Page 28 – Practical Gastro

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
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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
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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
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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
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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.

References

Grant BF, Goldstein RB, Saha TD, et al. Epidemiology of DSM-5 Alcohol Use Disorder: Results From the National Epidemiologic Survey on Alcohol and Related Conditions III. JAMA Psychiatry. 2015;72(8):757-766.
Grant BF, Chou SP, Saha TD, et al. Prevalence of 12-Month Alcohol Use, High-Risk Drinking, and DSM-IV Alcohol Use Disorder in the United States, 2001-2002 to 2012-2013: Results From the National Epidemiologic Survey on Alcohol and Related Conditions. JAMA Psychiatry. 2017;74(9):911-923.
Medici V, Halsted CH. Folate, alcohol, and liver disease. Mol Nutr Food Res. 2013;57(4):596-606.
Osiezagha K, Ali S, Freeman C, et al. Thiamine deficiency and delirium. Innov Clin Neurosci. 2013;10(4):26-32.
Maguire D, Talwar D, Burns A, et al. A prospective evaluation of thiamine and magnesium status in relation to clinicopathological characteristics and 1-year mortality in patients with alcohol withdrawal syndrome. J Transl Med. 2019;17(1):384.
Rees E, Gowing LR. Supplementary thiamine is still important in alcohol dependence. Alcohol. Jan-Feb 2013;48(1):88-92.
Whitfield KC, Bourassa MW, Adamolekun B et al. Thiamine deficiency disorders: diagnosis, prevalence, and a roadmap for global control programs. Ann N Y Acad Sci. 2018 Oct;1430(1):3-43.
Arts NJ, Walvoort SJ, Kessels RP. Korsakoff’s syndrome: a critical review. Neuropsychiatr Dis Treat. 2017;13:2875-2890.
Donnino MW, Vega J, Miller J, et al. Myths and misconceptions of Wernicke’s encephalopathy: what every emergency physician should know. Ann Emerg Med. 2007;50(6):715-721.
Selhub J, Morris MS, Jacques PF. In vitamin B12 deficiency, higher serum folate is associated with increased total homocysteine and methylmalonic acid concentrations. Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19995-20000.
Harper CG, Giles M, Finlay-Jones R. Clinical signs in the Wernicke-Korsakoff complex: a retrospective analysis of 131 cases diagnosed at necropsy. J Neurol Neurosurg Psychiatry. 1986 ;49(4):341-5.
Reynolds EH. The neurology of folic acid deficiency. Handb Clin Neurol. 2014;120:927-943.

