It is Getting Harder to Treat H pylori -Here’s Why

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In a recent study (A Savoldi et al. Gastroenterol 2018; 155: 1372-82, editorial pg 1287), the authors conducted a systematic review and meta-analysis to examine the prevalence of antibiotic resistance to Helicobacter pylori. The authors identified 178 studies with 66,142 H pylori isolates. Tables 2 & 3 provide comprehensive data.

Key points:

  • In the Americas region, primary resistance to clarithromycin, metronidazole, levofloxacin and amoxicillin was 10%, 23%, 15%, and 10% respectively.
  • In the European region, primary resistance to clarithromycin, metronidazole, levofloxacin and amoxicillin was 18%, 32%, 11%, and 0% respectively.

Antibiotic resistance is increasing: 

  • In the Americas region, resistance in 2006-2008 compared to 2012-201 for clarithromycin, & metronidazole: 11%–>20%, 26%–>29% respectively.
  • In the European region, resistance in 2006-2008 compared to 2012-201 for clarithromycin, & metronidazole: 28%–>28%, 38%–>46% respectively.
  • “The resistance rates to clarithromycin, metronidazole, and levofloxacin have increased over time in all WHO regions.”  Other regions with data in study included Eastern Mediterranean, Southeast Asia, and Western Pacific.
  • In the study, the authors also “describe a clear significant association between antibiotic resistance and treatment failure.”

In their discussion, the authors note that the incidence of gastric cancer is higher in areas with increased antibiotic resistance.  Though there has been a decline in gastric cancer, “based on our data, we can hypothesize that this trend in reduction is expected to revert soon because available treatment can no longer guarantee a satisfactory eradication rate.”

From editorial:

  • “H pylori is not one of those bacteria in which resistance develops as an epidemic by horizonatal transfer of mobile genetic elements…Resistance in H pylori only occurs unevenly by mutations…Fortunately, resistance occurs “very seldomly for …amoxicillin and tetracycline.”
  • Treatment failure is “almost 7 times greater (6.97) when the strain is clarithromycin resistant and even greater (8.18) when the strain is levofloxacin resistant.” Resistance to metronidazole confers a lesser degree of treatment failure risk: OR 2.52.

My take: This study provides some sobering news about H pylori prevalence and how it is becoming more difficult to treat.

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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Pooled Prevalence of resistance to clarithromycin (2006-2016). This is from Figure 2. Sections B & C (not shown) provide similar graphic info for metronidazole and levofloxacin

Delayed Recognition of Kawasaki Disease in Children with Presenting Intestinal Involvement

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A recent study (C Columba et al. Full text: Intestinal Involvement in Kawasaki Disease J Pediatr 2018; 202: 186-93) indicates that when patients with Kawaski’s present with predominantly intestinal symptoms that this may lead to a delay in diagnosis and potential cardiac complications. In this systematic review, 33 articles reporting 48 cases of Kawasaki disease with intestinal involvement were considered.

Some key points:

  • In this study, abdominal pain and vomiting were the most frequently reported symptoms, followed by diarrhea. Fever was typically present but other features of Kawaski disease were not apparent at presentation.  Presentation can include dilated bowel loops suggestive of obstruction (pseudo-obstruction), pancreatitis, and intestinal vasculitis/bowel wall thickening.
  • “The prevalence of gastrointestinal involvement in Kawasaki disease is unknown as available data can only be derived from single reports and few case series. Miyake et al in their retrospective case series of 310 children with Kawasaki disease reported gastrointestinal involvement in only 7 cases (2.3%).”
  • “Abdominal symptoms in Kawasaki disease are more often due to hydrops of the gallbladder. In Taiwan, a routine abdominal ultrasound showed hydrops of the gallbladder in 21% of patients with Kawasaki disease.”

My take: Since early treatment of Kawasaki disease may improve outcomes, it is worthwhile to consider this in the differential diagnosis of patients presenting with possible obstruction and in those who have fever in addition to pain/emesis.

