Amy Karon

For patients with obesity who want to lose weight but for whom conventional weight-loss strategies have failed, the combination of intragastric balloon placement and lifestyle modifications may be preferable to lifestyle modifications alone, according to new clinical practice guidelines from the American Gastroenterological Association.

In randomized clinical trials of patients with obesity (body mass index >30 kg/m²), placing an intragastric balloon (IGB) significantly improved key outcomes such as weight loss, metabolic parameters (such as fasting blood glucose, hemoglobin A1c), and rates of remission of diabetes, hypertension, and dyslipidemia, compared with standard noninvasive weight loss interventions, Thiruvengadam Muniraj, MD, MRCP, of Yale University in New Haven, Conn., and associates wrote in Gastroenterology. However, concomitant lifestyle modifications of “moderate to high intensity” are strongly recommended “to maintain and augment weight loss” after IGB placement, according to the guidelines published in Gastroenterology.

Obesity (BMI >30), affects approximately 40% of U.S. adults, but only about 1.1% of eligible patients receive bariatric weight-loss surgery, and few are aware that endoscopic treatment is an option, according to the guideline. Early IGB models were associated with “a number of devastating adverse events,” spurring their removal from the U.S. market in the 1980s and 1990s. Since then, however, several new models of IGBs have become available. The guidelines noted that, in seven randomized, controlled trials of these newer IGBs, there were no deaths and only a 5.6% overall rate of serious adverse events – most commonly injury to the gastrointestinal tract at 6-8 months’ follow-up. “More recently, postmarketing surveillance of IGB has reported additional rare adverse events of hyperinflation, acute pancreatitis, and death,” but overall, “IGBs appear to be associated with both a favorable adverse event and patient tolerability profile.”

Three models of fluid-filled balloons and two models of gas-filled balloons are currently available in the United States, the guidelines noted. The authors did not recommend one specific type or model over another. They cite limited data indicating that “fluid-filled balloons may be associated with more weight loss, lower tolerability, and less favorable safety profile, than gas filled balloons. Shared decision-making is suggested for determining device choice.”

Relatively few studies have evaluated lifestyle modifications after IGB placement. In one study of 80 patients, a very-low-calorie ketogenic diet led to significantly more weight loss (on average, 7.1 kg), compared with a conventional low-calorie diet. “Although diet does augment and sustain weight loss in patients receiving IGB therapy, it is unclear whether other lifestyle modifications (e.g., exercise) would have the same impact,” the guideline authors wrote.

They strongly recommended prophylactic proton pump inhibitor (PPI) therapy after IGB placement. The procedure can erode the gastrointestinal mucosa, and studies in which patients received prophylactic PPIs reported lower rates of serious adverse events, most notably upper GI bleeding. However, the numerous short- and long-term risks of these drugs make it “imperative that the lowest dose, frequency, and duration of PPIs be used in patients undergoing IGB therapy.”

Intragastric balloons can cause nausea and vomiting, leading to their premature removal. Therefore, when placing an IGB, concomitant antiemetic therapy is recommended along with an anesthetic that is unlikely to cause nausea. “Evidence is insufficient to recommend a specific antiemetic regimen” and “choice of regimen [should be] based on institutional policy, clinical context, and availability,” according to the guidelines.

Based on low-quality evidence, they included a conditional recommendation for daily vitamin supplementation with one to two adult-dose multivitamins after IGB placement. They suggest against perioperative laboratory screening for nutritional deficiencies, based on a lack of supporting evidence. However, since nutritional deficiencies with IGB placement have been reported, decisions about screening for nutritional deficiencies should be tailored based on clinical judgment.

To create the guideline, the authors reviewed databases for studies published through January 2020 in which patients with obesity had an IGB placed for at least 6 months. In all, 79 articles were cited, including more than 10 randomized clinical trials.

An update of the clinical practice guidelines is expected in 2024. The AGA Institute provided the only funding. Dr. Muniraj and five coauthors reported having no conflicts of interest. The other two coauthors disclosed relationships with Nestle Health Sciences, the American Society for Gastrointestinal Endoscopy, the American College of Gastroenterology, and the Association of American Indian Physicians.
 

For patients with obesity who want to lose weight but for whom conventional weight-loss strategies have failed, the combination of intragastric balloon placement and lifestyle modifications may be preferable to lifestyle modifications alone, according to new clinical practice guidelines from the American Gastroenterological Association.

In randomized clinical trials of patients with obesity (body mass index >30 kg/m²), placing an intragastric balloon (IGB) significantly improved key outcomes such as weight loss, metabolic parameters (such as fasting blood glucose, hemoglobin A1c), and rates of remission of diabetes, hypertension, and dyslipidemia, compared with standard noninvasive weight loss interventions, Thiruvengadam Muniraj, MD, MRCP, of Yale University in New Haven, Conn., and associates wrote in Gastroenterology. However, concomitant lifestyle modifications of “moderate to high intensity” are strongly recommended “to maintain and augment weight loss” after IGB placement, according to the guidelines published in Gastroenterology.

Obesity (BMI >30), affects approximately 40% of U.S. adults, but only about 1.1% of eligible patients receive bariatric weight-loss surgery, and few are aware that endoscopic treatment is an option, according to the guideline. Early IGB models were associated with “a number of devastating adverse events,” spurring their removal from the U.S. market in the 1980s and 1990s. Since then, however, several new models of IGBs have become available. The guidelines noted that, in seven randomized, controlled trials of these newer IGBs, there were no deaths and only a 5.6% overall rate of serious adverse events – most commonly injury to the gastrointestinal tract at 6-8 months’ follow-up. “More recently, postmarketing surveillance of IGB has reported additional rare adverse events of hyperinflation, acute pancreatitis, and death,” but overall, “IGBs appear to be associated with both a favorable adverse event and patient tolerability profile.”

Three models of fluid-filled balloons and two models of gas-filled balloons are currently available in the United States, the guidelines noted. The authors did not recommend one specific type or model over another. They cite limited data indicating that “fluid-filled balloons may be associated with more weight loss, lower tolerability, and less favorable safety profile, than gas filled balloons. Shared decision-making is suggested for determining device choice.”

Relatively few studies have evaluated lifestyle modifications after IGB placement. In one study of 80 patients, a very-low-calorie ketogenic diet led to significantly more weight loss (on average, 7.1 kg), compared with a conventional low-calorie diet. “Although diet does augment and sustain weight loss in patients receiving IGB therapy, it is unclear whether other lifestyle modifications (e.g., exercise) would have the same impact,” the guideline authors wrote.

They strongly recommended prophylactic proton pump inhibitor (PPI) therapy after IGB placement. The procedure can erode the gastrointestinal mucosa, and studies in which patients received prophylactic PPIs reported lower rates of serious adverse events, most notably upper GI bleeding. However, the numerous short- and long-term risks of these drugs make it “imperative that the lowest dose, frequency, and duration of PPIs be used in patients undergoing IGB therapy.”

Intragastric balloons can cause nausea and vomiting, leading to their premature removal. Therefore, when placing an IGB, concomitant antiemetic therapy is recommended along with an anesthetic that is unlikely to cause nausea. “Evidence is insufficient to recommend a specific antiemetic regimen” and “choice of regimen [should be] based on institutional policy, clinical context, and availability,” according to the guidelines.

Based on low-quality evidence, they included a conditional recommendation for daily vitamin supplementation with one to two adult-dose multivitamins after IGB placement. They suggest against perioperative laboratory screening for nutritional deficiencies, based on a lack of supporting evidence. However, since nutritional deficiencies with IGB placement have been reported, decisions about screening for nutritional deficiencies should be tailored based on clinical judgment.

To create the guideline, the authors reviewed databases for studies published through January 2020 in which patients with obesity had an IGB placed for at least 6 months. In all, 79 articles were cited, including more than 10 randomized clinical trials.

An update of the clinical practice guidelines is expected in 2024. The AGA Institute provided the only funding. Dr. Muniraj and five coauthors reported having no conflicts of interest. The other two coauthors disclosed relationships with Nestle Health Sciences, the American Society for Gastrointestinal Endoscopy, the American College of Gastroenterology, and the Association of American Indian Physicians.
 

For patients with obesity who want to lose weight but for whom conventional weight-loss strategies have failed, the combination of intragastric balloon placement and lifestyle modifications may be preferable to lifestyle modifications alone, according to new clinical practice guidelines from the American Gastroenterological Association.

In randomized clinical trials of patients with obesity (body mass index >30 kg/m²), placing an intragastric balloon (IGB) significantly improved key outcomes such as weight loss, metabolic parameters (such as fasting blood glucose, hemoglobin A1c), and rates of remission of diabetes, hypertension, and dyslipidemia, compared with standard noninvasive weight loss interventions, Thiruvengadam Muniraj, MD, MRCP, of Yale University in New Haven, Conn., and associates wrote in Gastroenterology. However, concomitant lifestyle modifications of “moderate to high intensity” are strongly recommended “to maintain and augment weight loss” after IGB placement, according to the guidelines published in Gastroenterology.

Obesity (BMI >30), affects approximately 40% of U.S. adults, but only about 1.1% of eligible patients receive bariatric weight-loss surgery, and few are aware that endoscopic treatment is an option, according to the guideline. Early IGB models were associated with “a number of devastating adverse events,” spurring their removal from the U.S. market in the 1980s and 1990s. Since then, however, several new models of IGBs have become available. The guidelines noted that, in seven randomized, controlled trials of these newer IGBs, there were no deaths and only a 5.6% overall rate of serious adverse events – most commonly injury to the gastrointestinal tract at 6-8 months’ follow-up. “More recently, postmarketing surveillance of IGB has reported additional rare adverse events of hyperinflation, acute pancreatitis, and death,” but overall, “IGBs appear to be associated with both a favorable adverse event and patient tolerability profile.”

Three models of fluid-filled balloons and two models of gas-filled balloons are currently available in the United States, the guidelines noted. The authors did not recommend one specific type or model over another. They cite limited data indicating that “fluid-filled balloons may be associated with more weight loss, lower tolerability, and less favorable safety profile, than gas filled balloons. Shared decision-making is suggested for determining device choice.”

Relatively few studies have evaluated lifestyle modifications after IGB placement. In one study of 80 patients, a very-low-calorie ketogenic diet led to significantly more weight loss (on average, 7.1 kg), compared with a conventional low-calorie diet. “Although diet does augment and sustain weight loss in patients receiving IGB therapy, it is unclear whether other lifestyle modifications (e.g., exercise) would have the same impact,” the guideline authors wrote.

They strongly recommended prophylactic proton pump inhibitor (PPI) therapy after IGB placement. The procedure can erode the gastrointestinal mucosa, and studies in which patients received prophylactic PPIs reported lower rates of serious adverse events, most notably upper GI bleeding. However, the numerous short- and long-term risks of these drugs make it “imperative that the lowest dose, frequency, and duration of PPIs be used in patients undergoing IGB therapy.”

Intragastric balloons can cause nausea and vomiting, leading to their premature removal. Therefore, when placing an IGB, concomitant antiemetic therapy is recommended along with an anesthetic that is unlikely to cause nausea. “Evidence is insufficient to recommend a specific antiemetic regimen” and “choice of regimen [should be] based on institutional policy, clinical context, and availability,” according to the guidelines.

Based on low-quality evidence, they included a conditional recommendation for daily vitamin supplementation with one to two adult-dose multivitamins after IGB placement. They suggest against perioperative laboratory screening for nutritional deficiencies, based on a lack of supporting evidence. However, since nutritional deficiencies with IGB placement have been reported, decisions about screening for nutritional deficiencies should be tailored based on clinical judgment.

To create the guideline, the authors reviewed databases for studies published through January 2020 in which patients with obesity had an IGB placed for at least 6 months. In all, 79 articles were cited, including more than 10 randomized clinical trials.

An update of the clinical practice guidelines is expected in 2024. The AGA Institute provided the only funding. Dr. Muniraj and five coauthors reported having no conflicts of interest. The other two coauthors disclosed relationships with Nestle Health Sciences, the American Society for Gastrointestinal Endoscopy, the American College of Gastroenterology, and the Association of American Indian Physicians.
 

Clinicians who manage patients with cirrhosis should incorporate palliative care “irrespective of transplant candidacy,” according to a clinical practice update from the American Gastroenterological Association.

“[T]his care should be based on needs assessment instead of prognosis alone, delivered concurrently with curative or life-prolonging treatments, and tailored to the stage of disease,” wrote Puneeta Tandon, MD, of University of Alberta in Edmonton, Alta., and associates. Their report is in Clinical Gastroenterology and Hepatology.

Cirrhosis has a median survival ranging from 2 years for decompensated disease to 12 years for compensated disease, according to one systemic review. Moreover, even compensated cirrhosis incurs “a high burden of physical and psychological symptoms,” which increases as cirrhosis progresses, the update authors noted.

According to another review, there is established evidence outside cirrhosis that palliative care – including comprehensive symptom management, advance care planning, and timely referrals to specialty palliative care and hospice support – has the potential to significantly improve quality of life, end-of-life care, health care costs, coordination among providers, and caregiver outcomes.

However, the update authors noted that there remain few guidelines or guidance statements regarding palliative care in cirrhosis. Hence, the clinical practice update reviews 10 best practices to help clinicians fill this gap.

Providers “from any specialty, within any healthcare setting” can help provide palliative care for patients with cirrhosis, the experts emphasized. This is, in part, because of the growing population with cirrhosis being met with a limited number of palliative care specialists; dealing with this reality can be helped by inviting other providers to learn about and engage in palliative care.

Another best practice statement addressed assessing symptoms “within physical, psychological, social, and spiritual domains related to [patients’] liver disease, its treatment, and prognosis.” This approach is needed because of the complex effects that a life-threatening illness and its symptoms can have on many variables, including loss of independence/identity, financial stress, and impact on personal relationships. A systematic review of symptom prevalence in end-stage liver disease revealed a complex milieu, including pain, muscle cramps, sexual dysfunction, insomnia, and anxiety.

High-quality communication is important in palliative care, including discussion of prognosis and goals of care. Providers specializing in gastroenterology/hepatology should reevaluate prognosis and clarify prognosis and goals of care with patients and caregivers during routine visits and sentinel events, such as new complications, a hospital or intensive care admission, and when transplant eligibility is determined. However, prognostication in cirrhosis can be challenging, the experts noted. The update authors also acknowledged that, while more research is needed to inform practice regarding communicating with patients with serious illness about palliative care and goals of care, there are courses and resources meant to help improve those skills, including those provided by Vital Talk, Respecting Choices, and the Serious Illness Conversation Guide.

