Author Archives: gutsandgrowth

Unknown's avatar

About gutsandgrowth

I am a pediatric gastroenterologist at GI Care for Kids (previously called CCDHC) in Atlanta, Georgia. The goal of my blog is to share some of my reading in my field more broadly. In addition, I wanted to provide my voice to a wide range of topics that often have inaccurate or incomplete information. Before starting this blog in 2011, I would tear out articles from journals and/or keep notes in a palm pilot. This blog helps provide an updated source of information that is easy to access and search, along with links to useful multimedia sources. I was born and raised in Chattanooga. After graduating from the University of Virginia, I attended Baylor College of Medicine. I completed residency and fellowship training at the University of Cincinnati at the Children’s Hospital Medical Center. I received funding from the National Institutes of Health for molecular biology research of the gastrointestinal tract. During my fellowship, I had the opportunity to work with some of the most amazing pediatric gastroenterologists and mentors. Some of these individuals included Mitchell Cohen, William Balistreri, James Heubi, Jorge Bezerra, Colin Rudolph, John Bucuvalas, and Michael Farrell. I am grateful for their teaching and their friendship. During my training with their help, I received a nationwide award for the best research by a GI fellow. I have authored numerous publications/presentations including original research, case reports, review articles, and textbook chapters on various pediatric gastrointestinal problems. In addition, I have been recognized by Atlanta Magazine as a "Top Doctor" in my field multiple times. Currently, I am the vice chair of the section of nutrition for the Georgia Chapter of the American Academy of Pediatrics. In addition, I am an adjunct Associate Clinical Professor of Pediatrics at Emory University School of Medicine. Other society memberships have included the North American Society for Pediatric Gastroenterology Hepatology and Nutrition (NASPGHAN), American Academy of Pediatrics, the Food Allergy Network, the American Gastroenterology Association, the American Association for the Study of Liver Diseases, and the Crohn’s and Colitis Foundation. As part of a national pediatric GI organization called NASPGHAN (and its affiliated website GIKids), I have helped develop educational materials on a wide-range of gastrointestinal and liver diseases which are used across the country. Also, I have been an invited speaker for national campaigns to improve the evaluation and treatment of gastroesophageal reflux disease, celiac disease, eosinophilic esophagitis, hepatitis C, and inflammatory bowel disease (IBD). Some information on these topics has been posted at my work website, www.gicareforkids.com, which has links to multiple other useful resources. I am fortunate to work at GI Care For Kids. Our group has 17 terrific physicians with a wide range of subspecialization, including liver diseases, feeding disorders, eosinophilic diseases, inflammatory bowel disease, cystic fibrosis, DiGeorge/22q, celiac disease, and motility disorders. Many of our physicians are recognized nationally for their achievements. Our group of physicians have worked closely together for many years. None of the physicians in our group have ever left to join other groups. I have also worked with the same nurse (Bernadette) since I moved to Atlanta in 1997. For many families, more practical matters about our office include the following: – 14 office/satellite locations – physicians who speak Spanish – cutting edge research – on-site nutritionists – on-site psychology support for abdominal pain and feeding disorders – participation in ImproveCareNow to better the outcomes for children with inflammatory bowel disease – office endoscopy suite (lower costs and easier scheduling) – office infusion center (lower costs and easier for families) – easy access to nursing advice (each physician has at least one nurse) I am married and have two sons (both adults). I like to read, walk/hike, bike, swim, and play tennis with my free time. I do not have any financial relationships with pharmaceutical companies or other financial relationships to disclose. I have helped enroll patients in industry-sponsored research studies.

Don’t Give Up Too Soon (with Hepatitis B treatment)

Posted on by

A recent study shows that ongoing treatment with entecavir is usually effective in “primary nonresponders” (Hepatology 2014; 59: 1303-10).

This study retrospectively reviewed a study with 1254 treatment-naive patients who received entecavir (ETV) 0.5 mg/day for >6 months. Only 16 (1.28%) patients were considered “primary nonresponders.”  The latter was defined as a <2 log drop in HBV DNA after 6 months of therapy by AASLD or <1 log drop after 3 months by EASL.