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Evidence-Based IBS Treatment Recommendations from ACG

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A recent  American College of Gastroenterology Task Force conducted a systematic review (AC Ford et al. The American Journal of Gastroenterology 2018;113:1–18 ) to update management recommendations for irritable bowel syndrome -Link:

American College of Gastroenterology Monograph on Management of Irritable Bowel Syndrome

The highlights of this report are summarized at Gastroenterology & Hepatoloy: Highlights of the Updated Evidence-Based IBS Treatment Monograph

A few excerpts:

“There have been numerous studies performed on the roles of diet and dietary manipulation in IBS. Three fairly firm conclusions were made following the review of these studies: (1) the low–fermentable oligosaccharide, disaccharide, monosaccharide, and polyol (FODMAP) diet seems to be effective for overall IBS symptom improvement; (2) a gluten-free diet is not effective for symptom improvement; and (3) conducting tests to detect various types of allergies or intolerances in order to base a diet on those results does not appear to be effective. Of these 3 conclusions, the most impressive data that came out of the research was the evidence for the low-FODMAP diet. Not only were there more studies on this diet, but the results were fairly consistent and favorable, at least for the short-term management of IBS.”

” We did not find evidence supporting the idea that prebiotics and synbiotics were effective in IBS management… In ­contrast, studies demonstrated that probiotics did improve global gastrointestinal symptoms, as well as the individual symptoms of bloating and flatulence in patients with IBS. However, determining which probiotic is best was difficult”

“Three prosecretory agents are available: linaclotide (Linzess, Allergan/Ironwood Pharmaceuticals), lubiprostone (Amitiza, Takeda), and plecanatide (Trulance, Synergy Pharmaceuticals), with plecanatide being the most recently approved agent. All 3 of these agents had convincing data to support their use in patients with constipation-predominant IBS”

My take: In IBS patients, if dietary therapy is recommended, current evidence favors a low FODMAP diet rather than a gluten-free diet.

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Image above -Parker Ridge Trail

Finite Therapy with Oral Antivirals for Chronic Hepatitis B Infection

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A recent study (WJ Jeng et al. Hepatology 2018; 68: 425-34) indicates that many patients with Hepatitis B e Antigen-Negative Chronic Hepatitis B benefit from a finite treatment with oral antivirals.

These findings are discussed by P Lampertico and T Berg (editorial 397-400). In the Jeng study, the investigators prospectively followed the effect of antiviral cessation in 691 individuals after patients had undetectable HBV DNA and met Asian Pacific Association for the Study of Liver guidelines for stopping.  HBsAg clearance occurred in 13% who discontinued therapy compared to 3% during nucleos(t)ide treatment.  The authors note that virologic relapse occurred in 79% and that the immune system activation driven by clinical relapse can be beneficial in yielding a cure.  Clinical decompensation was infrequent and most could be retreated; three patients with cirrhosis and decompensation died

My take: These studies show that in carefully-selected and carefully-monitored patients with HBeAg-negative chronic hepatitis B infection, it is feasible to successfully stop oral antiviral therapy.

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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

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Pediatric Liver Enzyme Reference Values

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A recent study (S Bussler et al. Hepatology 2018; 1319-1330)  provides reference age-related reference values for ALT, AST, and GGT for children from 11 months of age through 16 years.  This study from Leipzig used the LIFE Child prospective longitudinal population-based cohort with 3,131 cases (normal weight).

  • Figure 2 provides age- and sex-related percentiles for ALT.  At all ages and in both genders, the 90% cutoff was ~30 IU (or less).
  • Figure 3 provides age- and sex-related percentiles for AST.  There was a negative sloping curve with both genders, such that the 90% cutoff was ~60 IU at ~1 yr and ~40 IU at ~13 yr. Females tended to have modestly higher values.
  • Figure 4 provides age- and sex-related percentiles for GGT.  At all ages and in both genders, the 90% cutoff was ~25 IU. Males tended to have modestly higher values.