Cirrhosis “has physical, mental, and financial consequences” for caregivers, especially when patients have decompensated disease. To support caregivers, clinicians can routinely evaluate their burdens and needs. Tools such as the Caregiver Strain Index are useful and can be administered by ancillary staff. Clinicians also can reach out to primary care and palliative care providers to identify local resources for caregiver support.

“Because lack of time is one of the major barriers to administering palliative care, healthcare providers should consider how they can optimize efficiencies in palliative care delivery,” the experts wrote. Examples include identifying local billing codes, arranging for ancillary staff to screen patients on their palliative care needs, and setting up multidisciplinary teams that work together to deliver palliative care. If access to specialty palliative care is limited, providers can collaborate with local specialist teams to set “clear triggers and pathways for referral.”

Finally, hospice referrals are often delayed for patients with cirrhosis. “Find out your local referral criteria for hospice and what would be required to refer a cirrhosis patient there,” the experts advised. “Healthcare providers caring for patients with cirrhosis should provide timely referral to hospice for patients who have comfort-oriented goals and prognosis of 6 months or less.”

The authors of the clinical practice update received no funding support. They reported having no relevant conflicts of interest.

Clinicians who manage patients with cirrhosis should incorporate palliative care “irrespective of transplant candidacy,” according to a clinical practice update from the American Gastroenterological Association.

“[T]his care should be based on needs assessment instead of prognosis alone, delivered concurrently with curative or life-prolonging treatments, and tailored to the stage of disease,” wrote Puneeta Tandon, MD, of University of Alberta in Edmonton, Alta., and associates. Their report is in Clinical Gastroenterology and Hepatology.

Cirrhosis has a median survival ranging from 2 years for decompensated disease to 12 years for compensated disease, according to one systemic review. Moreover, even compensated cirrhosis incurs “a high burden of physical and psychological symptoms,” which increases as cirrhosis progresses, the update authors noted.

According to another review, there is established evidence outside cirrhosis that palliative care – including comprehensive symptom management, advance care planning, and timely referrals to specialty palliative care and hospice support – has the potential to significantly improve quality of life, end-of-life care, health care costs, coordination among providers, and caregiver outcomes.

However, the update authors noted that there remain few guidelines or guidance statements regarding palliative care in cirrhosis. Hence, the clinical practice update reviews 10 best practices to help clinicians fill this gap.

Providers “from any specialty, within any healthcare setting” can help provide palliative care for patients with cirrhosis, the experts emphasized. This is, in part, because of the growing population with cirrhosis being met with a limited number of palliative care specialists; dealing with this reality can be helped by inviting other providers to learn about and engage in palliative care.

Another best practice statement addressed assessing symptoms “within physical, psychological, social, and spiritual domains related to [patients’] liver disease, its treatment, and prognosis.” This approach is needed because of the complex effects that a life-threatening illness and its symptoms can have on many variables, including loss of independence/identity, financial stress, and impact on personal relationships. A systematic review of symptom prevalence in end-stage liver disease revealed a complex milieu, including pain, muscle cramps, sexual dysfunction, insomnia, and anxiety.

High-quality communication is important in palliative care, including discussion of prognosis and goals of care. Providers specializing in gastroenterology/hepatology should reevaluate prognosis and clarify prognosis and goals of care with patients and caregivers during routine visits and sentinel events, such as new complications, a hospital or intensive care admission, and when transplant eligibility is determined. However, prognostication in cirrhosis can be challenging, the experts noted. The update authors also acknowledged that, while more research is needed to inform practice regarding communicating with patients with serious illness about palliative care and goals of care, there are courses and resources meant to help improve those skills, including those provided by Vital Talk, Respecting Choices, and the Serious Illness Conversation Guide.

Cirrhosis “has physical, mental, and financial consequences” for caregivers, especially when patients have decompensated disease. To support caregivers, clinicians can routinely evaluate their burdens and needs. Tools such as the Caregiver Strain Index are useful and can be administered by ancillary staff. Clinicians also can reach out to primary care and palliative care providers to identify local resources for caregiver support.

“Because lack of time is one of the major barriers to administering palliative care, healthcare providers should consider how they can optimize efficiencies in palliative care delivery,” the experts wrote. Examples include identifying local billing codes, arranging for ancillary staff to screen patients on their palliative care needs, and setting up multidisciplinary teams that work together to deliver palliative care. If access to specialty palliative care is limited, providers can collaborate with local specialist teams to set “clear triggers and pathways for referral.”

Finally, hospice referrals are often delayed for patients with cirrhosis. “Find out your local referral criteria for hospice and what would be required to refer a cirrhosis patient there,” the experts advised. “Healthcare providers caring for patients with cirrhosis should provide timely referral to hospice for patients who have comfort-oriented goals and prognosis of 6 months or less.”

The authors of the clinical practice update received no funding support. They reported having no relevant conflicts of interest.

Clinicians who manage patients with cirrhosis should incorporate palliative care “irrespective of transplant candidacy,” according to a clinical practice update from the American Gastroenterological Association.

“[T]his care should be based on needs assessment instead of prognosis alone, delivered concurrently with curative or life-prolonging treatments, and tailored to the stage of disease,” wrote Puneeta Tandon, MD, of University of Alberta in Edmonton, Alta., and associates. Their report is in Clinical Gastroenterology and Hepatology.

Cirrhosis has a median survival ranging from 2 years for decompensated disease to 12 years for compensated disease, according to one systemic review. Moreover, even compensated cirrhosis incurs “a high burden of physical and psychological symptoms,” which increases as cirrhosis progresses, the update authors noted.

According to another review, there is established evidence outside cirrhosis that palliative care – including comprehensive symptom management, advance care planning, and timely referrals to specialty palliative care and hospice support – has the potential to significantly improve quality of life, end-of-life care, health care costs, coordination among providers, and caregiver outcomes.

However, the update authors noted that there remain few guidelines or guidance statements regarding palliative care in cirrhosis. Hence, the clinical practice update reviews 10 best practices to help clinicians fill this gap.

Providers “from any specialty, within any healthcare setting” can help provide palliative care for patients with cirrhosis, the experts emphasized. This is, in part, because of the growing population with cirrhosis being met with a limited number of palliative care specialists; dealing with this reality can be helped by inviting other providers to learn about and engage in palliative care.

Another best practice statement addressed assessing symptoms “within physical, psychological, social, and spiritual domains related to [patients’] liver disease, its treatment, and prognosis.” This approach is needed because of the complex effects that a life-threatening illness and its symptoms can have on many variables, including loss of independence/identity, financial stress, and impact on personal relationships. A systematic review of symptom prevalence in end-stage liver disease revealed a complex milieu, including pain, muscle cramps, sexual dysfunction, insomnia, and anxiety.

High-quality communication is important in palliative care, including discussion of prognosis and goals of care. Providers specializing in gastroenterology/hepatology should reevaluate prognosis and clarify prognosis and goals of care with patients and caregivers during routine visits and sentinel events, such as new complications, a hospital or intensive care admission, and when transplant eligibility is determined. However, prognostication in cirrhosis can be challenging, the experts noted. The update authors also acknowledged that, while more research is needed to inform practice regarding communicating with patients with serious illness about palliative care and goals of care, there are courses and resources meant to help improve those skills, including those provided by Vital Talk, Respecting Choices, and the Serious Illness Conversation Guide.

Cirrhosis “has physical, mental, and financial consequences” for caregivers, especially when patients have decompensated disease. To support caregivers, clinicians can routinely evaluate their burdens and needs. Tools such as the Caregiver Strain Index are useful and can be administered by ancillary staff. Clinicians also can reach out to primary care and palliative care providers to identify local resources for caregiver support.

“Because lack of time is one of the major barriers to administering palliative care, healthcare providers should consider how they can optimize efficiencies in palliative care delivery,” the experts wrote. Examples include identifying local billing codes, arranging for ancillary staff to screen patients on their palliative care needs, and setting up multidisciplinary teams that work together to deliver palliative care. If access to specialty palliative care is limited, providers can collaborate with local specialist teams to set “clear triggers and pathways for referral.”

Finally, hospice referrals are often delayed for patients with cirrhosis. “Find out your local referral criteria for hospice and what would be required to refer a cirrhosis patient there,” the experts advised. “Healthcare providers caring for patients with cirrhosis should provide timely referral to hospice for patients who have comfort-oriented goals and prognosis of 6 months or less.”

The authors of the clinical practice update received no funding support. They reported having no relevant conflicts of interest.

Antimicrobial resistance is the most common cause of treatment-refractory Helicobacter pylori infection, but before switching antibiotics, clinicians should screen for factors such as treatment nonadherence or inadequate suppression of gastric acid, according to a clinical practice update from the American Gastroenterological Association.

“Inadequate acid suppression is associated with H. pylori eradication failure. The use of high-dose and more potent PPIs, PPIs not metabolized by CYP2C19, or potassium-competitive acid blockers, if available, should be considered in cases of refractory H. pylori infection,” wrote Shailja C. Shah, MD, MPH, of Vanderbilt University Medical Center in Nashville, Tenn., and coauthors Prasad G. Iyer, MD, and Steven F. Moss, MD. . Their report is in Gastroenterology.

H. pylori infection is the most common cause of gastric cancer. Although eradication is widely recommended, it can be challenging because of strain diversity, rising antimicrobial resistance, a dearth of recent head-to-head clinical trials, and sparse epidemiologic and sensitivity data, the experts noted. For this reason, before selecting an eradication regimen, it is vital to thoroughly review a patient’s history of antibiotics – for example, any prior macrolide or fluoroquinolone exposure should preclude the use of clarithromycin- or levofloxacin-based regimens “given the high likelihood of resistance,” the experts wrote. They also advised that clinicians should avoid levofloxacin unless the H. pylori strain is known to be sensitive to it or if population rates of levofloxacin resistance rates are known to be less than 15%. However, amoxicillin, tetracycline, and rifabutin resistance are rare, and these agents “can be considered for subsequent therapies in refractory H. pylori infection.”

A longer antimicrobial regimen (such as 14 vs. 7 days) is more likely to eradicate H. pylori. If first-line bismuth quadruple therapy (such as a PPI plus bismuth, metronidazole, and tetracycline) fails, then second-line options include another bismuth-containing quadruple-agent regimen, or triple therapy with rifabutin or levofloxacin plus high-dose dual PPI therapy and amoxicillin. If patient history contains “penicillin allergy” but does not list anaphylaxis, then penicillin allergy testing can help determine if amoxicillin-based regimens are an option. The authors also note that, when used, amoxicillin should be dosed at 2 g/day in divided doses three to four times per day in order to avoid low trough levels because this might be associated with H. pylori eradication failure. For metronidazole, regardless of in vitro resistance, eradication is more likely if patients receive 1.5-2 g/day, in divided doses, with concomitant bismuth.

Treatment nonadherence contributes to refractory H. pylori infection and may be caused by the complexity of the treatment regimen, high pill burden, and side effects. To improve adherence, the experts advised counseling patients on the rationale for the treatment regimen, the dosing instructions, the importance of completing the full course of therapy, and providing anticipatory guidance regarding common side effects. If a patient adheres to second-line treatment and it still fails, then susceptibility testing is advised before starting another regimen. Depending on the results, options may include levofloxacin-based quadruple therapy, another round of bismuth-based quadruple therapy, a PPI plus amoxicillin and rifabutin, or high-dose PPI therapy plus high-dose amoxicillin (2-3 g/day divided across three to four doses).

Other considerations include how to approach patients and caregivers, particularly the elderly and other vulnerable patients, with shared decision-making to help them weigh the potential benefits of continuing to try to eradicate H. pylori against the risk of possible adverse effects and the “inconvenience of repeated exposure to antibiotics and high-dose acid suppression,” the experts wrote. They also advised tracking rates of eradication success and relevant demographic and clinical data, including patients’ antibiotic history. Publicly sharing aggregated, deidentified results can help other local clinicians select eradication regimens. Finally, the use of probiotics and other adjunctive therapies “should be considered experimental” since these have no clear benefit for treating refractory H. pylori infection.

Dr. Shah was funded by an AGA Research Scholar Award and a Veterans Affairs Career Development Award. She reported having no conflicts of interest. Dr. Iyer and Dr. Moss disclosed ties to Exact Sciences, Pentax Medical, Redhill Biopharma, Phathom, American Molecular Laboratories, and Takeda.

Antimicrobial resistance is the most common cause of treatment-refractory Helicobacter pylori infection, but before switching antibiotics, clinicians should screen for factors such as treatment nonadherence or inadequate suppression of gastric acid, according to a clinical practice update from the American Gastroenterological Association.

“Inadequate acid suppression is associated with H. pylori eradication failure. The use of high-dose and more potent PPIs, PPIs not metabolized by CYP2C19, or potassium-competitive acid blockers, if available, should be considered in cases of refractory H. pylori infection,” wrote Shailja C. Shah, MD, MPH, of Vanderbilt University Medical Center in Nashville, Tenn., and coauthors Prasad G. Iyer, MD, and Steven F. Moss, MD. . Their report is in Gastroenterology.

H. pylori infection is the most common cause of gastric cancer. Although eradication is widely recommended, it can be challenging because of strain diversity, rising antimicrobial resistance, a dearth of recent head-to-head clinical trials, and sparse epidemiologic and sensitivity data, the experts noted. For this reason, before selecting an eradication regimen, it is vital to thoroughly review a patient’s history of antibiotics – for example, any prior macrolide or fluoroquinolone exposure should preclude the use of clarithromycin- or levofloxacin-based regimens “given the high likelihood of resistance,” the experts wrote. They also advised that clinicians should avoid levofloxacin unless the H. pylori strain is known to be sensitive to it or if population rates of levofloxacin resistance rates are known to be less than 15%. However, amoxicillin, tetracycline, and rifabutin resistance are rare, and these agents “can be considered for subsequent therapies in refractory H. pylori infection.”

A longer antimicrobial regimen (such as 14 vs. 7 days) is more likely to eradicate H. pylori. If first-line bismuth quadruple therapy (such as a PPI plus bismuth, metronidazole, and tetracycline) fails, then second-line options include another bismuth-containing quadruple-agent regimen, or triple therapy with rifabutin or levofloxacin plus high-dose dual PPI therapy and amoxicillin. If patient history contains “penicillin allergy” but does not list anaphylaxis, then penicillin allergy testing can help determine if amoxicillin-based regimens are an option. The authors also note that, when used, amoxicillin should be dosed at 2 g/day in divided doses three to four times per day in order to avoid low trough levels because this might be associated with H. pylori eradication failure. For metronidazole, regardless of in vitro resistance, eradication is more likely if patients receive 1.5-2 g/day, in divided doses, with concomitant bismuth.