National Institutes of Health Office of Dietary Supplements (2021, January 15). Folate. Ods.od.nih.gov/factsheets/Folate- HealthProfessional/.
Bleich S, Degner D, Bandelow B, et al. Plasma homocysteine is a predictor of alcohol withdrawal seizures. Neuroreport. 2000;11(12):2749-2752.
Palmer BF, Clegg DJ. Electrolyte Disturbances in Patients with Chronic Alcohol-Use Disorder. N Engl J Med. 2017;377(14):1368-1377.
Ayuk J, Gittoes NJ. How should hypomagnesaemia be investigated and treated? Clin Endocrinol (Oxf). 2011;75(6):743-746.
Traviesa DC. Magnesium deficiency: a possible cause of thiamine refractoriness in Wernicke-Korsakoff encephalopathy. J Neurol Neurosurg Psychiatry. 1974;37(8):959-962.
Peake RW, Godber IM, Maguire D. The effect of magnesium administration on erythrocyte transketolase activity in alcoholic patients treated with thiamine. Scott Med J. 2013;58(3):139- 142.
Friedli N, Odermatt J, Reber E, et al. Refeeding syndrome: update and clinical advice for prevention, diagnosis and treatment. Curr Opin Gastroenterol. 2020 Mar;36(2):136-140.
Thomson AD, Marshall EJ. The natural history and pathophysiology of Wernicke’s Encephalopathy and Korsakoff’s Psychosis. Alcohol Alcohol. 2006;41(2):151-158.
Day E, Bentham PW, Callaghan R. Thiamine for prevention and treatment of Wernicke-Korsakoff Syndrome in people who abuse alcohol. Cochrane Database Syst Rev. 2013 Jul 1;2013(7):CD004033.
Flannery AH, Adkins DA, Cook AM. Unpeeling the Evidence for the Banana Bag: Evidence-Based Recommendations for the Management of Alcohol-Associated Vitamin and Electrolyte Deficiencies in the ICU. Crit Care Med. 2016;44(8):1545-1552.
Tallaksen CM, Sande A, Bøhmer T, et al. Kinetics of thiamin and thiamin phosphate esters in human blood, plasma and urine after 50 mg intravenously or orally. Eur J Clin Pharmacol. 1993;44(1):73-78.
Thomson AD. Mechanisms of vitamin deficiency in chronic alcohol misusers and the development of the Wernicke- Korsakoff syndrome. Alcohol Alcohol Suppl. 2000;35(1):2-7.
Wilson EC, Stanley G, Mirza Z. The Long-Term Cost to the UK NHS and Social Services of Different Durations of IV Thiamine (Vitamin B1) for Chronic Alcohol Misusers with Symptoms of Wernicke’s Encephalopathy Presenting at the Emergency Department. Appl Health Econ Health Policy. 2016;14(2):205-215.
Schabelman E, Kuo D. Glucose before thiamine for Wernicke encephalopathy: a literature review. J Emerg Med. 2012;42(4):488-494.
Pieroth R, Paver S, Day S, et al. Folate and Its Impact on Cancer Risk. Curr Nutr Rep. 2018;7(3):70-84.
National Toxicology Program US Department of Health and Human Services (2015, August). Identifying Research Needs for Assessing Safe Use of High Intakes of Folic Acid. https:// ntp.niehs.nih.gov/ntp/ohat/folicacid/final_monograph_508.pdf
Auyk J, Gittoes NJL. How should hypomagnesemia be investigated and treated? Clin Endocrinol (Oxf). 2011 Dec;75(6):743-6.
Assadi F. Hypomagnesemia: an evidence-based approach to clinical cases. Iran J Kidney Dis. 2010 Jan;4(1):13-9
Reber E, Friedli N, Vasiloglou MF, et al. Management of Refeeding Syndrome in Medical Inpatients. J Clin Med. 2019;8(12).
Santolaria F, Perez-Manzano JL, Milena A et al. Nutritional assessment in alcoholic patients. Its relationship with alcoholic intake, feeding habits, organic complications and social problems. Drug Alcohol Depend. 2000 Jun 1;59(3):295-304.
Ijaz S, Thorley H, Porter K. Interventions for preventing or treating malnutrition in homeless problem-drinkers: a systematic review. Int J Equity Health. 2018 Jan 16;17(1):8.
Knudsen AW, Jensen JEB, Norgaard-Lassen I, et al. Nutritional intake and status in persons with alcohol dependencey: data from an outpatient treatment programme. Eur J Nutr. 2014 Oct;53(7):1483-92.
The ASAM Clinical Practice Guideline on Alcohol Withdrawal Management. J Addict Med. May/Jun 2020;14(3S Suppl 1):1-72.
Haber P. Guidelines for the Treatment of Alcohohol Problems. Australian Government Department of Health and Ageing. June 2009. Online ISBN: 1-74186-977-3.
Lingford-Hughes AR, Welch S, Peters L et al. BAP updated guidelines: evidence-based guidelines for the pharmacological management of substance abuse, harmful use, addiction and comorbidity: recommendations from the BAP. J Psychophamacol. 2012 Jul;26(7):899-952.
Galvin R, Brathen G, Ivashynka A, et al. ESNS guidelines for diagnosis, therapy and prevention of Wernicke encephalopathy. Eur J Neurol. 2010 Dec;17(12):1408-18.
National Collaborating Centre for Mental Health (UK). NICE Clinical Guidelines, No 115. Alcohol-Use Disorders: Diagnosis, Assessment, and Management of Harmful Drinking and Alcohol Dependence. Leicester (UK): British Psychological Society; 2011.
Thomson AD, Cook CCH, Touquet R et al. The Royal College of Physicians report on alcohol: guidelines for managing Wernicke’s encehpalopathy in the accident and Emergency Department. Alcohol Alcohol. Nov-Dec 2002;37(6):513-21.
Thomson AD, Guerrini I, Marshal J. The evolution and treatment of Korsakoff’s syndrome: out of sight, out of mind? Neuropsychol Rev. 2012 Jun;22(2):81-92.