These values overall are similar to previous studies. From NASPGHAN NAFLD Guidelines: For ALT: “In the United States, sex-specific biologically based cutoffs have been determined from nationally representative data and have been validated in a fairly diverse cohort. These cutoffs are 22 mg/dL for girls and 26 mg/dL for boys. A Canadian study found the upper limit of normal for ALT to be 30 mg/dL in children 1 to 12 years of age, and 24 mg/dL in those between 13 and 19 years”

Related blog post: Pediatric NAFLD Guidelines 2017

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Another Reason For HPV Vaccine –Prevention of Anal Cancer

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Briefly noted: A recent study (L Vuitton et al. Clin Gastroenterol Hepatol 2018; 16: 1768-76) document a high prevalence of anal canal high-risk human papillomavirus (HPV)  infection in all subjects (n=469, median age 54 years) and even higher rates in patients with Crohn’s disease (n=70).  The authors detected HPV DNA in anal tissues from 34% of the subjects and high risk (oncogenic) HPV in 18%.  In patients with Crohn’s disease, high risk HPV was detected in 30%.

My take: HPV infection predisposes to anal cancer which represent 3-4% of lower-digestive tract cancers. The high rate of HPV

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TARGET Study: Does Energy-Dense Nutrition Improve Outcomes in the Critically Ill

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A recent double-blind randomized study (NEJM 2018; 379: 1823-44) examined the outcomes of 3957 adult patients undergoing mechanical ventilation who received either a 1.5 kcal formula or 1.0 kcal formula for provision of enteral nutrition.

Key Findings:

  • While the volume of formula was similar, the 1.5 kcal group received a mean of 1863 kcal/day compared to 1262 kcal/day for the 1.0 kcal group.
  • Yet, this did not translate into a survival benefit.  By day 90, 26.8% of the 1.5 kcal group had died compared with 25.7% of the 1.0 kcal group (RR 1.05, 95% CI 0.94-1.16, P=0.41)
  • Higher caloric delivery did not affect survival, receipt of organ support, duration of hospital stay, the incidence of infective complications or adverse events.
  • Regurgitation was more common in the 1.5 kcal group: 18.9% vs 15.7%, RR 1.20, 95% CI 1.05-1.38)
  • The 1.5 kcal group were more likely to receive promotility medications (47.4% vs 39.6%, RR 1.20)
  • The 1.5 kcal group were more likely to receive insulin (55.8% vs 49.0%, RR 1.14)

In their discussion, the authors note that only 2% of patients had a BMI less than 18.5; thus, their cohort is unable to determine whether these patients could benefit from increased calories.

My take (borrowed in part from authors): “Increasing energy intake with the administration of energy-dense enteral nutrition did not affect survival among critically ill adults.” These types of studies are important in challenging assumptions that meeting calorie needs (with enteral or parenteral nutrition) will improve outcomes in hospitalized patients–though, this may be true in some populations.

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Does Screening for Hepatocellular Carcinoma Improve Outcomes in Patients with Cirrhosis?

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Despite widespread recommendations to screen patients with cirrhosis for hepatocellular carcinoma (HCC), a recent study (AM Moon et al. Gastroenterol 2018; 16: 1777-85) found “No Association Between Screening for Hepatocellular Carcinoma and Reduced Cancer-Related Mortality in Patients with Cirrhosis.” The title of the study did not make sense to me based on previous publications that have noted increased risk of HCC in patients with cirrhosis and the presumption that screening would allow effective interventions to prevent death due to HCC.  So I looked at the study a little closer:

Background/Methods: The authors utilized a matched case-control study within the U.S. Veterans Affairs health care system to determine whether ultrasonography (US) or alpha-fetoprotein (AFP) screening was associated with decreased cancer-related mortality.

They identified 238 patients with cirrhosis who died of HCC between 2013-2015 –all of whom had a diagnosis of cirrhosis at least 4 years before the diagnosis of HCC.  Then, they matched them with a control patient with cirrhosis who did not have HCC and had been identified at least 4 years prior to matched case’s HCC.