Treatment nonadherence contributes to refractory H. pylori infection and may be caused by the complexity of the treatment regimen, high pill burden, and side effects. To improve adherence, the experts advised counseling patients on the rationale for the treatment regimen, the dosing instructions, the importance of completing the full course of therapy, and providing anticipatory guidance regarding common side effects. If a patient adheres to second-line treatment and it still fails, then susceptibility testing is advised before starting another regimen. Depending on the results, options may include levofloxacin-based quadruple therapy, another round of bismuth-based quadruple therapy, a PPI plus amoxicillin and rifabutin, or high-dose PPI therapy plus high-dose amoxicillin (2-3 g/day divided across three to four doses).

Other considerations include how to approach patients and caregivers, particularly the elderly and other vulnerable patients, with shared decision-making to help them weigh the potential benefits of continuing to try to eradicate H. pylori against the risk of possible adverse effects and the “inconvenience of repeated exposure to antibiotics and high-dose acid suppression,” the experts wrote. They also advised tracking rates of eradication success and relevant demographic and clinical data, including patients’ antibiotic history. Publicly sharing aggregated, deidentified results can help other local clinicians select eradication regimens. Finally, the use of probiotics and other adjunctive therapies “should be considered experimental” since these have no clear benefit for treating refractory H. pylori infection.

Dr. Shah was funded by an AGA Research Scholar Award and a Veterans Affairs Career Development Award. She reported having no conflicts of interest. Dr. Iyer and Dr. Moss disclosed ties to Exact Sciences, Pentax Medical, Redhill Biopharma, Phathom, American Molecular Laboratories, and Takeda.

Antimicrobial resistance is the most common cause of treatment-refractory Helicobacter pylori infection, but before switching antibiotics, clinicians should screen for factors such as treatment nonadherence or inadequate suppression of gastric acid, according to a clinical practice update from the American Gastroenterological Association.

“Inadequate acid suppression is associated with H. pylori eradication failure. The use of high-dose and more potent PPIs, PPIs not metabolized by CYP2C19, or potassium-competitive acid blockers, if available, should be considered in cases of refractory H. pylori infection,” wrote Shailja C. Shah, MD, MPH, of Vanderbilt University Medical Center in Nashville, Tenn., and coauthors Prasad G. Iyer, MD, and Steven F. Moss, MD. . Their report is in Gastroenterology.

H. pylori infection is the most common cause of gastric cancer. Although eradication is widely recommended, it can be challenging because of strain diversity, rising antimicrobial resistance, a dearth of recent head-to-head clinical trials, and sparse epidemiologic and sensitivity data, the experts noted. For this reason, before selecting an eradication regimen, it is vital to thoroughly review a patient’s history of antibiotics – for example, any prior macrolide or fluoroquinolone exposure should preclude the use of clarithromycin- or levofloxacin-based regimens “given the high likelihood of resistance,” the experts wrote. They also advised that clinicians should avoid levofloxacin unless the H. pylori strain is known to be sensitive to it or if population rates of levofloxacin resistance rates are known to be less than 15%. However, amoxicillin, tetracycline, and rifabutin resistance are rare, and these agents “can be considered for subsequent therapies in refractory H. pylori infection.”

A longer antimicrobial regimen (such as 14 vs. 7 days) is more likely to eradicate H. pylori. If first-line bismuth quadruple therapy (such as a PPI plus bismuth, metronidazole, and tetracycline) fails, then second-line options include another bismuth-containing quadruple-agent regimen, or triple therapy with rifabutin or levofloxacin plus high-dose dual PPI therapy and amoxicillin. If patient history contains “penicillin allergy” but does not list anaphylaxis, then penicillin allergy testing can help determine if amoxicillin-based regimens are an option. The authors also note that, when used, amoxicillin should be dosed at 2 g/day in divided doses three to four times per day in order to avoid low trough levels because this might be associated with H. pylori eradication failure. For metronidazole, regardless of in vitro resistance, eradication is more likely if patients receive 1.5-2 g/day, in divided doses, with concomitant bismuth.

Treatment nonadherence contributes to refractory H. pylori infection and may be caused by the complexity of the treatment regimen, high pill burden, and side effects. To improve adherence, the experts advised counseling patients on the rationale for the treatment regimen, the dosing instructions, the importance of completing the full course of therapy, and providing anticipatory guidance regarding common side effects. If a patient adheres to second-line treatment and it still fails, then susceptibility testing is advised before starting another regimen. Depending on the results, options may include levofloxacin-based quadruple therapy, another round of bismuth-based quadruple therapy, a PPI plus amoxicillin and rifabutin, or high-dose PPI therapy plus high-dose amoxicillin (2-3 g/day divided across three to four doses).

Other considerations include how to approach patients and caregivers, particularly the elderly and other vulnerable patients, with shared decision-making to help them weigh the potential benefits of continuing to try to eradicate H. pylori against the risk of possible adverse effects and the “inconvenience of repeated exposure to antibiotics and high-dose acid suppression,” the experts wrote. They also advised tracking rates of eradication success and relevant demographic and clinical data, including patients’ antibiotic history. Publicly sharing aggregated, deidentified results can help other local clinicians select eradication regimens. Finally, the use of probiotics and other adjunctive therapies “should be considered experimental” since these have no clear benefit for treating refractory H. pylori infection.

Dr. Shah was funded by an AGA Research Scholar Award and a Veterans Affairs Career Development Award. She reported having no conflicts of interest. Dr. Iyer and Dr. Moss disclosed ties to Exact Sciences, Pentax Medical, Redhill Biopharma, Phathom, American Molecular Laboratories, and Takeda.

Obesity, a risk factor for nonalcoholic fatty liver disease (NAFLD) and a prevalent comorbidity among people with cirrhosis of all etiologies, is associated with a number of untoward health outcomes, and weight loss is an important goal, according to a clinical practice update from the American Gastroenterological Association. According to one study cited in the update, approximately 30% of patients with cirrhosis have comorbid obesity, and this figure may increase even further as the epidemic of NAFLD progresses.

For obese patients with cirrhosis, weight loss “is an important therapeutic goal” because obesity heightens risks of portal vein thrombosis, portal hypertension, hepatocellular carcinoma, liver failure in acute on chronic liver disease, and other concerns. Despite no longer being an absolute contraindication, obesity can also complicate liver transplantation considerations, Heather Patton, MD, of the Veterans Affairs San Diego Healthcare System and associates wrote in Clinical Gastroenterology and Hepatology. Consideration of individuals with cirrhosis, however, requires careful scrutiny of surgical candidacy, appropriate resources for care of patients with advanced liver disease, and a high-volume bariatric surgical center given the inherent risks of surgical procedures in this patient population.

For patients with cirrhosis and obesity, laparoscopic sleeve gastrectomy is probably the best option for bariatric surgery because it preserves endoscopic access to the biliary tree, facilitates gradual weight loss, and does not cause malabsorption, according to the update.

Clinicians and patients should time bariatric surgery based on liver disease stage – for patients with decompensated disease, surgery should be performed only at the same time as or after liver transplantation, the experts wrote. Clinicians should also evaluate candidacy for liver transplantation before bariatric surgery “so that patients who are ineligible for transplant (and their families) have a clear understanding of this, avoiding the need for the medical team to address this issue urgently if the patient’s condition deteriorates postoperatively.”

One review suggested that bariatric surgery is “the most effective and durable” means of weight loss, according to the authors of the update; however, another review suggested increased surgical risk for bariatric surgery among patients with cirrhosis, so the update’s authors advised individualized risk-benefit assessments. These assessments are made even more complicated by scarcity of relevant randomized trial data, so the experts identified PubMed-indexed, peer-reviewed articles published between 2000 and 2020 and used these to make 10 best practice advice statements for bariatric surgery in obese patients with cirrhosis.

The surgical, anesthesia, and medical teams must be well versed in assessing and operating on patients with portal hypertension and cirrhosis and in managing these patients postoperatively, the experts wrote. The preoperative assessment should include cirrhosis status (compensated versus decompensated), the presence and severity of sarcopenia, ascites, and portal hypertension, and candidacy for liver transplantation. It is vital to check for clinically significant portal hypertension (CSPH) because endoscopic devices should not be used in patients with gastric and/or esophageal varices. To do so, upper endoscopy and cross-sectional imaging are advised, pending better data on noninvasive assessment methods. For patients without CSPH, endoscopic bariatric treatment can be somewhat less effective for weight loss but also might be less likely to lead to postoperative complications. However, head-to-head and long-term safety data are not yet available.

The experts also noted that bariatric surgery increases the effects (blood levels) of alcohol and can increase patients’ risk for developing an alcohol use disorder. Therefore, clinicians should carefully the history of alcohol use and repeatedly educate patients about the risks of consuming alcohol after bariatric surgery. According to a study from 2012 and a review from 2015, male sex, younger age, less social support, and regular or “problematic” alcohol use before bariatric surgery heighten the risk for developing an alcohol use disorder afterward, the experts noted.

Funding sources included the Robert H. Yauk Charitable Trust Gift for Liver Transplant Research 2017-2020 and Regenerative Medicine for Prevention of Post-Transplant Biliary Complications. The authors reported having no conflicts of interest.

This article was updated Feb. 23, 2021.

Obesity, a risk factor for nonalcoholic fatty liver disease (NAFLD) and a prevalent comorbidity among people with cirrhosis of all etiologies, is associated with a number of untoward health outcomes, and weight loss is an important goal, according to a clinical practice update from the American Gastroenterological Association. According to one study cited in the update, approximately 30% of patients with cirrhosis have comorbid obesity, and this figure may increase even further as the epidemic of NAFLD progresses.

For obese patients with cirrhosis, weight loss “is an important therapeutic goal” because obesity heightens risks of portal vein thrombosis, portal hypertension, hepatocellular carcinoma, liver failure in acute on chronic liver disease, and other concerns. Despite no longer being an absolute contraindication, obesity can also complicate liver transplantation considerations, Heather Patton, MD, of the Veterans Affairs San Diego Healthcare System and associates wrote in Clinical Gastroenterology and Hepatology. Consideration of individuals with cirrhosis, however, requires careful scrutiny of surgical candidacy, appropriate resources for care of patients with advanced liver disease, and a high-volume bariatric surgical center given the inherent risks of surgical procedures in this patient population.

For patients with cirrhosis and obesity, laparoscopic sleeve gastrectomy is probably the best option for bariatric surgery because it preserves endoscopic access to the biliary tree, facilitates gradual weight loss, and does not cause malabsorption, according to the update.

Clinicians and patients should time bariatric surgery based on liver disease stage – for patients with decompensated disease, surgery should be performed only at the same time as or after liver transplantation, the experts wrote. Clinicians should also evaluate candidacy for liver transplantation before bariatric surgery “so that patients who are ineligible for transplant (and their families) have a clear understanding of this, avoiding the need for the medical team to address this issue urgently if the patient’s condition deteriorates postoperatively.”

One review suggested that bariatric surgery is “the most effective and durable” means of weight loss, according to the authors of the update; however, another review suggested increased surgical risk for bariatric surgery among patients with cirrhosis, so the update’s authors advised individualized risk-benefit assessments. These assessments are made even more complicated by scarcity of relevant randomized trial data, so the experts identified PubMed-indexed, peer-reviewed articles published between 2000 and 2020 and used these to make 10 best practice advice statements for bariatric surgery in obese patients with cirrhosis.

The surgical, anesthesia, and medical teams must be well versed in assessing and operating on patients with portal hypertension and cirrhosis and in managing these patients postoperatively, the experts wrote. The preoperative assessment should include cirrhosis status (compensated versus decompensated), the presence and severity of sarcopenia, ascites, and portal hypertension, and candidacy for liver transplantation. It is vital to check for clinically significant portal hypertension (CSPH) because endoscopic devices should not be used in patients with gastric and/or esophageal varices. To do so, upper endoscopy and cross-sectional imaging are advised, pending better data on noninvasive assessment methods. For patients without CSPH, endoscopic bariatric treatment can be somewhat less effective for weight loss but also might be less likely to lead to postoperative complications. However, head-to-head and long-term safety data are not yet available.

The experts also noted that bariatric surgery increases the effects (blood levels) of alcohol and can increase patients’ risk for developing an alcohol use disorder. Therefore, clinicians should carefully the history of alcohol use and repeatedly educate patients about the risks of consuming alcohol after bariatric surgery. According to a study from 2012 and a review from 2015, male sex, younger age, less social support, and regular or “problematic” alcohol use before bariatric surgery heighten the risk for developing an alcohol use disorder afterward, the experts noted.

Funding sources included the Robert H. Yauk Charitable Trust Gift for Liver Transplant Research 2017-2020 and Regenerative Medicine for Prevention of Post-Transplant Biliary Complications. The authors reported having no conflicts of interest.

This article was updated Feb. 23, 2021.

Obesity, a risk factor for nonalcoholic fatty liver disease (NAFLD) and a prevalent comorbidity among people with cirrhosis of all etiologies, is associated with a number of untoward health outcomes, and weight loss is an important goal, according to a clinical practice update from the American Gastroenterological Association. According to one study cited in the update, approximately 30% of patients with cirrhosis have comorbid obesity, and this figure may increase even further as the epidemic of NAFLD progresses.

For obese patients with cirrhosis, weight loss “is an important therapeutic goal” because obesity heightens risks of portal vein thrombosis, portal hypertension, hepatocellular carcinoma, liver failure in acute on chronic liver disease, and other concerns. Despite no longer being an absolute contraindication, obesity can also complicate liver transplantation considerations, Heather Patton, MD, of the Veterans Affairs San Diego Healthcare System and associates wrote in Clinical Gastroenterology and Hepatology. Consideration of individuals with cirrhosis, however, requires careful scrutiny of surgical candidacy, appropriate resources for care of patients with advanced liver disease, and a high-volume bariatric surgical center given the inherent risks of surgical procedures in this patient population.

For patients with cirrhosis and obesity, laparoscopic sleeve gastrectomy is probably the best option for bariatric surgery because it preserves endoscopic access to the biliary tree, facilitates gradual weight loss, and does not cause malabsorption, according to the update.

Clinicians and patients should time bariatric surgery based on liver disease stage – for patients with decompensated disease, surgery should be performed only at the same time as or after liver transplantation, the experts wrote. Clinicians should also evaluate candidacy for liver transplantation before bariatric surgery “so that patients who are ineligible for transplant (and their families) have a clear understanding of this, avoiding the need for the medical team to address this issue urgently if the patient’s condition deteriorates postoperatively.”

One review suggested that bariatric surgery is “the most effective and durable” means of weight loss, according to the authors of the update; however, another review suggested increased surgical risk for bariatric surgery among patients with cirrhosis, so the update’s authors advised individualized risk-benefit assessments. These assessments are made even more complicated by scarcity of relevant randomized trial data, so the experts identified PubMed-indexed, peer-reviewed articles published between 2000 and 2020 and used these to make 10 best practice advice statements for bariatric surgery in obese patients with cirrhosis.

