be given to magnesium and phosphorous repletion based on serum levels in those at risk for refeeding syndrome. Folic acid repletion at 1 mg daily likely provides adequate treatment for deficient states. A daily MVM is a reasonable strategy to provide the remaining vitamins and minerals that are commonly deficient in this population. There are no studies examining long term benefits of outpatient nutrient replacement in patients with AUD and, hence, providers should individualize supplementation strategies based on the level of ongoing alcohol use, dietary intake, financial status and signs and symptoms of deficiency.

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