GUIDELINES FOR AUTHORS

Guidelines for Authors

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^{Bernatsky S, Clarke AE, Suissa S. Hematologic malignant neoplasms after drug exposure in rheumatoid arthritis. Arch Intern Med. 2008;168:378-81.}

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A SPECIAL ARTICLE

Benign Rectal Strictures: A Review Article

Ammar Ahmad,Padmini Krishnamurthy

The aim of this review article is to assess the various etiologies and different management techniques for benign rectal strictures. A systematic review was performed using PubMed central using the keywords that included ‘benign’, ‘stricture or strictures’, and ‘rectum, rectal, or anorectal’. Retrospective studies, prospective studies, case series, and case reports describing etiology or management of benign rectal strictures were included in this review article. A total of 730 cases of benign rectal strictures were identified in 79 articles. Anastomotic stricture was the most common cause of benign rectal strictures. Different techniques were used to manage benign rectal strictures including Hegar dilation, balloon dilation, stent placement, microsurgery, or other surgical techniques. The initial technique used for management was dependent on the provider as there are no clear guidelines for management of benign rectal strictures.

INTRODUCTION

Benign rectal strictures can be iatrogenic after a major colorectal surgery or spontaneous due to medical conditions. The most common cause of benign rectal strictures are anastomotic strictures. Rectal strictures behave differently from colonic strictures due to rectum’s anatomical relation with the anal canal, proximity to pelvic organs, and unique blood supply. Different management techniques such as surgical repair, endoscopic balloon dilation, rectal stent placement, medical treatment alone, or a combination of treatments have been used to treat benign rectal strictures. In this article, we describe the etiologies and management of benign rectal strictures.

Methods

A PubMed Central search was carried out, using the search term (benign) AND (stricture or strictures) AND (rectum or rectal or anorectal). Only articles that described strictures known to be benign at the time of diagnosis were included. Retrospective studies, prospective studies, case series, and case reports were included. Content from references found in the articles were included if deemed relevant. In total, 79 articles are included in this review article.

Clinical Presentation

Rectal strictures can present with minor symptoms to progressive constipation and on occasion, obstipation. Symptoms include left lower quadrant abdominal pain, increased frequency of bowel movements, difficulty in defecation, feeling of inadequate evacuation, pencil-thin stools, anal pain, and fecal urgency. Stenosis is often defined as inability to pass a 12mm diameter sigmoidoscope1 or narrowing to less than one-finger breadth by digital rectal examination.²

Etiology of Rectal Strictures

Anastomotic strictures are the most common cause of benign rectal strictures. Non-operative etiologies of rectal strictures include inflammatory bowel disease, rectal ischemia, sexually transmitted disease, radiation, endometriosis, pelvic actinomycosis, chronic suppository usage, and solitary rectal ulcer.^3–17 Few cases of strictures have been reported after submucosal endoscopic dissection.¹⁸

Anastomotic Rectal Strictures

Post-operative anastomotic strictures develop in 3 to 30% of patients undergoing colorectal resection.^3,19-22 Anastomotic rectal strictures are predominantly seen following resection of rectal cancer with colorectal or coloanal anastomosis (with residual rectal cuff). Other surgeries that can lead to anastomotic rectal strictures include hemorrhoidectomy and colorectal resection for extensive diverticular disease.^1,22 Rectal strictures are more likely to form after stapled anastomosis compared to hand-sewn anastomosis.^22–27 Ischemia, post-operative anastomotic leakage, and postoperative radiation are major risk factors for development of anastomotic strictures.^{2,19,22,28,29} Other contributing factors include obesity, incomplete “doughnut” construction, low-lying anastomosis, and post-operative infection.^19,30Temporary diverting ileostomy or colostomy may contribute to anastomotic strictures due to absence of dilation of anastomosis by fecal stream.^31–33

Inflammatory Bowel Disease (IBD)

Anorectal strictures are more commonly seen in Crohn’s disease but can also be seen in ulcerative colitis. They are frequently present with fistulizing disease and proctitis.^8,34 Rectal stricture in ulcerative colitis may portend development of cancer. The pathophysiology remains speculative since both inflammatory and fibrotic components frequently occur in anorectal strictures in patients with inflammatory bowel disease. The presence of anorectal strictures in Crohn’s disease is a predictor of poor outcomes.⁹

Miscellaneous Etiologies of Rectal Strictures

Radiation Induced Rectal Strictures

Rectal stricture is a rare complication of pelvic irradiation. Chronic radiation proctitis has been reported in up to 20% of patients receiving radiation of the pelvis, and rectal stricture occurs in about 1 to 15% of these cases.35 Radiation causes histologic alterations such as obliterative endarteritis, tissue ischemia and necrosis leading to submucosal collagen deposition. These changes result in transmural fibrosis and formation of rectal strictures.²