The surgical, anesthesia, and medical teams must be well versed in assessing and operating on patients with portal hypertension and cirrhosis and in managing these patients postoperatively, the experts wrote. The preoperative assessment should include cirrhosis status (compensated versus decompensated), the presence and severity of sarcopenia, ascites, and portal hypertension, and candidacy for liver transplantation. It is vital to check for clinically significant portal hypertension (CSPH) because endoscopic devices should not be used in patients with gastric and/or esophageal varices. To do so, upper endoscopy and cross-sectional imaging are advised, pending better data on noninvasive assessment methods. For patients without CSPH, endoscopic bariatric treatment can be somewhat less effective for weight loss but also might be less likely to lead to postoperative complications. However, head-to-head and long-term safety data are not yet available.

The experts also noted that bariatric surgery increases the effects (blood levels) of alcohol and can increase patients’ risk for developing an alcohol use disorder. Therefore, clinicians should carefully the history of alcohol use and repeatedly educate patients about the risks of consuming alcohol after bariatric surgery. According to a study from 2012 and a review from 2015, male sex, younger age, less social support, and regular or “problematic” alcohol use before bariatric surgery heighten the risk for developing an alcohol use disorder afterward, the experts noted.

Funding sources included the Robert H. Yauk Charitable Trust Gift for Liver Transplant Research 2017-2020 and Regenerative Medicine for Prevention of Post-Transplant Biliary Complications. The authors reported having no conflicts of interest.

This article was updated Feb. 23, 2021.

Endoscopy with biopsies is best for diagnosing immune-mediated enterocolitis in patients receiving immune checkpoint inhibitors (ICIs), but another option is to first test the stool for lactoferrin or calprotectin to identify patients with mild diarrhea who could benefit from endoscopy, according to a clinical practice update from the American Gastroenterological Association.

Writing in Gastroenterology, Michael Dougan, MD, PhD, of Harvard Medical School, Boston, and colleagues noted that stool lactoferrin had been found in one study to be 90% sensitive for detecting histologic inflammation, while another study found that mucosal inflammation is absent in 20%-30% of patients with suspected ICI enterocolitis. Nonetheless, clinicians should consider diagnostic endoscopy before starting high-dose corticosteroids for ICI enterocolitis, especially because “colonic ulceration identified by endoscopy is the only established factor that predicts how ICI enterocolitis will respond to treatment,” Dr. Dougan and colleagues wrote. If performed, endoscopy must be prompt because ICI colitis can progress within days, especially if patients are receiving ipilimumab.

ICIs can induce autoimmune inflammation in almost any organ system because they target pathways that play “key roles in regulating autoimmunity,” the experts wrote. The gastrointestinal tract is one of the most common sites of toxicity: One study from 2006 and another from 2019 suggested that colitis, with or without enteritis, affects up to 40% of patients depending on the pathway targeted by the treatment. Oncologists manage most gastrointestinal ICI toxicities, but gastroenterologists and hepatologists often help with diagnosis, risk assessment, and managing complex, atypical, or treatment-refractory cases; to help guide this process, the experts reviewed the literature and made 15 relevant recommendations.

The authors noted that the differential diagnosis is broad, but suggested that Clostridioides difficile testing and stool culture (or stool pathogen testing, where available) should be performed in all patients to rule out infectious causes prior to any immunosuppressive treatments, such as corticosteroids. Abdominal imaging is not recommended if a patient only has diarrhea but can help rule out complications if fever, bleeding, or abdominal pain are also present. Laboratory blood tests are rarely informative.

High-dose glucocorticoids are usually effective, often being started at 0.5-2.0 mg/kg prednisone or equivalent daily and tapered over 4-6 weeks after clinical improvement, but these doses and schedules have not been rigorously examined. For glucocorticoid-refractory ICI enterocolitis, infliximab and vedolizumab “are reasonable options” for second line immunosuppression and should be individualized based on the underlying cancer and other risk factors; patients usually respond to these immunomodulators in less than a week, “an important contrast with IBD,” the experts wrote. Most cases of ICI enterocolitis do not recur unless the ICI is restarted, but “many patients require the full loading dose for infliximab or vedolizumab, and maintenance therapy may still be required for certain cases.”

ICI-induced hepatitis is less common, affecting less than 5% of patients in clinical trials according to the authors, but incidence rises if patients are on ICI combinations or an ICI plus chemotherapy. Before starting any ICI, patients’ total bilirubin, alkaline phosphatase, AST, and ALT levels should be checked, as should testing for hepatitis B. Liver chemistries should be repeated before each ICI cycle, and rising chemistries should trigger an assessment for other causes of liver injury.

Patients with Common Terminology Criteria for Adverse Events (CTCAE) grade 1 hepatitis – defined as AST or ALT 1-3 times the upper limit of normal or total bilirubin 1-1.5 times upper limit of normal – should receive liver function tests once or twice weekly. For CTCAE grade 2 hepatitis, (AST/ALT more than 3-5 times upper limit of normal or total bilirubin more than 1.5-3 times upper limit of normal), ICI should be held until resolution to grade 1, and corticosteroids (prednisone or its equivalent dosed at 0.5-1.0 mg/kg daily) should be considered if there are clinical symptoms of liver toxicity. For grade 3 hepatitis (AST/ALT greater than 5-20 times upper limit of normal or total bilirubin more than 3-10 times upper limit of normal), ICI therapy should be halted, “and urgent consultation with a gastroenterologist/hepatologist is appropriate.” In this context, methylprednisone (1-2 mg/kg) is suggested, and azathioprine or mycophenolate mofetil can be considered if clinical hepatitis does not improve in 3-5 days. For CTCAE grade 4 hepatitis, hospitalization is recommended, and patients should permanently stop the ICI and receive 2 mg/kg per day of methylprednisolone or its equivalent.

The authors received no funding support. Dr. Dougan reported consulting or advisory relationships with Neoleukin Therapeutics, Genentech, Tillotts Pharma, and Partner Therapeutics and grant support from Novartis and Genentech. Two coauthors also reported ties to several pharmaceutical companies.
 

Endoscopy with biopsies is best for diagnosing immune-mediated enterocolitis in patients receiving immune checkpoint inhibitors (ICIs), but another option is to first test the stool for lactoferrin or calprotectin to identify patients with mild diarrhea who could benefit from endoscopy, according to a clinical practice update from the American Gastroenterological Association.

Writing in Gastroenterology, Michael Dougan, MD, PhD, of Harvard Medical School, Boston, and colleagues noted that stool lactoferrin had been found in one study to be 90% sensitive for detecting histologic inflammation, while another study found that mucosal inflammation is absent in 20%-30% of patients with suspected ICI enterocolitis. Nonetheless, clinicians should consider diagnostic endoscopy before starting high-dose corticosteroids for ICI enterocolitis, especially because “colonic ulceration identified by endoscopy is the only established factor that predicts how ICI enterocolitis will respond to treatment,” Dr. Dougan and colleagues wrote. If performed, endoscopy must be prompt because ICI colitis can progress within days, especially if patients are receiving ipilimumab.

ICIs can induce autoimmune inflammation in almost any organ system because they target pathways that play “key roles in regulating autoimmunity,” the experts wrote. The gastrointestinal tract is one of the most common sites of toxicity: One study from 2006 and another from 2019 suggested that colitis, with or without enteritis, affects up to 40% of patients depending on the pathway targeted by the treatment. Oncologists manage most gastrointestinal ICI toxicities, but gastroenterologists and hepatologists often help with diagnosis, risk assessment, and managing complex, atypical, or treatment-refractory cases; to help guide this process, the experts reviewed the literature and made 15 relevant recommendations.

The authors noted that the differential diagnosis is broad, but suggested that Clostridioides difficile testing and stool culture (or stool pathogen testing, where available) should be performed in all patients to rule out infectious causes prior to any immunosuppressive treatments, such as corticosteroids. Abdominal imaging is not recommended if a patient only has diarrhea but can help rule out complications if fever, bleeding, or abdominal pain are also present. Laboratory blood tests are rarely informative.

High-dose glucocorticoids are usually effective, often being started at 0.5-2.0 mg/kg prednisone or equivalent daily and tapered over 4-6 weeks after clinical improvement, but these doses and schedules have not been rigorously examined. For glucocorticoid-refractory ICI enterocolitis, infliximab and vedolizumab “are reasonable options” for second line immunosuppression and should be individualized based on the underlying cancer and other risk factors; patients usually respond to these immunomodulators in less than a week, “an important contrast with IBD,” the experts wrote. Most cases of ICI enterocolitis do not recur unless the ICI is restarted, but “many patients require the full loading dose for infliximab or vedolizumab, and maintenance therapy may still be required for certain cases.”

ICI-induced hepatitis is less common, affecting less than 5% of patients in clinical trials according to the authors, but incidence rises if patients are on ICI combinations or an ICI plus chemotherapy. Before starting any ICI, patients’ total bilirubin, alkaline phosphatase, AST, and ALT levels should be checked, as should testing for hepatitis B. Liver chemistries should be repeated before each ICI cycle, and rising chemistries should trigger an assessment for other causes of liver injury.

Patients with Common Terminology Criteria for Adverse Events (CTCAE) grade 1 hepatitis – defined as AST or ALT 1-3 times the upper limit of normal or total bilirubin 1-1.5 times upper limit of normal – should receive liver function tests once or twice weekly. For CTCAE grade 2 hepatitis, (AST/ALT more than 3-5 times upper limit of normal or total bilirubin more than 1.5-3 times upper limit of normal), ICI should be held until resolution to grade 1, and corticosteroids (prednisone or its equivalent dosed at 0.5-1.0 mg/kg daily) should be considered if there are clinical symptoms of liver toxicity. For grade 3 hepatitis (AST/ALT greater than 5-20 times upper limit of normal or total bilirubin more than 3-10 times upper limit of normal), ICI therapy should be halted, “and urgent consultation with a gastroenterologist/hepatologist is appropriate.” In this context, methylprednisone (1-2 mg/kg) is suggested, and azathioprine or mycophenolate mofetil can be considered if clinical hepatitis does not improve in 3-5 days. For CTCAE grade 4 hepatitis, hospitalization is recommended, and patients should permanently stop the ICI and receive 2 mg/kg per day of methylprednisolone or its equivalent.

The authors received no funding support. Dr. Dougan reported consulting or advisory relationships with Neoleukin Therapeutics, Genentech, Tillotts Pharma, and Partner Therapeutics and grant support from Novartis and Genentech. Two coauthors also reported ties to several pharmaceutical companies.
 

Endoscopy with biopsies is best for diagnosing immune-mediated enterocolitis in patients receiving immune checkpoint inhibitors (ICIs), but another option is to first test the stool for lactoferrin or calprotectin to identify patients with mild diarrhea who could benefit from endoscopy, according to a clinical practice update from the American Gastroenterological Association.

Writing in Gastroenterology, Michael Dougan, MD, PhD, of Harvard Medical School, Boston, and colleagues noted that stool lactoferrin had been found in one study to be 90% sensitive for detecting histologic inflammation, while another study found that mucosal inflammation is absent in 20%-30% of patients with suspected ICI enterocolitis. Nonetheless, clinicians should consider diagnostic endoscopy before starting high-dose corticosteroids for ICI enterocolitis, especially because “colonic ulceration identified by endoscopy is the only established factor that predicts how ICI enterocolitis will respond to treatment,” Dr. Dougan and colleagues wrote. If performed, endoscopy must be prompt because ICI colitis can progress within days, especially if patients are receiving ipilimumab.

ICIs can induce autoimmune inflammation in almost any organ system because they target pathways that play “key roles in regulating autoimmunity,” the experts wrote. The gastrointestinal tract is one of the most common sites of toxicity: One study from 2006 and another from 2019 suggested that colitis, with or without enteritis, affects up to 40% of patients depending on the pathway targeted by the treatment. Oncologists manage most gastrointestinal ICI toxicities, but gastroenterologists and hepatologists often help with diagnosis, risk assessment, and managing complex, atypical, or treatment-refractory cases; to help guide this process, the experts reviewed the literature and made 15 relevant recommendations.

The authors noted that the differential diagnosis is broad, but suggested that Clostridioides difficile testing and stool culture (or stool pathogen testing, where available) should be performed in all patients to rule out infectious causes prior to any immunosuppressive treatments, such as corticosteroids. Abdominal imaging is not recommended if a patient only has diarrhea but can help rule out complications if fever, bleeding, or abdominal pain are also present. Laboratory blood tests are rarely informative.

High-dose glucocorticoids are usually effective, often being started at 0.5-2.0 mg/kg prednisone or equivalent daily and tapered over 4-6 weeks after clinical improvement, but these doses and schedules have not been rigorously examined. For glucocorticoid-refractory ICI enterocolitis, infliximab and vedolizumab “are reasonable options” for second line immunosuppression and should be individualized based on the underlying cancer and other risk factors; patients usually respond to these immunomodulators in less than a week, “an important contrast with IBD,” the experts wrote. Most cases of ICI enterocolitis do not recur unless the ICI is restarted, but “many patients require the full loading dose for infliximab or vedolizumab, and maintenance therapy may still be required for certain cases.”

ICI-induced hepatitis is less common, affecting less than 5% of patients in clinical trials according to the authors, but incidence rises if patients are on ICI combinations or an ICI plus chemotherapy. Before starting any ICI, patients’ total bilirubin, alkaline phosphatase, AST, and ALT levels should be checked, as should testing for hepatitis B. Liver chemistries should be repeated before each ICI cycle, and rising chemistries should trigger an assessment for other causes of liver injury.

Patients with Common Terminology Criteria for Adverse Events (CTCAE) grade 1 hepatitis – defined as AST or ALT 1-3 times the upper limit of normal or total bilirubin 1-1.5 times upper limit of normal – should receive liver function tests once or twice weekly. For CTCAE grade 2 hepatitis, (AST/ALT more than 3-5 times upper limit of normal or total bilirubin more than 1.5-3 times upper limit of normal), ICI should be held until resolution to grade 1, and corticosteroids (prednisone or its equivalent dosed at 0.5-1.0 mg/kg daily) should be considered if there are clinical symptoms of liver toxicity. For grade 3 hepatitis (AST/ALT greater than 5-20 times upper limit of normal or total bilirubin more than 3-10 times upper limit of normal), ICI therapy should be halted, “and urgent consultation with a gastroenterologist/hepatologist is appropriate.” In this context, methylprednisone (1-2 mg/kg) is suggested, and azathioprine or mycophenolate mofetil can be considered if clinical hepatitis does not improve in 3-5 days. For CTCAE grade 4 hepatitis, hospitalization is recommended, and patients should permanently stop the ICI and receive 2 mg/kg per day of methylprednisolone or its equivalent.