Key findings:

  • There was no significant difference between the cases and the controls in the proportions who underwent screening:
  • For U/S screening: 52.9% cases and 54.2% for controls.
  • For AFP (serum) screening, 74.8% vs 73.5% respectively.
  • For either U/S or AFP screening, 81.1% vs 79.4%.
  • For both U/S and AFP screening, 46.6% vs 48.3% respectively.
  • Table 4 provides odds ratios and adjusted odds ratios for the cases compared to controls.  The Adjusted Odds ratios for U/S 0-4 years before index case was 0.95, for AFP 1.08, and for either U/S or AFP 1.11.

The authors found that HCC screening with U/S and/or AFP was not associated with decreased risk of HCC-related mortality.

In their study, the authors note that most studies on HCC screening have been observational which have numerous limitations including lead-time biases (which can overestimate the benefits of screening) and patient selection.  Two randomized controlled trials reached conflicting conclusions; these trials were conducted in China where HCC is mainly associated with hepatitis B infection.

The authors point out that liver societies like AASLD and EASL have recommended U/S every 6 months with or without AFP measurements for HCC surveillance in patients with cirrhosis.  However, non-liver societies have NOT “endorsed HCC screening because of the lack of high-quality data.”  Neither the US Preventive Services Task Force nor the American Cancer Society make recommendations for HCC screening.  And, “the National Cancer Institute found no evidence that screening decreases mortality from HCC but did find evidence that screening could result in harm.”

Strengths of this study:

  • All VA patients have access to medical care; this limits bias due to access to HCC screening
  • The matched-case control design with random controls across a system that delivers care to 8 million veterans across the country indicates that the findings are likely  “typical of community-based settings” and likely to yield “estimates of the impact of screening …[that] approximates the results that would be expected from a randomized controlled trial”

Why Have Previous Studies Indicated that HCC Screening is Worthwhile?

  • According to the authors, even though HCC detected by screening is on average detected at an earlier stage than those detected due to symptoms, “this does not prove that screening leads to earlier detection. Another explanation is that screening is more likely to identify slow-growing tumors, which have a lower stage, and more likely to miss the fast-growing tumors, which are identified at a higher stage by symptoms.”
  • “It is possible that the HCCs most likely to lead to death are the HCCs least likely to be identified by current screening modalities at an early stage.”
  • In addition,  “whether early treatment for HCC in patients with cirrhosis leads to a decrease in case fatality is questionable.”  Patients who receive surgical resection or locoregional treatments remain at risk for recurrent HCC, new HCC and progressive liver dysfunction.  While liver transplantation can cure HCC and cirrhosis, only a “small minority of patients with HCC undergo liver transplantation.”  In 2012, only 1,733 patients received liver transplantation for HCC out of a reported 24,696 incident cases.

My take: This study offers a lot of insight regarding HCC screening and questions its usefulness, though I doubt this study will change how most hepatologists practice.

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PEG Placement in Cystic Fibrosis

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A small retrospective study (RT Khalaf et al.NCP 2018; LINK: doi.org/10.1002/ncp.10219) showed that PEG placement was associated with a trend (not statistically significant) towards improved lung function in children with cystic fibrosis (CF). Reference from Kipp Ellsworth twitter feed.  There were 20 patients who had PEG placed compared to 40 patients who did not.

Findings:

  • BMI percentile increased per month for those with PEG (0.51, 95% confidence interval (CI) = −0.05–1.08, P = .08), but decreased for those without PEG (−0.03, 95% CI = −0.33–0.28, P = .86); however, the difference (0.54; 95% CI = −0.10–1.18, P = .10) was not statistically significant.
  • FEV1 change with time showed a decrease for patients with PEG (−0.04; 95% CI = −0.30–0.22, P = .74) and those without PEG (−.22; 95% CI = −0.45–0.01, P = .06). Although the FEV1 decrease for those without PEG was higher than those with PEG, the difference between the groups was not statistically significant (0.18; 95% CI = −0.17–0.52, P = .32)

My take: While the differences are not statistically-significant, this study indicates that PEG placement is NOT detrimental to lung function in CF and may be beneficial.

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