Infectious Rectal Strictures

Sexually transmitted infections (STIs) due to anal intercourse have been reported to cause rectal strictures in both HIV and non-HIV patients. Lymphogranuloma venereum caused by chlamydia trachomatis is the most frequently reported sexually transmitted infection to cause rectal strictures.⁵ A case report implicating HSV-2 as the cause of benign rectal stricture has been reported.4 These strictures can occur in HIV patients even with CD4 counts > 200 x 106/L. Biopsies with histological evaluation using special stains and serology is used to confirm diagnosis.⁵ Rare cases of rectal strictures due to actinomycosis infection have also been reported due to contiguous spread from intrauterine devices.^10,17

Foreign Body Strictures

Benign rectal strictures can develop due to reactive inflammation and fibrosis around a foreign body.⁶ Strictures can develop following rectal administration of cation binding resins such as sodium polystyrene sulfonate or calcium polystyrene sulfonate and are usually diagnosed by presence of characteristic crystals on histology.³⁶ Chronic suppository usage is also noted to cause anorectal stenosis and strictures due to chronic reactive inflammation.^11,12

Endometriosis

Endometriosis should be suspected in women presenting with rectal stricture at a young age without any other explanation for the stricture. These patients generally have menstrual irregularity and cyclic abdominal pain that worsens during menstruation. The presence of ectopic endometrial tissue in the muscularis propria and subserosa or mesentery is thought to be the cause of the stricture.⁷

Solitary Rectal Ulcer Syndrome

Solitary rectal ulcer Syndrome is a benign disease that is often missed as a cause of rectal bleeding. It is thought to occur due to chronic hypoperfusion leading to ischemic injury to the rectal mucosa. Rarely, it can lead to stenosis or stricture of the rectum. Symptoms generally include chronic constipation, abdominal pain, rectal bleeding, and mucosal discharge.14,37

Ischemic Rectal Stricture

Ischemic proctitis is rare because the rectum has abundant blood supply and rich collaterals. A stricture due to ischemic proctitis develops due to acute compromise in blood flow usually in the setting of hypovolemic shock in patients with inadequate collateral circulation around the rectum.38

Complication of Submucosal Dissection

Endoscopic submucosal dissection is widely used as a minimally invasive treatment for colorectal neoplasms. It can help avoid surgical treatments that can result in anal dysfunction and the need for permanent colostomy. Although rare, endoscopic submucosal dissection can result in the formation of a stricture when the lesion being resected is large and extends into the lower rectum.18

Medical Management of Strictures

Management of benign rectal stricture depends on the etiology and often requires endoscopic or surgical intervention. Infectious strictures due to chlamydia or actinomycoses heal well with antibiotic treatment.^4,5 Rectal strictures due to inflammatory bowel disease have a healing rate of 59% with anti-tumor necrosis factor- agents with or without immunomodulators.⁹ It is important to biopsy strictures occurring after surgical resection of colorectal cancer and strictures related to IBD to rule out cancer.⁹ Stool softeners and laxatives are often needed, with high fiber diet even after resolution of stricture.²²

Specific Management of Strictures

Treatment of benign rectal strictures can be difficult and usually requires multiple modalities. These include dilation with Hegar or bougie dilators, endoscopic interventions (balloon dilation, stent placement), or surgical treatment. Case reports, small case series, and retrospective studies comprise most of the published literature.Consequently, novel methods may have to be used keeping in mind maximum benefit and safety of the patient. Mechanical dilation or endoscopic methods are attempted first, as surgical treatment is difficult and has high risk of end-colostomy.

Dilation by Hegar Dilators

Hegar dilators, often used by surgeons in the initial management of benign rectal strictures, are least invasive and most cost-effective mode of treatment. Dilation is usually started with ^14-20 French dilators and is gradually increase up to a maximum of 60 French dilators.^29,39 Based on our review of literature, Hegar dilators were effective in 56.1% of the cases (Table 2).

Endoscopic Balloon Dilation

For a majority of the cases, endoscopic balloon dilation is considered the first line of treatment. It can be performed using through the scope hydrostatic or combined endoscopic-fluoroscopic pneumatic balloon dilators.^22,24,40,41 Dilation under fluoroscopic guidance allows for better visualization and control over the process and ability to increase the balloon diameter as needed.⁴⁰Based on our review, balloon dilation has an overall success rate of 77.5% (Table 2). Dilation is considered successful when a 13mm colonoscope can be passed easily through the stricture with resolution of symptoms.24 Recurrence of symptoms occurred in 60% of cases after one dilation session. Consequently, on average two to three dilation sessions are required to achieve successful results.^42–47 More dilation sessions are generally required for low lying rectal strictures.¹⁸ If successful results are not achieved in five or more dilation sessions, alternative methods should be pursued.⁴⁸ There are no guidelines for time intervals between dilation sessions and is typically four weeks or more.⁴⁰In high-grade strictures, with a lumen < 7 mm, argon plasma coagulation or laser can be used to make a small incision that allows the endoscope to pass through the stricture for balloon dilation.^22,49 Endoscopic balloon dilation is especially effective for shorter strictures, usually < 2 cm in length with low complication rates.^50–52 Perforation is reported in about 1.1% of cases and abscess is reported in 0.2% of cases.⁵³