The authors received no funding support. Dr. Dougan reported consulting or advisory relationships with Neoleukin Therapeutics, Genentech, Tillotts Pharma, and Partner Therapeutics and grant support from Novartis and Genentech. Two coauthors also reported ties to several pharmaceutical companies.
 

Most patients with normal findings on functional luminal imaging probe (FLIP) showed no clinical evidence of a major esophageal motor disorder, even when their high-resolution manometry (HRM) test results were abnormal, according to the results of a single-center retrospective cohort study.

Among 111 study participants with normal FLIP findings, 79% also showed no evidence of a major esophageal motor disorder on esophageal high-resolution manometry (HRM), wrote Alexandra J. Baumann, DO, of Northwestern University, Chicago, and associates. “Among the remaining 21% with apparent disagreement with HRM, [those] with normal FLIP panometry carried overall clinical impressions of not having a major esophageal motor disorder and subsequently were treated conservatively without the need for surgical interventions,” they reported. For patients with normal upper endoscopy and normal FLIP panometry, “the initial clinical management strategy could be directed toward addressing gastroesophageal reflux or a functional syndrome,” they wrote in Clinical Gastroenterology and Hepatology.

FLIP uses high-resolution impedance planimetry to evaluate esophageal lumen parameters, distensibility, and contractility in response to distension. Although HRM is standard for evaluating esophageal motility, false negatives and positives can result from challenges with interpreting outflow obstructions and normal lower-esophageal sphincter relaxation pressures among patients with clinical achalasia.

Hence, the researchers evaluated correlations between FLIP and HRM in 111 patients with esophageal symptoms and nonobstructive endoscopy findings who were evaluated at the Esophageal Center of Northwestern University between 2012 and 2019. Gastroenterologists performed additional studies, such as barium esophagrams, at their discretion. By study design, all patients had normal FLIP results, defined as an esophagogastric junction distensibility index above 3.0 mm² per mm Hg and a normal contractile response (that is, normal repetitive retrograde contractions and a repetitive antegrade contraction pattern that met the Rule-of-6s). Three clinicians evaluated and reached consensus on each FLIP study. Esophageal HRM data were interpreted based on the Chicago classification system (version 3.0).

Patients with normal FLIP panometry findings “did not have a clinical impression of a major esophageal motor disorder,” the researchers reported. In all, 23 (21%) patients with normal FLIP results had discrepant (abnormal) HRM findings, most of which were false positives or equivocal.

For example, among 20 patients whose HRM suggested an esophagogastric junction outflow obstruction, 17 showed normal bolus transit on supine swallows and 16 showed normalization of integrated relaxation pressure after adjunctive maneuvers. Similarly, among 10 patients who underwent a barium esophagram, 8 showed normal emptying, 1 showed a temporary delay but no retention, and 1 had an incomplete study. “The overall clinical impression was not of an achalasia variant in any of these 20 patients with [esophagogastric junction outflow obstruction] on HRM, and thus none underwent botulinum toxin injection, pneumatic dilation, or lower-esophageal sphincter myotomy at our center,” the researchers wrote. Among 17 patients who were available for clinical follow-up, 4 underwent empiric dilation, of whom none had mucosal disruption. One patient was diagnosed with dysphagia lusoria based on cross-sectional imaging, while the rest were managed conservatively.

Similarly, among 10 patients with at least 50% ineffective swallows on HRM, 5 showed normal barium emptying and 9 were managed conservatively (the remaining patient underwent cricopharyngeal dilation for concurrent oropharyngeal dysphagia). The strong correlation between HRM and esophagrams in this study indicates that“[n]ormal findings from FLIP panometry can be used to exclude esophageal motility disorders at the time of endoscopy, possibly reducing the need for high-resolution manometry evaluation of some patients,” the investigators concluded. “However, further longitudinal studies are needed to support this approach.”

The work was supported by the Public Health Service and the American College of Gastroenterology. Dr. Baumann reported having no conflicts of interest. Four coinvestigators disclosed relevant ties to Crospon, Given Imaging, Ironwood, Medtronic, Sandhill Scientific, Torax, and other companies..

SOURCE: Baumann AJ et al. Clin Gastroenterol Hepatol 2020 Mar 20. doi: 10.1016/j.cgh.2020.03.040.

Most patients with normal findings on functional luminal imaging probe (FLIP) showed no clinical evidence of a major esophageal motor disorder, even when their high-resolution manometry (HRM) test results were abnormal, according to the results of a single-center retrospective cohort study.

Among 111 study participants with normal FLIP findings, 79% also showed no evidence of a major esophageal motor disorder on esophageal high-resolution manometry (HRM), wrote Alexandra J. Baumann, DO, of Northwestern University, Chicago, and associates. “Among the remaining 21% with apparent disagreement with HRM, [those] with normal FLIP panometry carried overall clinical impressions of not having a major esophageal motor disorder and subsequently were treated conservatively without the need for surgical interventions,” they reported. For patients with normal upper endoscopy and normal FLIP panometry, “the initial clinical management strategy could be directed toward addressing gastroesophageal reflux or a functional syndrome,” they wrote in Clinical Gastroenterology and Hepatology.

FLIP uses high-resolution impedance planimetry to evaluate esophageal lumen parameters, distensibility, and contractility in response to distension. Although HRM is standard for evaluating esophageal motility, false negatives and positives can result from challenges with interpreting outflow obstructions and normal lower-esophageal sphincter relaxation pressures among patients with clinical achalasia.

Hence, the researchers evaluated correlations between FLIP and HRM in 111 patients with esophageal symptoms and nonobstructive endoscopy findings who were evaluated at the Esophageal Center of Northwestern University between 2012 and 2019. Gastroenterologists performed additional studies, such as barium esophagrams, at their discretion. By study design, all patients had normal FLIP results, defined as an esophagogastric junction distensibility index above 3.0 mm² per mm Hg and a normal contractile response (that is, normal repetitive retrograde contractions and a repetitive antegrade contraction pattern that met the Rule-of-6s). Three clinicians evaluated and reached consensus on each FLIP study. Esophageal HRM data were interpreted based on the Chicago classification system (version 3.0).

Patients with normal FLIP panometry findings “did not have a clinical impression of a major esophageal motor disorder,” the researchers reported. In all, 23 (21%) patients with normal FLIP results had discrepant (abnormal) HRM findings, most of which were false positives or equivocal.

For example, among 20 patients whose HRM suggested an esophagogastric junction outflow obstruction, 17 showed normal bolus transit on supine swallows and 16 showed normalization of integrated relaxation pressure after adjunctive maneuvers. Similarly, among 10 patients who underwent a barium esophagram, 8 showed normal emptying, 1 showed a temporary delay but no retention, and 1 had an incomplete study. “The overall clinical impression was not of an achalasia variant in any of these 20 patients with [esophagogastric junction outflow obstruction] on HRM, and thus none underwent botulinum toxin injection, pneumatic dilation, or lower-esophageal sphincter myotomy at our center,” the researchers wrote. Among 17 patients who were available for clinical follow-up, 4 underwent empiric dilation, of whom none had mucosal disruption. One patient was diagnosed with dysphagia lusoria based on cross-sectional imaging, while the rest were managed conservatively.

Similarly, among 10 patients with at least 50% ineffective swallows on HRM, 5 showed normal barium emptying and 9 were managed conservatively (the remaining patient underwent cricopharyngeal dilation for concurrent oropharyngeal dysphagia). The strong correlation between HRM and esophagrams in this study indicates that“[n]ormal findings from FLIP panometry can be used to exclude esophageal motility disorders at the time of endoscopy, possibly reducing the need for high-resolution manometry evaluation of some patients,” the investigators concluded. “However, further longitudinal studies are needed to support this approach.”

The work was supported by the Public Health Service and the American College of Gastroenterology. Dr. Baumann reported having no conflicts of interest. Four coinvestigators disclosed relevant ties to Crospon, Given Imaging, Ironwood, Medtronic, Sandhill Scientific, Torax, and other companies..

SOURCE: Baumann AJ et al. Clin Gastroenterol Hepatol 2020 Mar 20. doi: 10.1016/j.cgh.2020.03.040.

Most patients with normal findings on functional luminal imaging probe (FLIP) showed no clinical evidence of a major esophageal motor disorder, even when their high-resolution manometry (HRM) test results were abnormal, according to the results of a single-center retrospective cohort study.

Among 111 study participants with normal FLIP findings, 79% also showed no evidence of a major esophageal motor disorder on esophageal high-resolution manometry (HRM), wrote Alexandra J. Baumann, DO, of Northwestern University, Chicago, and associates. “Among the remaining 21% with apparent disagreement with HRM, [those] with normal FLIP panometry carried overall clinical impressions of not having a major esophageal motor disorder and subsequently were treated conservatively without the need for surgical interventions,” they reported. For patients with normal upper endoscopy and normal FLIP panometry, “the initial clinical management strategy could be directed toward addressing gastroesophageal reflux or a functional syndrome,” they wrote in Clinical Gastroenterology and Hepatology.

FLIP uses high-resolution impedance planimetry to evaluate esophageal lumen parameters, distensibility, and contractility in response to distension. Although HRM is standard for evaluating esophageal motility, false negatives and positives can result from challenges with interpreting outflow obstructions and normal lower-esophageal sphincter relaxation pressures among patients with clinical achalasia.

Hence, the researchers evaluated correlations between FLIP and HRM in 111 patients with esophageal symptoms and nonobstructive endoscopy findings who were evaluated at the Esophageal Center of Northwestern University between 2012 and 2019. Gastroenterologists performed additional studies, such as barium esophagrams, at their discretion. By study design, all patients had normal FLIP results, defined as an esophagogastric junction distensibility index above 3.0 mm² per mm Hg and a normal contractile response (that is, normal repetitive retrograde contractions and a repetitive antegrade contraction pattern that met the Rule-of-6s). Three clinicians evaluated and reached consensus on each FLIP study. Esophageal HRM data were interpreted based on the Chicago classification system (version 3.0).

Patients with normal FLIP panometry findings “did not have a clinical impression of a major esophageal motor disorder,” the researchers reported. In all, 23 (21%) patients with normal FLIP results had discrepant (abnormal) HRM findings, most of which were false positives or equivocal.

For example, among 20 patients whose HRM suggested an esophagogastric junction outflow obstruction, 17 showed normal bolus transit on supine swallows and 16 showed normalization of integrated relaxation pressure after adjunctive maneuvers. Similarly, among 10 patients who underwent a barium esophagram, 8 showed normal emptying, 1 showed a temporary delay but no retention, and 1 had an incomplete study. “The overall clinical impression was not of an achalasia variant in any of these 20 patients with [esophagogastric junction outflow obstruction] on HRM, and thus none underwent botulinum toxin injection, pneumatic dilation, or lower-esophageal sphincter myotomy at our center,” the researchers wrote. Among 17 patients who were available for clinical follow-up, 4 underwent empiric dilation, of whom none had mucosal disruption. One patient was diagnosed with dysphagia lusoria based on cross-sectional imaging, while the rest were managed conservatively.

Similarly, among 10 patients with at least 50% ineffective swallows on HRM, 5 showed normal barium emptying and 9 were managed conservatively (the remaining patient underwent cricopharyngeal dilation for concurrent oropharyngeal dysphagia). The strong correlation between HRM and esophagrams in this study indicates that“[n]ormal findings from FLIP panometry can be used to exclude esophageal motility disorders at the time of endoscopy, possibly reducing the need for high-resolution manometry evaluation of some patients,” the investigators concluded. “However, further longitudinal studies are needed to support this approach.”

The work was supported by the Public Health Service and the American College of Gastroenterology. Dr. Baumann reported having no conflicts of interest. Four coinvestigators disclosed relevant ties to Crospon, Given Imaging, Ironwood, Medtronic, Sandhill Scientific, Torax, and other companies..

SOURCE: Baumann AJ et al. Clin Gastroenterol Hepatol 2020 Mar 20. doi: 10.1016/j.cgh.2020.03.040.

Aspirin “rescued” a cystic intestinal phenotype driven by the Wnt pathway, reduced stem cell expression and function, and increased the expression of Dickkopf (DKK)–1, a Wnt antagonist that is frequently lost as colorectal cancer (CRC) progresses, according to recent study findings.

“Dysregulated Wnt signaling, [which is] primarily driven by adenomatous polyposis coli (APC) gene mutations, is fundamental to cancer initiation in both sporadic CRC and familial adenomatous polyposis (FAP). ... Our observations reveal a novel mechanism of aspirin-mediated Wnt inhibition through DKK-1 increase and potential ‘pheno-markers’ for chemoprevention and adjuvant aspirin human trials,” wrote Karen Dunbar, PhD, and her associates in Cellular and Molecular Gastroenterology and Hepatology.

Aspirin shows benefits in sporadic and familial adenoma, significantly reduces CRC incidence, and may delay disease progression while improving survival. “Understanding the biology responsible for this protective effect is key to developing biomarker-led approaches for rational clinical use,” wrote Dr. Dunbar, now with the University of Dundee (Scotland) and colleagues.

She and her coinvestigators found that aspirin promoted the wild-type (budding, noncystic) phenotype in intestinal organoids derived from APC-deficient mice and humans with FAP. They saw the same effect in live APC-deficient mice. With the help of an RNAscope, they confirmed that aspirin significantly reduced RNA transcripts for Lgr5 and TROY, which are stem cell markers in CRC. Aspirin also reduced Lgr5 expression in APC-deficient mice and in human organoids derived from normal colonic mucosa, sporadic colorectal tumors, and colorectal tumors from patients with FAP.

In wound-closure models, aspirin inhibited Wnt and epithelial-mesenchymal transition (EMT) while decreasing migration and invasion by colorectal cancer cells. Aspirin accomplished this by increasing the phosphorylation of GSK-3beta and beta-catenin. Notably, aspirin increased the production of E-cadherin, which buffers excess beta-catenin and thereby limits overactivated Wnt to promote an epithelial, rather than mesenchymal, phenotype. “The novel observation that the aspirin-mediated E-cadherin increase is paralleled by greater E-cadherin–beta-catenin binding further supports the hypothesis that aspirin promotes an epithelial phenotype through Wnt inhibition,” the researchers wrote.

In colorectal cells and FAP organoids, aspirin also increased the expression of the Wnt antagonist DKK-1, which in turn correlated with lower stem cell function. “In humans, high serum DKK-1 correlates with increasing colorectal cancer stage, whereas tissue DKK-1 expression is lost with cancer progression,” the researchers explained. “Here, we demonstrate that aspirin robustly increases DKK-1 expression in CRC models, which contributes to EMT and [cancer stem cell] inhibition observed with aspirin.”