Stent Placement for Rectal Strictures

Stent placement is usually the next option for treatment of rectal strictures that do not resolve with endoscopic balloon dilation. They are usually used for strictures longer than 2 cm.^55,56 Most of the published literature on stents are case reports and case series. Three different types of stents have been used for rectal strictures: fully covered selfexpanding metal stents, uncovered metal stents, and biodegradable stents.^4,56–60 Uncovered metal stents are rarely used due to risk of mucosal hyperplasia leading to re-occlusion. Additionally, uncovered stents cannot be removed via endoscopic method, resulting in the need for surgery.⁵⁵

Fully covered self-expanding metal stents are most frequently used due to low tissue ingrowth and ease of removal.61 Based on our review, the success rate of fully covered self-expanding metal stents was 68.5% (Table 2). Migration of the stent was the most common complication and was reported in 31% of the cases. In some cases, migration occurs after stricture has sufficiently dilated.⁶²In a case series of four patients, migration was avoided with “upside-down” deployment of fully covered self-expanding metal stents.61 Rare complications such as stent fracture, coloenteric fistula, and perforation have been reported.^56,62,63 Less serious complications of rectal stent placement include abdominal pain, rectal pain, and tenesmus.60,61 It is unclear as to how long metal stents should be left in place, and removal has been reported as early as four weeks to as late as 30 months.^57,62

Biodegradable stents have been predominantly used for esophageal strictures.^56,64,65 They are more flexible, do not have to be removed as they usually self-disintegrate, and have a mean patency of 4 months.^56,66 Since they tend to be wider and longer, they are poorly tolerated in strictures closer to the anus. Based on our review, the success rate of biodegradable stents was 66.7% (Table 2). Migration was the most common complication, occurring in 27% of cases. Acute intestinal obstruction due to stent migration occurred in one case and required emergent surgical intervention.⁵⁵

Surgery for Rectal Strictures

Surgery is the last resort for treatment of benign rectal strictures since there is a high risk of endcolostomy and creation of permanent stoma. About 28% of patients have refractory strictures requiring surgical correction.68 Several minimally invasive surgical options have been reported for refractory benign rectal strictures, especially involving the lower rectum. These include transanal minimally invasive surgery (TAMIS), transanal endoscopic microsurgery (TEM), laparoscopic stricturoplasty using transanal radial linear cutter, and transanal stapler resection of stricture.^69–78Resection with re-anastomosis is more successful in upper rectal strictures (>10 cm from anal verge), although coloanal anastomosis for mid and lower rectal strictures (within 10 cm of anal verge) have also shown satisfactory long-term functional results.^68,79 Some recalcitrant rectal strictures in Crohn’s disease may need proctectomy and creation of a stoma.⁸

CONCLUSION

Benign rectal strictures are a common complication of rectal anastomotic surgeries but can also be caused by other etiologies such as Crohn’s disease, ischemia, infection, complication of endoscopic submucosal dissection, endometriosis, and chronic suppository usage. Management of rectal strictures is based on underlying etiology and may include both endoscopic and/or surgical interventions. This article provides guidance for the treatment of benign rectal strictures in different clinical scenarios.

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NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #210

Vitamin D Replacement in Adults: Current Strategies in Clinical Management

May 2021 • Volume XLV, Issue 5

Ronak M. Patel,Lindsay Bazydlo,Sue A. Brown,Alan C. Dalkin

Vitamin D, a prohormone, is needed for proper calcium homeostasis and potentially a host of additional physiologic functions. With changes in diet and an age-related decline in dermal production of vitamin D, practitioners often encounter patients with varying degrees of vitamin D insufficiency or deficiency. It is imperative to recognize and treat vitamin D deficiency before it manifests with detrimental effects on the body. This review will provide background on the physiology of vitamin D, common causes of hypovitaminosis D and conclude by providing a practical guide to vitamin D replacement and monitoring in common clinical scenarios.