Taken together, the findings “highlight two novel phenotypic indicators of aspirin response, the cystic-phenotype rescue and reduced stem cell marker expression, which may serve as enhanced biomarkers, compared with individual Wnt components,” they concluded. “Through targeting Wnt signaling at multiple levels, aspirin enhances commitment to differentiation, and hence, phenotypic markers of Wnt inhibition represent better targets [for] therapeutic exploitation.”

Dr. Dunbar and her associates reported having no relevant conflicts of interest. The work was supported by Cancer Research UK and the Chief Scientist Office of Scotland, the MRC Centre, and the CRUK.

SOURCE: Dunbar K et al. Cell Mol Gastroenterol Hepatol. 2020 Sep 21. doi: 10.1016/j.jcmgh.2020.09.010.

Aspirin “rescued” a cystic intestinal phenotype driven by the Wnt pathway, reduced stem cell expression and function, and increased the expression of Dickkopf (DKK)–1, a Wnt antagonist that is frequently lost as colorectal cancer (CRC) progresses, according to recent study findings.

“Dysregulated Wnt signaling, [which is] primarily driven by adenomatous polyposis coli (APC) gene mutations, is fundamental to cancer initiation in both sporadic CRC and familial adenomatous polyposis (FAP). ... Our observations reveal a novel mechanism of aspirin-mediated Wnt inhibition through DKK-1 increase and potential ‘pheno-markers’ for chemoprevention and adjuvant aspirin human trials,” wrote Karen Dunbar, PhD, and her associates in Cellular and Molecular Gastroenterology and Hepatology.

Aspirin shows benefits in sporadic and familial adenoma, significantly reduces CRC incidence, and may delay disease progression while improving survival. “Understanding the biology responsible for this protective effect is key to developing biomarker-led approaches for rational clinical use,” wrote Dr. Dunbar, now with the University of Dundee (Scotland) and colleagues.

She and her coinvestigators found that aspirin promoted the wild-type (budding, noncystic) phenotype in intestinal organoids derived from APC-deficient mice and humans with FAP. They saw the same effect in live APC-deficient mice. With the help of an RNAscope, they confirmed that aspirin significantly reduced RNA transcripts for Lgr5 and TROY, which are stem cell markers in CRC. Aspirin also reduced Lgr5 expression in APC-deficient mice and in human organoids derived from normal colonic mucosa, sporadic colorectal tumors, and colorectal tumors from patients with FAP.

In wound-closure models, aspirin inhibited Wnt and epithelial-mesenchymal transition (EMT) while decreasing migration and invasion by colorectal cancer cells. Aspirin accomplished this by increasing the phosphorylation of GSK-3beta and beta-catenin. Notably, aspirin increased the production of E-cadherin, which buffers excess beta-catenin and thereby limits overactivated Wnt to promote an epithelial, rather than mesenchymal, phenotype. “The novel observation that the aspirin-mediated E-cadherin increase is paralleled by greater E-cadherin–beta-catenin binding further supports the hypothesis that aspirin promotes an epithelial phenotype through Wnt inhibition,” the researchers wrote.

In colorectal cells and FAP organoids, aspirin also increased the expression of the Wnt antagonist DKK-1, which in turn correlated with lower stem cell function. “In humans, high serum DKK-1 correlates with increasing colorectal cancer stage, whereas tissue DKK-1 expression is lost with cancer progression,” the researchers explained. “Here, we demonstrate that aspirin robustly increases DKK-1 expression in CRC models, which contributes to EMT and [cancer stem cell] inhibition observed with aspirin.”

Taken together, the findings “highlight two novel phenotypic indicators of aspirin response, the cystic-phenotype rescue and reduced stem cell marker expression, which may serve as enhanced biomarkers, compared with individual Wnt components,” they concluded. “Through targeting Wnt signaling at multiple levels, aspirin enhances commitment to differentiation, and hence, phenotypic markers of Wnt inhibition represent better targets [for] therapeutic exploitation.”

Dr. Dunbar and her associates reported having no relevant conflicts of interest. The work was supported by Cancer Research UK and the Chief Scientist Office of Scotland, the MRC Centre, and the CRUK.

SOURCE: Dunbar K et al. Cell Mol Gastroenterol Hepatol. 2020 Sep 21. doi: 10.1016/j.jcmgh.2020.09.010.

Aspirin “rescued” a cystic intestinal phenotype driven by the Wnt pathway, reduced stem cell expression and function, and increased the expression of Dickkopf (DKK)–1, a Wnt antagonist that is frequently lost as colorectal cancer (CRC) progresses, according to recent study findings.

“Dysregulated Wnt signaling, [which is] primarily driven by adenomatous polyposis coli (APC) gene mutations, is fundamental to cancer initiation in both sporadic CRC and familial adenomatous polyposis (FAP). ... Our observations reveal a novel mechanism of aspirin-mediated Wnt inhibition through DKK-1 increase and potential ‘pheno-markers’ for chemoprevention and adjuvant aspirin human trials,” wrote Karen Dunbar, PhD, and her associates in Cellular and Molecular Gastroenterology and Hepatology.

Aspirin shows benefits in sporadic and familial adenoma, significantly reduces CRC incidence, and may delay disease progression while improving survival. “Understanding the biology responsible for this protective effect is key to developing biomarker-led approaches for rational clinical use,” wrote Dr. Dunbar, now with the University of Dundee (Scotland) and colleagues.

She and her coinvestigators found that aspirin promoted the wild-type (budding, noncystic) phenotype in intestinal organoids derived from APC-deficient mice and humans with FAP. They saw the same effect in live APC-deficient mice. With the help of an RNAscope, they confirmed that aspirin significantly reduced RNA transcripts for Lgr5 and TROY, which are stem cell markers in CRC. Aspirin also reduced Lgr5 expression in APC-deficient mice and in human organoids derived from normal colonic mucosa, sporadic colorectal tumors, and colorectal tumors from patients with FAP.

In wound-closure models, aspirin inhibited Wnt and epithelial-mesenchymal transition (EMT) while decreasing migration and invasion by colorectal cancer cells. Aspirin accomplished this by increasing the phosphorylation of GSK-3beta and beta-catenin. Notably, aspirin increased the production of E-cadherin, which buffers excess beta-catenin and thereby limits overactivated Wnt to promote an epithelial, rather than mesenchymal, phenotype. “The novel observation that the aspirin-mediated E-cadherin increase is paralleled by greater E-cadherin–beta-catenin binding further supports the hypothesis that aspirin promotes an epithelial phenotype through Wnt inhibition,” the researchers wrote.

In colorectal cells and FAP organoids, aspirin also increased the expression of the Wnt antagonist DKK-1, which in turn correlated with lower stem cell function. “In humans, high serum DKK-1 correlates with increasing colorectal cancer stage, whereas tissue DKK-1 expression is lost with cancer progression,” the researchers explained. “Here, we demonstrate that aspirin robustly increases DKK-1 expression in CRC models, which contributes to EMT and [cancer stem cell] inhibition observed with aspirin.”

Taken together, the findings “highlight two novel phenotypic indicators of aspirin response, the cystic-phenotype rescue and reduced stem cell marker expression, which may serve as enhanced biomarkers, compared with individual Wnt components,” they concluded. “Through targeting Wnt signaling at multiple levels, aspirin enhances commitment to differentiation, and hence, phenotypic markers of Wnt inhibition represent better targets [for] therapeutic exploitation.”

Dr. Dunbar and her associates reported having no relevant conflicts of interest. The work was supported by Cancer Research UK and the Chief Scientist Office of Scotland, the MRC Centre, and the CRUK.

SOURCE: Dunbar K et al. Cell Mol Gastroenterol Hepatol. 2020 Sep 21. doi: 10.1016/j.jcmgh.2020.09.010.

Once-daily treatment with the lipid-lowering agent bezafibrate significantly reduced moderate to severe pruritis among patients with cholestasis, according to the findings of a multicenter, double-blind, randomized, placebo-controlled study (Fibrates for Itch, or FITCH).

Two weeks after completing treatment, 45% of bezafibrate recipients met the primary endpoint, reporting at least a 50% decrease in itch on a 10-point visual analog scale (VAS), compared with 11% of patients in the placebo group (P = .003). There was also a statistically significant decrease in serum alkaline phosphatase (ALP) levels from baseline (35% vs. 6%, respectively; P = .03) that corresponded with improved pruritus, and bezafibrate significantly improved both morning and evening pruritus. Bezafibrate was not associated with myalgia, rhabdomyolysis, or serum alanine transaminase elevations but did lead to a 3% increase in serum creatinine that “was not different from the placebo group,” wrote Elsemieke de Vries, MD, PhD, of the department of gastroenterology & hepatology at Tytgat Institute for Liver and Intestinal Research, Amsterdam, and of department of gastroenterology & metabolism at Amsterdam University Medical Centers, and associates. Their report is in Gastroenterology.

Up to 70% of patients with cholangitis experience pruritus. Current guidelines recommend management with cholestyramine, rifampin, naltrexone, or sertraline, but efficacy and tolerability are subpar, the investigators wrote. In a recent study, a selective inhibitor of an ileal bile acid transporter (GSK2330672) reduced pruritus in primary biliary cholangitis but frequently was associated with diarrhea. In another recent study of patients with primary biliary cholangitis who had responded inadequately to ursodeoxycholic acid (BEZURSO), bezafibrate induced biochemical responses that correlated with improvements in pruritis (a secondary endpoint).

Lysophosphatidic acid (LPA) has been implicated in cholangiopathy-associated pruritus but is not found in bile. However, biliary drainage rapidly improves severe itch in patients with primary biliary cholangitis. Therefore, Dr. de Vries and associates hypothesized that an as-yet unknown factor in bile contributes to pruritus in fibrosing cholangiopathies and that bezafibrate reduces itch by “alleviating hepatobiliary cholestasis and injury and, thereby, reducing formation and biliary secretion of this biliary factor X.”

The FITCH study, which was conducted at seven academic hospitals in the Netherlands and one in Spain, enrolled 74 patients 18 years and older with primary biliary cholangitis or primary or secondary sclerosing cholangitis who reported having pruritus with an intensity of at least 5 on the 10-point VAS at baseline (with 10 indicating “worst itch possible”; median, 7; interquartile range, 7-8). Patients with hepatocellular cholestasis caused by medications or pregnancy were excluded. Ages among most participants ranged from 30s to 50s, and approximately two-thirds were female. None had received another pruritus treatment within 10 days of enrollment, and prior treatment with bezafibrate was not allowed. Patients received once-daily bezafibrate (400 mg) or placebo tablets for 21 days, with visits to the outpatient clinic on days 0, 21, and 35.

There were no serious adverse events or new safety signals. One event of oral pain was considered possibly related to bezafibrate, and itch and jaundice worsened in two patients after completing treatment. As in the 24-month BEZURSO study, increases in serum creatinine were modest and similar between groups (3% with bezafibrate and 5% with placebo). Myalgia and increases in serum alanine transaminase were observed in BEZURSO but not in FITCH. However, the short treatment duration provides “no judgment on long-term safety [of bezafibrate] in complex diseases such as primary sclerosing cholangitis or primary biliary cholangitis,” the investigators wrote.

Four patients discontinued treatment – three stopped placebo because of “unbearable pruritus,” and one stopped bezafibrate after developing acute bacterial cholangitis that required emergency treatment. Although FITCH excluded patients whose estimated glomerular filtration rate was less than 60 mL/min per 1.73 m², one such patient was accidentally enrolled. Her serum creatinine, measured in mmol/L, rose from 121 at baseline to 148 on day 21, and then dropped to 134 after 2 weeks off treatment.

The trial was supported by patient donations, the Netherlands Society of Gastroenterology, and Instituto de Salud Carlos III. The investigators reported having no conflicts of interest.

SOURCE: de Vries E et al. Gastroenterology. 2020 Oct 5. doi: 10.1053/j.gastro.2020.10.001.

Once-daily treatment with the lipid-lowering agent bezafibrate significantly reduced moderate to severe pruritis among patients with cholestasis, according to the findings of a multicenter, double-blind, randomized, placebo-controlled study (Fibrates for Itch, or FITCH).

Two weeks after completing treatment, 45% of bezafibrate recipients met the primary endpoint, reporting at least a 50% decrease in itch on a 10-point visual analog scale (VAS), compared with 11% of patients in the placebo group (P = .003). There was also a statistically significant decrease in serum alkaline phosphatase (ALP) levels from baseline (35% vs. 6%, respectively; P = .03) that corresponded with improved pruritus, and bezafibrate significantly improved both morning and evening pruritus. Bezafibrate was not associated with myalgia, rhabdomyolysis, or serum alanine transaminase elevations but did lead to a 3% increase in serum creatinine that “was not different from the placebo group,” wrote Elsemieke de Vries, MD, PhD, of the department of gastroenterology & hepatology at Tytgat Institute for Liver and Intestinal Research, Amsterdam, and of department of gastroenterology & metabolism at Amsterdam University Medical Centers, and associates. Their report is in Gastroenterology.

Up to 70% of patients with cholangitis experience pruritus. Current guidelines recommend management with cholestyramine, rifampin, naltrexone, or sertraline, but efficacy and tolerability are subpar, the investigators wrote. In a recent study, a selective inhibitor of an ileal bile acid transporter (GSK2330672) reduced pruritus in primary biliary cholangitis but frequently was associated with diarrhea. In another recent study of patients with primary biliary cholangitis who had responded inadequately to ursodeoxycholic acid (BEZURSO), bezafibrate induced biochemical responses that correlated with improvements in pruritis (a secondary endpoint).

Lysophosphatidic acid (LPA) has been implicated in cholangiopathy-associated pruritus but is not found in bile. However, biliary drainage rapidly improves severe itch in patients with primary biliary cholangitis. Therefore, Dr. de Vries and associates hypothesized that an as-yet unknown factor in bile contributes to pruritus in fibrosing cholangiopathies and that bezafibrate reduces itch by “alleviating hepatobiliary cholestasis and injury and, thereby, reducing formation and biliary secretion of this biliary factor X.”

The FITCH study, which was conducted at seven academic hospitals in the Netherlands and one in Spain, enrolled 74 patients 18 years and older with primary biliary cholangitis or primary or secondary sclerosing cholangitis who reported having pruritus with an intensity of at least 5 on the 10-point VAS at baseline (with 10 indicating “worst itch possible”; median, 7; interquartile range, 7-8). Patients with hepatocellular cholestasis caused by medications or pregnancy were excluded. Ages among most participants ranged from 30s to 50s, and approximately two-thirds were female. None had received another pruritus treatment within 10 days of enrollment, and prior treatment with bezafibrate was not allowed. Patients received once-daily bezafibrate (400 mg) or placebo tablets for 21 days, with visits to the outpatient clinic on days 0, 21, and 35.