INTRODUCTION

Vitamin D plays a critical role in human health. Well recognized is the importance of vitamin D in the absorption of calcium and phosphate mineral and the subsequent actions on bone mineralization, bone strength, and fracture protection.¹ In recent years, increasing preclinical evidence supports a role for vitamin D in a multitude of extra-skeletal physiological functions while low vitamin D levels have been linked in observational studies to immune dysfunction, malignancies (e.g. breast, colon, prostate), skeletal muscle strength, cardiovascular, and glycemic regulation.^2,3 Despite these associations, randomized controlled trials are either lacking or do not consistently find that vitamin D supplementation alters most of these non-skeletal outcomes.^4-7 However, it is generally agreed that perturbations in vitamin D metabolism can have an important impact on human health and hence screening for, and adequately treating, vitamin D deficiency is important for general health purposes.⁸

There exist two primary sources of vitamin D in humans: dermal production of vitamin D3 (cholecalciferol) and nutritional supplementation with either vitamin D3 or vitamin D2 (ergocalciferol). Shortfalls in dietary intake, reduction in ultraviolet light exposure needed for dermal biosynthesis of vitamin D, age-related decline in dermal production of vitamin D, disorders altering the gastrointestinal absorption of fats, and conditions that accelerate the metabolism of vitamin D stores can all predispose an individual to vitamin D deficiency. It is not surprising that hypovitaminosis D can be present in a wide array of clinical scenarios.

Conversely, while wide-spread supplementation of milk, juices, cereal, and daily multivitamins and calcium preparations with vitamin D is part of a general health approach to prevent vitamin D deficiency, over-replacement with vitamin D can have adverse consequences. Excess absorption of calcium and phosphate can predispose to hypercalciuria and nephrolithiasis and much less commonly, calcium mineral deposition of soft tissues and organs such as the kidney, thereby adversely altering function. It is the purpose of this article to:

briefly review the physiology and regulation of vitamin D activity
identify common clinical conditions in adults in which an evaluation of vitamin D status is indicated
review commercially available assays for vitamin D with their specific advantages and limitations,
propose a practical therapeutic plan for adults that includes monitoring and treatment goals that are generally acceptable for most patients with vitamin D deficiency

Physiology of Calcium Homeostasis and the Role of Vitamin D

The central player in the regulation of calcium is parathyroid hormone (PTH). PTH synthesis and secretion are directly regulated by the extracellular calcium concentration via the Calcium-sensing receptor (CaSR) through an inhibitory mechanism. Activation of the CaSR results in a reduction in PTH. Conversely, hypocalcemia increases PTH. Target organs for PTH action include the bone and kidney. PTH increases bone turnover and osteoclast action to release calcium and phosphorus into the circulation. In terms of renal actions, PTH enhances resorption of filtered calcium thereby limiting renal losses of calcium. In addition, and relevant to this review, PTH drives conversion of stored 25-hydroxyvitamin D (calcidiol) into the active metabolite ¹,25-dihydroxyvitamin D (calcitriol) via the actions of 1-alpha hydroxylase (CYP27B1). Calcitriol, in turn, enhances gastrointestinal absorption of calcium and phosphorus in the small bowel, though there may be a small contribution of calcidiol in this regard. In addition, and to a more modest degree, calcitriol favors bone mineralization and the deposition of calcium mineral into newly formed bone (osteoid). The increase in circulating calcium then feeds back at the level of the parathyroid gland to inhibit further PTH secretion

Stored vitamin D, i.e. calcidiol, is the product of 25-hydroxylation by the hepatocytes. Both vitamin D2 and D3 , regardless of their source, are fully and rapidly converted to calcidiol such that measurement of cholecalciferol or ergocalciferol is not practical. Calcidiol circulates attached to a vitamin D binding protein (high affinity, low capacity) and albumin (low affinity, high capacity), both products of hepatic biosynthesis. While the capacity to synthesize calcidiol from the parent compounds is generally well in excess of normal physiologic needs, severe hepatic dysfunction and end-stage liver disease can be associated with vitamin D deficiency due to a decline in calcidiol production.

Due to the feedback regulation described above, vitamin D toxicity due to excess ingestion of calcidiol is unlikely. If calcidiol levels rise above the normal range, calcium feedback to the parathyroid glands inhibits parathyroid hormone release, via activation of the CaSR, which in turn reduces the conversion of calcidiol to calcitriol. In effect, thereby preventing further enhancement in calcium absorption. None-the-less, excess levels of vitamin D (> 80 ng/mL) can increase circulating calcium levels which results in hypercalcemia and hypercalciuria and a long-term risk of nephrolithiasis.

Clinical Presentation of Vitamin D Deficiency, Differential Diagnosis and Laboratory Testing in Adults

The majority of patients with vitamin D deficiency have few, if any signs or symptoms related to the condition. Over the long term, reductions in vitamin D can lead to a reduction in circulating calcium, secondary hyperparathyroidism, increased bone remodeling and mobilization of calcium from bone. Severe vitamin D deficiency can result in osteomalacia that is often asymptomatic, but in some can be associated with diffuse bone pain. In addition, enhanced bone fragility can present with fracture from a ground level fall. The associated laboratory studies include a reduced 25-hydroxyvitamin D, normal or lownormal calcium levels, elevated PTH and alkaline phosphatase levels and a reduced 24-hour urinary calcium excretion rate.

There remains some discussion on the proper diagnostic nomenclature for patients with hypovitaminosis D. The Endocrine Society’s practice guidelines9 detail three categories:
1. Vitamin D sufficiency: 25-hydroxyvitamin D of > 30 ng/mL (75 nmol/L)
2. Vitamin D insufficiency: 25-hydroxyvitamin D between 21-29 ng/mL (51-74 nmol/L)
3. Vitamin D deficiency: 25-hydroxyvitamin D of < 20 ng/mL (<50 nmol/L)

It is important to note that the biologic contributions of either vitamin D2 or vitamin D3 are similar and hence differentiation between the two forms is not important for diagnostic purposes. Of greater import, measurement of 1,25-dihydroxyvitamin D (calcitriol) is not included in the identification of vitamin D deficient patients. Calcitriol levels are maintained in the normal range even in the presence of severe calcidiol deficiency and will not reflect many patients’ vitamin D balance.

A full discussion of the causes of vitamin D insufficiency and deficiency is beyond the scope of this manuscript. In overview, malabsorptive conditions predispose to deficiencies of all fatsoluble vitamins. Infectious etiologies (e.g. C. Difficile), inflammatory (e.g. ulcerative colitis) and iatrogenic (e.g. bariatric surgery) all can result in substantial reductions in vitamin D stores. In addition, with aging, dermal production of cholecalciferol declines and hence even reasonable UV light exposure may not be sufficient to maintain normal 25-hydroxyvitamin D levels.

It is also important to mention that there are acute causes of vitamin D deficiency. In patients receiving care in an intensive care unit for severe illness, there is some data suggesting that 25-hydroxyvitamin D levels may abruptly drop below the reference range.^10,11 That said, data supporting a benefit for urgent restoration of vitamin D levels is lacking. Hence, we neither check vitamin D levels, nor add vitamin D replacement in this patient population.

Measurement of Vitamin D

An immunoassay can use a variety of detection techniques and 2 methods for the measurement of 25-hydroxyvitamin D are chemiluminescence and radioactivity. Chemiluminescent immunoassays can be automated and allow for a faster turn-around time, with the downside being that it is unable to distinguish between 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 and is reported only as a total 25-hydroxyvitamin D level. Radioactivity as a detection method is becoming less common but radioimmunoassays (RIA) are still available. In general, immunoassays tend to underestimate the concentration of 25-hydroxyvitamin D2 due to a lower affinity of the antibody for this analyte compared to 25-hydroxyvitamin D3. Liquid chromatography tandem mass spectrometry is a popular choice for measuring 25-hydroxyvitamin D, as it separates and measures 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 individually and has been established as the gold standard to which chemiluminescent and RIA assays are compared.

A study comparing measurements from different laboratories using either highperformance liquid chromatography (HPLC), RIA, or automated chemiluminescent assays for measurements of serum 25-hydroxyvitamin D demonstrated that the degree of variability of the results between methods and between laboratories, even when using the same method, confounded the diagnosis of vitamin D insufficiency.12 Specifically, some chemiluminescent and RIA assays were found to underestimate the contribution of 25-hydroxyvitamin D2 to total circulating 25-hydroxyvitamin D levels. Since ergocalciferol (vitamin D2) is often used for treatment of hypovitaminosis D, the inability to measure 25-hydroxyvitamin D2 could result in apparent laboratory failures in assessing therapeutic responses and/or lead to a misdiagnosis of vitamin D insufficiency or deficiency. Increases in unmeasured vitamin D could potentially result in dose escalation and subsequent dangerous consequences such as hypervitaminosis D. As a result, we suggest ascertaining the specific assay for 25-hydroxyvitamin D used by your own laboratory, not only during diagnosis (although measurement of only 25-hydroxyvitamin D3 in that setting would be of little harm), but also when monitoring response to treatment.