There were no serious adverse events or new safety signals. One event of oral pain was considered possibly related to bezafibrate, and itch and jaundice worsened in two patients after completing treatment. As in the 24-month BEZURSO study, increases in serum creatinine were modest and similar between groups (3% with bezafibrate and 5% with placebo). Myalgia and increases in serum alanine transaminase were observed in BEZURSO but not in FITCH. However, the short treatment duration provides “no judgment on long-term safety [of bezafibrate] in complex diseases such as primary sclerosing cholangitis or primary biliary cholangitis,” the investigators wrote.

Four patients discontinued treatment – three stopped placebo because of “unbearable pruritus,” and one stopped bezafibrate after developing acute bacterial cholangitis that required emergency treatment. Although FITCH excluded patients whose estimated glomerular filtration rate was less than 60 mL/min per 1.73 m², one such patient was accidentally enrolled. Her serum creatinine, measured in mmol/L, rose from 121 at baseline to 148 on day 21, and then dropped to 134 after 2 weeks off treatment.

The trial was supported by patient donations, the Netherlands Society of Gastroenterology, and Instituto de Salud Carlos III. The investigators reported having no conflicts of interest.

SOURCE: de Vries E et al. Gastroenterology. 2020 Oct 5. doi: 10.1053/j.gastro.2020.10.001.

Once-daily treatment with the lipid-lowering agent bezafibrate significantly reduced moderate to severe pruritis among patients with cholestasis, according to the findings of a multicenter, double-blind, randomized, placebo-controlled study (Fibrates for Itch, or FITCH).

Two weeks after completing treatment, 45% of bezafibrate recipients met the primary endpoint, reporting at least a 50% decrease in itch on a 10-point visual analog scale (VAS), compared with 11% of patients in the placebo group (P = .003). There was also a statistically significant decrease in serum alkaline phosphatase (ALP) levels from baseline (35% vs. 6%, respectively; P = .03) that corresponded with improved pruritus, and bezafibrate significantly improved both morning and evening pruritus. Bezafibrate was not associated with myalgia, rhabdomyolysis, or serum alanine transaminase elevations but did lead to a 3% increase in serum creatinine that “was not different from the placebo group,” wrote Elsemieke de Vries, MD, PhD, of the department of gastroenterology & hepatology at Tytgat Institute for Liver and Intestinal Research, Amsterdam, and of department of gastroenterology & metabolism at Amsterdam University Medical Centers, and associates. Their report is in Gastroenterology.

Up to 70% of patients with cholangitis experience pruritus. Current guidelines recommend management with cholestyramine, rifampin, naltrexone, or sertraline, but efficacy and tolerability are subpar, the investigators wrote. In a recent study, a selective inhibitor of an ileal bile acid transporter (GSK2330672) reduced pruritus in primary biliary cholangitis but frequently was associated with diarrhea. In another recent study of patients with primary biliary cholangitis who had responded inadequately to ursodeoxycholic acid (BEZURSO), bezafibrate induced biochemical responses that correlated with improvements in pruritis (a secondary endpoint).

Lysophosphatidic acid (LPA) has been implicated in cholangiopathy-associated pruritus but is not found in bile. However, biliary drainage rapidly improves severe itch in patients with primary biliary cholangitis. Therefore, Dr. de Vries and associates hypothesized that an as-yet unknown factor in bile contributes to pruritus in fibrosing cholangiopathies and that bezafibrate reduces itch by “alleviating hepatobiliary cholestasis and injury and, thereby, reducing formation and biliary secretion of this biliary factor X.”

The FITCH study, which was conducted at seven academic hospitals in the Netherlands and one in Spain, enrolled 74 patients 18 years and older with primary biliary cholangitis or primary or secondary sclerosing cholangitis who reported having pruritus with an intensity of at least 5 on the 10-point VAS at baseline (with 10 indicating “worst itch possible”; median, 7; interquartile range, 7-8). Patients with hepatocellular cholestasis caused by medications or pregnancy were excluded. Ages among most participants ranged from 30s to 50s, and approximately two-thirds were female. None had received another pruritus treatment within 10 days of enrollment, and prior treatment with bezafibrate was not allowed. Patients received once-daily bezafibrate (400 mg) or placebo tablets for 21 days, with visits to the outpatient clinic on days 0, 21, and 35.

There were no serious adverse events or new safety signals. One event of oral pain was considered possibly related to bezafibrate, and itch and jaundice worsened in two patients after completing treatment. As in the 24-month BEZURSO study, increases in serum creatinine were modest and similar between groups (3% with bezafibrate and 5% with placebo). Myalgia and increases in serum alanine transaminase were observed in BEZURSO but not in FITCH. However, the short treatment duration provides “no judgment on long-term safety [of bezafibrate] in complex diseases such as primary sclerosing cholangitis or primary biliary cholangitis,” the investigators wrote.

Four patients discontinued treatment – three stopped placebo because of “unbearable pruritus,” and one stopped bezafibrate after developing acute bacterial cholangitis that required emergency treatment. Although FITCH excluded patients whose estimated glomerular filtration rate was less than 60 mL/min per 1.73 m², one such patient was accidentally enrolled. Her serum creatinine, measured in mmol/L, rose from 121 at baseline to 148 on day 21, and then dropped to 134 after 2 weeks off treatment.

The trial was supported by patient donations, the Netherlands Society of Gastroenterology, and Instituto de Salud Carlos III. The investigators reported having no conflicts of interest.

SOURCE: de Vries E et al. Gastroenterology. 2020 Oct 5. doi: 10.1053/j.gastro.2020.10.001.

A new clinical practice update from the American Gastroenterological Association seeks to provide gastroenterologists with practical and evidence-based advice for management of colonic diverticulitis.

For example, clinicians should consider lower endoscopy and CT scans of the abdomen and pelvis with oral and intravenous contrast to rule out chronic diverticular inflammation, diverticular stricture or fistula, ischemic colitis, constipation, and inflammatory bowel disease, Anne F. Peery, MD, MSCR, of the University of North Carolina, Chapel Hill, and associates wrote in Gastroenterology.

“In our practice, patients are reassured to know that ongoing symptoms are common and often attributable to visceral hypersensitivity,” they wrote. “This conversation is particularly important after a negative workup. If needed, ongoing abdominal pain can be treated with a low to modest dose of a tricyclic antidepressant.”

The update from the AGA includes 13 other recommendations, with noteworthy advice to use antibiotics selectively, rather than routinely, in cases of acute uncomplicated diverticulitis in immunocompetent patients. In a recent large meta-analysis, antibiotics did not shorten symptom duration or reduce rates of hospitalization, complications, or surgery in this setting. The clinical practice update advises using antibiotics if patients are frail or have comorbidities, vomiting or refractory symptoms, a C-reactive protein level above 140 mg/L, a baseline white blood cell count above 15 × 10⁹ cells/L, or fluid collection or a longer segment of inflammation on CT scan. Antibiotics also are strongly advised for immunocompromised patients, who are at greater risk for complications and severe diverticulitis. Because of this risk, clinicians should have “a low threshold” for cross-sectional imaging, antibiotic treatment, and consultation with a colorectal surgeon, according to the update.

The authors recommend CT if patients have severe symptoms or have not previously been diagnosed with diverticulitis based on imaging. Clinicians also should consider imaging if patients have had multiple recurrences, are not responding to treatment, are immunocompromised, or are considering prophylactic surgery (in which case imaging is used to pinpoint areas of disease).

Colonoscopy is advised after episodes of complicated diverticulitis or after a first episode of uncomplicated diverticulitis if no high-quality colonoscopy has been performed in the past year. This colonoscopy is advised to rule out malignancy, which can be misdiagnosed as diverticulitis, and because diverticulitis (particularly complicated diverticulitis) has been associated with colon cancer in some studies, the update notes. Unless patients have “alarm symptoms” – that is, a change in stool caliber, iron deficiency anemia, bloody stools, weight loss, or abdominal pain – colonoscopy should be delayed until 6-8 weeks after the diverticulitis episode or until the acute symptoms resolve, whichever occurs later.

The decision to discuss elective segmental resection should be based on disease severity, not the prior number of episodes. Although elective surgery for diverticulitis has become increasingly common, patients should be aware that surgery often does not improve chronic gastrointestinal symptoms, such as abdominal pain, and that surgery reduces but does not eliminate the risk for recurrence. The authors recommended against surgery to prevent complicated diverticulitis in immunocompetent patients with a history of uncomplicated episodes. “In this population, complicated diverticulitis is most often the first presentation of diverticulitis and is less likely with recurrences,” the update states. For acute complicated diverticulitis that has been effectively managed without surgery, patients are at heightened risk for recurrence, but “a growing literature suggest[s] a more conservative and personalized approach” rather than the routine use of interval elective resection, the authors noted. For all patients, counseling regarding surgery should incorporate thoughtful discussions of immune status, values and preferences, and operative risks versus benefits, including effects on quality of life.

Dr. Peery and another author were supported by grants from the National Institutes of Health. The authors reported having no conflicts of interest.

SOURCE: Peery AF et al. Gastroenterology. 2020 Dec 3. doi: 10.1053/j.gastro.2020.09.059.

This article was updated Feb. 10, 2021.

A new clinical practice update from the American Gastroenterological Association seeks to provide gastroenterologists with practical and evidence-based advice for management of colonic diverticulitis.

For example, clinicians should consider lower endoscopy and CT scans of the abdomen and pelvis with oral and intravenous contrast to rule out chronic diverticular inflammation, diverticular stricture or fistula, ischemic colitis, constipation, and inflammatory bowel disease, Anne F. Peery, MD, MSCR, of the University of North Carolina, Chapel Hill, and associates wrote in Gastroenterology.

“In our practice, patients are reassured to know that ongoing symptoms are common and often attributable to visceral hypersensitivity,” they wrote. “This conversation is particularly important after a negative workup. If needed, ongoing abdominal pain can be treated with a low to modest dose of a tricyclic antidepressant.”

The update from the AGA includes 13 other recommendations, with noteworthy advice to use antibiotics selectively, rather than routinely, in cases of acute uncomplicated diverticulitis in immunocompetent patients. In a recent large meta-analysis, antibiotics did not shorten symptom duration or reduce rates of hospitalization, complications, or surgery in this setting. The clinical practice update advises using antibiotics if patients are frail or have comorbidities, vomiting or refractory symptoms, a C-reactive protein level above 140 mg/L, a baseline white blood cell count above 15 × 10⁹ cells/L, or fluid collection or a longer segment of inflammation on CT scan. Antibiotics also are strongly advised for immunocompromised patients, who are at greater risk for complications and severe diverticulitis. Because of this risk, clinicians should have “a low threshold” for cross-sectional imaging, antibiotic treatment, and consultation with a colorectal surgeon, according to the update.

The authors recommend CT if patients have severe symptoms or have not previously been diagnosed with diverticulitis based on imaging. Clinicians also should consider imaging if patients have had multiple recurrences, are not responding to treatment, are immunocompromised, or are considering prophylactic surgery (in which case imaging is used to pinpoint areas of disease).

Colonoscopy is advised after episodes of complicated diverticulitis or after a first episode of uncomplicated diverticulitis if no high-quality colonoscopy has been performed in the past year. This colonoscopy is advised to rule out malignancy, which can be misdiagnosed as diverticulitis, and because diverticulitis (particularly complicated diverticulitis) has been associated with colon cancer in some studies, the update notes. Unless patients have “alarm symptoms” – that is, a change in stool caliber, iron deficiency anemia, bloody stools, weight loss, or abdominal pain – colonoscopy should be delayed until 6-8 weeks after the diverticulitis episode or until the acute symptoms resolve, whichever occurs later.

The decision to discuss elective segmental resection should be based on disease severity, not the prior number of episodes. Although elective surgery for diverticulitis has become increasingly common, patients should be aware that surgery often does not improve chronic gastrointestinal symptoms, such as abdominal pain, and that surgery reduces but does not eliminate the risk for recurrence. The authors recommended against surgery to prevent complicated diverticulitis in immunocompetent patients with a history of uncomplicated episodes. “In this population, complicated diverticulitis is most often the first presentation of diverticulitis and is less likely with recurrences,” the update states. For acute complicated diverticulitis that has been effectively managed without surgery, patients are at heightened risk for recurrence, but “a growing literature suggest[s] a more conservative and personalized approach” rather than the routine use of interval elective resection, the authors noted. For all patients, counseling regarding surgery should incorporate thoughtful discussions of immune status, values and preferences, and operative risks versus benefits, including effects on quality of life.

Dr. Peery and another author were supported by grants from the National Institutes of Health. The authors reported having no conflicts of interest.

SOURCE: Peery AF et al. Gastroenterology. 2020 Dec 3. doi: 10.1053/j.gastro.2020.09.059.

This article was updated Feb. 10, 2021.

A new clinical practice update from the American Gastroenterological Association seeks to provide gastroenterologists with practical and evidence-based advice for management of colonic diverticulitis.

For example, clinicians should consider lower endoscopy and CT scans of the abdomen and pelvis with oral and intravenous contrast to rule out chronic diverticular inflammation, diverticular stricture or fistula, ischemic colitis, constipation, and inflammatory bowel disease, Anne F. Peery, MD, MSCR, of the University of North Carolina, Chapel Hill, and associates wrote in Gastroenterology.

“In our practice, patients are reassured to know that ongoing symptoms are common and often attributable to visceral hypersensitivity,” they wrote. “This conversation is particularly important after a negative workup. If needed, ongoing abdominal pain can be treated with a low to modest dose of a tricyclic antidepressant.”

The update from the AGA includes 13 other recommendations, with noteworthy advice to use antibiotics selectively, rather than routinely, in cases of acute uncomplicated diverticulitis in immunocompetent patients. In a recent large meta-analysis, antibiotics did not shorten symptom duration or reduce rates of hospitalization, complications, or surgery in this setting. The clinical practice update advises using antibiotics if patients are frail or have comorbidities, vomiting or refractory symptoms, a C-reactive protein level above 140 mg/L, a baseline white blood cell count above 15 × 10⁹ cells/L, or fluid collection or a longer segment of inflammation on CT scan. Antibiotics also are strongly advised for immunocompromised patients, who are at greater risk for complications and severe diverticulitis. Because of this risk, clinicians should have “a low threshold” for cross-sectional imaging, antibiotic treatment, and consultation with a colorectal surgeon, according to the update.

The authors recommend CT if patients have severe symptoms or have not previously been diagnosed with diverticulitis based on imaging. Clinicians also should consider imaging if patients have had multiple recurrences, are not responding to treatment, are immunocompromised, or are considering prophylactic surgery (in which case imaging is used to pinpoint areas of disease).