Strategies for Vitamin D Replacement

While many preparations of vitamin D and its metabolites are available to restore normal circulating levels of vitamin D, cholecalciferol and ergocalciferol are used more frequently as they are less expensive and, in particular, cholecalciferol is readily available to most patients in overthe-counter formulations (Table 1). While the biological activities of the two forms of vitamin D are comparable, in our practice cholecalciferol is generally the preferred formulation for vitamin D supplementation as there is data to suggest that it is more effective than ergocalciferol at increasing total 25-hydroxyvitamin D levels.^13-15 This observation may be due to a predictable decrease in vitamin D3 level seen in patients treated with ergocalciferol.¹⁶We do not utilize calcitriol in most instances unless the patient manifests clinical signs of hypocalcemia, have hypoparathyroidism (and the associated deficit in renal 1-hydroxylation) or if they would be more likely to absorb calcitriol (e.g. following bariatric surgery).

In adult patients without malabsorption, but with vitamin D deficiency (25-hydroxyvitamin D of < 20 ng/mL (<50 nmol/L)), we initially treat with 2,000-6,000 international units (IU) cholecalciferol daily or 50,000 IU of ergocalciferol (or cholecalciferol) weekly for 6-8 weeks.⁹ Once the course of therapy is complete, we repeat testing including a 25-hydroxyvitamin D level along with a measurement of serum calcium. In addition, in patients with secondary hyperparathyroidism prior to treatment, normalization of PTH levels can confirm adequacy of replacement, though we elect to do this infrequently to reduce cost and recognizing that changes in PTH levels can lag behind changes in vitamin D levels. Once replete, the vitamin D dose is reduced to a maintenance regimen generally of 2,000 IU/day cholecalciferol, or 50,000 IU of ergocalciferol (or cholecalciferol), every 14-30 days, and levels are again repeated in 2-3 months. We feel the majority of these patients are at a relatively high risk of repeat vitamin D deficiency in the future, and they are counseled that this is life-long therapy. Of note, in obese individuals, steady state levels may take a longer time to reach and hence we often delay repeat measurement for an additional 1-3 months.

Patients who have vitamin D insufficiency (25-hydroxyvitamin D between 21-29 ng/mL (51-74 nmol/L)) may be replaced with 400-2,000 IU cholecalciferol per day to achieve normal 25-hydroxyvitamin D levels. In general, we do not recommend high dose vitamin D without documentation of vitamin D deficiency as there are emerging data to suggest routine use of this type of supplementation in vitamin D replete individuals may not be beneficial.¹⁷

In patients with malabsorptive states, higher doses of vitamin D may be needed, even as high as 6,000 IU-10,000 IU daily of cholecalciferol or 50,000 IU twice weekly of ergocalciferol(or cholecalciferol) for short-term use.⁹ Once replete,these patients usually continue on slightly reduced or in some cases the same dose of vitamin D long term to avoid recurrence of vitamin D deficiency. We often follow vitamin D and calcium levels every 3-6 months going forward to ensure adequate replacement and less often once stable.

In addition, there are special patient populations that may benefit from treatment with metabolites of vitamin D. Patients with liver disease may have impairment of 25-hydroxylation of vitamin D and these patients may benefit from calcidiol (25-hydroxyvitamin D).^18,19 Similarly, patients with severe renal disease or end-stage renal disease (ESRD, beyond stage 3) may have impairment in 1-hydroxylation of 25-hydroxyvitamin D and may benefit from calcitriol (1,25-dihydroxyvitamin D).²⁰Vitamin D analogs are often used in the ESRD patient population to reduce the sequelae of severe secondary hyperparathyroidism and the decision whether to treat a low 25-hydroxyvitamin D level is complex. Indeed, in many instances, we do replace these patients with cholecalciferol or ergocalciferol, to potentially reduce the effects of secondary hyperparathyroidism, even while recognizing that calcium balance is not significantly altered as a result.

Summary

Vitamin D has an important role in many physiological functions, most prominent and well established are its roles in calcium homeostasis and bone health and deficiency may be asymptomatic. Screening patients for vitamin D deficiency should be performed in individuals presenting with low bone mineral density. Cholecalciferol (D3 ) is the preferred replacement supplement, inexpensive, and readily available over-the-counter. Monitoring the success of vitamin D replacement is key and needs to be tailored to the patient in light of the vitamin D preparation to ensure sufficiency and avoid toxicity. The treatment plans outlined within this manuscript should provide practitioners with safe and effective means to restore vitamin D levels to the normal range.

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