Colonoscopy is advised after episodes of complicated diverticulitis or after a first episode of uncomplicated diverticulitis if no high-quality colonoscopy has been performed in the past year. This colonoscopy is advised to rule out malignancy, which can be misdiagnosed as diverticulitis, and because diverticulitis (particularly complicated diverticulitis) has been associated with colon cancer in some studies, the update notes. Unless patients have “alarm symptoms” – that is, a change in stool caliber, iron deficiency anemia, bloody stools, weight loss, or abdominal pain – colonoscopy should be delayed until 6-8 weeks after the diverticulitis episode or until the acute symptoms resolve, whichever occurs later.

The decision to discuss elective segmental resection should be based on disease severity, not the prior number of episodes. Although elective surgery for diverticulitis has become increasingly common, patients should be aware that surgery often does not improve chronic gastrointestinal symptoms, such as abdominal pain, and that surgery reduces but does not eliminate the risk for recurrence. The authors recommended against surgery to prevent complicated diverticulitis in immunocompetent patients with a history of uncomplicated episodes. “In this population, complicated diverticulitis is most often the first presentation of diverticulitis and is less likely with recurrences,” the update states. For acute complicated diverticulitis that has been effectively managed without surgery, patients are at heightened risk for recurrence, but “a growing literature suggest[s] a more conservative and personalized approach” rather than the routine use of interval elective resection, the authors noted. For all patients, counseling regarding surgery should incorporate thoughtful discussions of immune status, values and preferences, and operative risks versus benefits, including effects on quality of life.

Dr. Peery and another author were supported by grants from the National Institutes of Health. The authors reported having no conflicts of interest.

SOURCE: Peery AF et al. Gastroenterology. 2020 Dec 3. doi: 10.1053/j.gastro.2020.09.059.

This article was updated Feb. 10, 2021.

Exercise and a hypocaloric, Mediterranean-style diet remain first-line interventions that can benefit all patients with nonalcoholic fatty liver disease (NAFLD), according to a clinical practice update from the American Gastroenterological Association.

“[W]eight loss is associated with a reduction in liver fat, which provides a potential for reversal of disease progression,” wrote Zobair M. Younossi, MD, MPH, of Inova Fairfax Medical Campus in Falls Church, Va., with his associates. Lifestyle modifications remain “the cornerstone for management” because, even though NAFLD affects approximately 25% of individuals worldwide according to one meta-analytic assessment, interventions such as medications, bariatric endoscopy, and surgery are usually reserved for the subset of patients with severe obesity, comorbid diabetes, or nonalcoholic steatohepatitis (NASH) with at least stage 2 fibrosis, the experts wrote in Gastroenterology.

They note that clinically significant weight loss typically requires a hypocaloric diet of 1,200-1,500 kilocalories/day or a decrease of 500-1,000 kilocalories/day from baseline. A Mediterranean diet of fresh vegetables, fruits, legumes, minimally processed whole grains, fish, olive oil, nuts, and seeds is recommended because its antioxidant, anti-inflammatory effects may slow NAFLD progression. This diet minimizes or eliminates sweets, refined grains, and red and processed meats. Fructose from fruit is not associated with NAFLD, but patients should consume little or no commercially prepared fructose, which has been linked to visceral adiposity, insulin resistance, hepatic inflammation, and fibrosis progression. Other hypocaloric diets have not been studied enough to support their routine use in NAFLD treatment, according to the clinical practice update.

For patients with NASH, which is the more severe form of NAFLD and is associated with significant morbidity and mortality caused by complications from cirrhosis, hepatic decompensation, and hepatocellular carcinoma, weight loss also has a big impact: Losing at least 5% of total body weight can decrease hepatic steatosis, losing at least 7% can resolve NASH, and losing at least 10% can lessen or stabilize hepatic fibrosis, according to level 1 evidence cited by the update. Weight loss “can significantly impact all aspects of NAFLD histology including fibrosis, but a goal of 10% total body weight loss should be considered for patients with overweight or obese NAFLD,” the authors wrote. Fat loss also improves liver histology in patients with lean NAFLD (body mass index, 26 kg/m² in non-Asian patients or 24 in Asians), for whom a hypocaloric diet targeting a more modest 3%-5% total body weight loss is recommended.

Because aerobic exercise reduces hepatic fat levels independently of hypocaloric diet, patients with NAFLD should consider a weekly regimen of 150-300 minutes of moderate-intensity exercise or 75-150 minutes of vigorous activity. Resistance training can complement aerobic exercise “but [is] not a replacement,” the authors noted. In addition, patients with NAFLD should restrict alcohol consumption to reduce the risk for liver-related events, and those with advanced hepatic fibrosis should “avoid alcohol entirely.” These recommendations reflect the findings of a large prospective study in which the consumption of even low amounts of alcohol led to worse liver-related outcomes among patients with NAFLD.

Clinicians should screen for and “aggressively” manage common NAFLD comorbidities, including diabetes mellitus, hypertension, and obstructive sleep apnea, according to the clinical practice update. Patients with coexisting metabolic conditions should be risk-stratified for cardiovascular disease and treated based on guidelines from the American College of Cardiology and the American Heart Association.

It is believed that sarcopenia affects patients with NASH cirrhosis because their livers cannot effectively store, metabolize, or mobilize carbohydrates, which leads to a catabolic state in which protein and fat are used as energy sources, according to the update. To avoid exacerbations, these patients may need to optimize their protein intake – a minimum of 1.2-1.5 g/kg of body weight is recommended – from sources of branched-chain amino acids, such as chicken, fish, eggs, nuts, lentils, or soy. Patients with sarcopenic NAFLD also should consume small, frequent meals spaced no more than 4-6 hours apart. When possible, they should consult with a specialized nutritionist. Moderate-intensity exercise may also benefit patients experiencing sarcopenia.

The researchers disclosed ties to Gilead Sciences, Intercept, Bristol Myers Squibb, Novo Nordisk, and several other companies. The review was commissioned and approved by the AGA Institute’s Clinical Practice Updates Committee and the AGA Governing Board.

SOURCE: Younossi ZM et al. Gastroenterology. 2020 Dec 8. doi: 10.1053/j.gastro.2020.11.051.

This article was updated Feb. 10, 2021.

Exercise and a hypocaloric, Mediterranean-style diet remain first-line interventions that can benefit all patients with nonalcoholic fatty liver disease (NAFLD), according to a clinical practice update from the American Gastroenterological Association.

“[W]eight loss is associated with a reduction in liver fat, which provides a potential for reversal of disease progression,” wrote Zobair M. Younossi, MD, MPH, of Inova Fairfax Medical Campus in Falls Church, Va., with his associates. Lifestyle modifications remain “the cornerstone for management” because, even though NAFLD affects approximately 25% of individuals worldwide according to one meta-analytic assessment, interventions such as medications, bariatric endoscopy, and surgery are usually reserved for the subset of patients with severe obesity, comorbid diabetes, or nonalcoholic steatohepatitis (NASH) with at least stage 2 fibrosis, the experts wrote in Gastroenterology.

They note that clinically significant weight loss typically requires a hypocaloric diet of 1,200-1,500 kilocalories/day or a decrease of 500-1,000 kilocalories/day from baseline. A Mediterranean diet of fresh vegetables, fruits, legumes, minimally processed whole grains, fish, olive oil, nuts, and seeds is recommended because its antioxidant, anti-inflammatory effects may slow NAFLD progression. This diet minimizes or eliminates sweets, refined grains, and red and processed meats. Fructose from fruit is not associated with NAFLD, but patients should consume little or no commercially prepared fructose, which has been linked to visceral adiposity, insulin resistance, hepatic inflammation, and fibrosis progression. Other hypocaloric diets have not been studied enough to support their routine use in NAFLD treatment, according to the clinical practice update.

For patients with NASH, which is the more severe form of NAFLD and is associated with significant morbidity and mortality caused by complications from cirrhosis, hepatic decompensation, and hepatocellular carcinoma, weight loss also has a big impact: Losing at least 5% of total body weight can decrease hepatic steatosis, losing at least 7% can resolve NASH, and losing at least 10% can lessen or stabilize hepatic fibrosis, according to level 1 evidence cited by the update. Weight loss “can significantly impact all aspects of NAFLD histology including fibrosis, but a goal of 10% total body weight loss should be considered for patients with overweight or obese NAFLD,” the authors wrote. Fat loss also improves liver histology in patients with lean NAFLD (body mass index, 26 kg/m² in non-Asian patients or 24 in Asians), for whom a hypocaloric diet targeting a more modest 3%-5% total body weight loss is recommended.

Because aerobic exercise reduces hepatic fat levels independently of hypocaloric diet, patients with NAFLD should consider a weekly regimen of 150-300 minutes of moderate-intensity exercise or 75-150 minutes of vigorous activity. Resistance training can complement aerobic exercise “but [is] not a replacement,” the authors noted. In addition, patients with NAFLD should restrict alcohol consumption to reduce the risk for liver-related events, and those with advanced hepatic fibrosis should “avoid alcohol entirely.” These recommendations reflect the findings of a large prospective study in which the consumption of even low amounts of alcohol led to worse liver-related outcomes among patients with NAFLD.

Clinicians should screen for and “aggressively” manage common NAFLD comorbidities, including diabetes mellitus, hypertension, and obstructive sleep apnea, according to the clinical practice update. Patients with coexisting metabolic conditions should be risk-stratified for cardiovascular disease and treated based on guidelines from the American College of Cardiology and the American Heart Association.

It is believed that sarcopenia affects patients with NASH cirrhosis because their livers cannot effectively store, metabolize, or mobilize carbohydrates, which leads to a catabolic state in which protein and fat are used as energy sources, according to the update. To avoid exacerbations, these patients may need to optimize their protein intake – a minimum of 1.2-1.5 g/kg of body weight is recommended – from sources of branched-chain amino acids, such as chicken, fish, eggs, nuts, lentils, or soy. Patients with sarcopenic NAFLD also should consume small, frequent meals spaced no more than 4-6 hours apart. When possible, they should consult with a specialized nutritionist. Moderate-intensity exercise may also benefit patients experiencing sarcopenia.

The researchers disclosed ties to Gilead Sciences, Intercept, Bristol Myers Squibb, Novo Nordisk, and several other companies. The review was commissioned and approved by the AGA Institute’s Clinical Practice Updates Committee and the AGA Governing Board.

SOURCE: Younossi ZM et al. Gastroenterology. 2020 Dec 8. doi: 10.1053/j.gastro.2020.11.051.

This article was updated Feb. 10, 2021.

Exercise and a hypocaloric, Mediterranean-style diet remain first-line interventions that can benefit all patients with nonalcoholic fatty liver disease (NAFLD), according to a clinical practice update from the American Gastroenterological Association.

“[W]eight loss is associated with a reduction in liver fat, which provides a potential for reversal of disease progression,” wrote Zobair M. Younossi, MD, MPH, of Inova Fairfax Medical Campus in Falls Church, Va., with his associates. Lifestyle modifications remain “the cornerstone for management” because, even though NAFLD affects approximately 25% of individuals worldwide according to one meta-analytic assessment, interventions such as medications, bariatric endoscopy, and surgery are usually reserved for the subset of patients with severe obesity, comorbid diabetes, or nonalcoholic steatohepatitis (NASH) with at least stage 2 fibrosis, the experts wrote in Gastroenterology.

They note that clinically significant weight loss typically requires a hypocaloric diet of 1,200-1,500 kilocalories/day or a decrease of 500-1,000 kilocalories/day from baseline. A Mediterranean diet of fresh vegetables, fruits, legumes, minimally processed whole grains, fish, olive oil, nuts, and seeds is recommended because its antioxidant, anti-inflammatory effects may slow NAFLD progression. This diet minimizes or eliminates sweets, refined grains, and red and processed meats. Fructose from fruit is not associated with NAFLD, but patients should consume little or no commercially prepared fructose, which has been linked to visceral adiposity, insulin resistance, hepatic inflammation, and fibrosis progression. Other hypocaloric diets have not been studied enough to support their routine use in NAFLD treatment, according to the clinical practice update.

For patients with NASH, which is the more severe form of NAFLD and is associated with significant morbidity and mortality caused by complications from cirrhosis, hepatic decompensation, and hepatocellular carcinoma, weight loss also has a big impact: Losing at least 5% of total body weight can decrease hepatic steatosis, losing at least 7% can resolve NASH, and losing at least 10% can lessen or stabilize hepatic fibrosis, according to level 1 evidence cited by the update. Weight loss “can significantly impact all aspects of NAFLD histology including fibrosis, but a goal of 10% total body weight loss should be considered for patients with overweight or obese NAFLD,” the authors wrote. Fat loss also improves liver histology in patients with lean NAFLD (body mass index, 26 kg/m² in non-Asian patients or 24 in Asians), for whom a hypocaloric diet targeting a more modest 3%-5% total body weight loss is recommended.

Because aerobic exercise reduces hepatic fat levels independently of hypocaloric diet, patients with NAFLD should consider a weekly regimen of 150-300 minutes of moderate-intensity exercise or 75-150 minutes of vigorous activity. Resistance training can complement aerobic exercise “but [is] not a replacement,” the authors noted. In addition, patients with NAFLD should restrict alcohol consumption to reduce the risk for liver-related events, and those with advanced hepatic fibrosis should “avoid alcohol entirely.” These recommendations reflect the findings of a large prospective study in which the consumption of even low amounts of alcohol led to worse liver-related outcomes among patients with NAFLD.

Clinicians should screen for and “aggressively” manage common NAFLD comorbidities, including diabetes mellitus, hypertension, and obstructive sleep apnea, according to the clinical practice update. Patients with coexisting metabolic conditions should be risk-stratified for cardiovascular disease and treated based on guidelines from the American College of Cardiology and the American Heart Association.

It is believed that sarcopenia affects patients with NASH cirrhosis because their livers cannot effectively store, metabolize, or mobilize carbohydrates, which leads to a catabolic state in which protein and fat are used as energy sources, according to the update. To avoid exacerbations, these patients may need to optimize their protein intake – a minimum of 1.2-1.5 g/kg of body weight is recommended – from sources of branched-chain amino acids, such as chicken, fish, eggs, nuts, lentils, or soy. Patients with sarcopenic NAFLD also should consume small, frequent meals spaced no more than 4-6 hours apart. When possible, they should consult with a specialized nutritionist. Moderate-intensity exercise may also benefit patients experiencing sarcopenia.

The researchers disclosed ties to Gilead Sciences, Intercept, Bristol Myers Squibb, Novo Nordisk, and several other companies. The review was commissioned and approved by the AGA Institute’s Clinical Practice Updates Committee and the AGA Governing Board.

SOURCE: Younossi ZM et al. Gastroenterology. 2020 Dec 8. doi: 10.1053/j.gastro.2020.11.051.

This article was updated Feb. 10, 2021.