Key findings:

  • The probability of achieving a virologic response (HBV DNA <15 IU/mL) was 95.8% at 54 months among these “nonresponders”
  • Primary nonresponders did not have ETV resistance; however, 13 (1%) of the entire cohort developed ETV resistance.
  • In this treatment cohort, the 5-year cumulative risk of hepatocellular carcinoma (HCC) was 2.5%.  Previous studies have shown that HBV suppression lowers the risk of HCC.

Take-home message: 

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.

 

OTCD –Another Reason for Acute Liver Failure

Posted on by

A recent study shows that a significant number of patients with Ornithine Transcarbamylase Deficiency (OTCD), which is the most common urea cycle defect (UCD), can present with significant hepatic involvement and even acute liver failure (ALF) (J Pediatr 2014; 164: 720-25).

This retrospective study reviewed 71 patients with OTCD at 2 centers.  Longitudinal data collected over 10 years was analyzed.

Key result:

  • 57% of the 49 patients with symptomatic OTCD had liver involvement and 29% of these patients met criteria for ALF

“Although the urea cycle enzymes are active in the liver, standard liver function generally has been considered to be largely unaffected in UCD.”   This study shows that this concept is mistaken.OTCD has been viewed mainly as a disorder that presents with marked hyperammonemia in the newborn period.  However, there is variable clinical expression and some may remain asymptomatic throughout their lifetime.

Take-home message: Check plasma amino acids, urine organic acids and urine orotic acids when patients do not have an established etiology for hepatic dysfunction, including ALF.

 

Related blog posts:

Shwachman-Diamond Syndrome

Posted on by

A recent study provides an update on the variable clinical presentation of Shwachman-Diamond syndrome (SDS) (J Pediatr 2014; 163: 866-70).

SDS, an autosomal recessive disorder, is characterized by exocrine pancreatic dysfunction, bone marrow dysfunction, and predisposition to myelodysplasia/leukemia.  It is due to a mutation in the SBDS gene located on chromosome 7q11 (found in ~90% of classically presenting cases of SDS.

Using a North American Registry, the authors reviewed the records of 37 patients (all who have had mutations in SBDS gene). Key findings:

  • Neutropenia was evident at presentation in 30/37 (81%)
  • Only 51% had both neutropenia and steatorrhea at presentation
  • 24/37 (65%) had congenital anomalies: 3 with ventricular septal defects, 1 malrotation, 1 imperforate anus, 9 thoracic dystrophy (rib abnormalities), 2 with short arms/legs, 4 with metaphyseal dysplasia, 1 with Chiari malformation (type 1), 2 with testicular atrophy.
  • Medical comorbidities included elevated LFTs in 15, adrenal insufficiency in 1, hypopituitarism in 1, type 1 diabetes in 1, hypothyroid in 1, and eczema in 11.

Take-home message: Normal pancreatic imaging studies and normal fecal elastase do not rule out SDS. In addition, frequently there are associated anomalies and comorbidities.

NAFLD –Analogous to a Dog Chasing A Bus?

Posted on by

I am not sure of the origin of the expression “what is a dog going to do if it catches a bus?”  However, I am reminded of this expression after reading a recent article about nonalcoholic fatty liver disease (J Pediatr 2014; 164: 707-13).

This retrospective study, “Histologic Abnormalities in Children with Nonalcoholic Fatty Liver Disease with Normal or Mildly Elevated Alanine Aminotransferase Levels,” analyzed 91 children (5-18 years) with suspected NAFLD who had normal or mildly elevated ALT values from 12 U.S. medical centers.  They obtained liver biopsy specimens within 180 days of the ALT measurement and compared them from 392 children with elevated ALT.

When reading this title, one has to wonder, how did they select these children for this study?  First of all the authors used two NASH CRN databases with 483 children.  The reasons for NAFLD evaluation at entry in the current study included symptoms of liver disease in 22%, identification during evaluation of another illness in 38%, routine physical exam (41%), and other causes in 6%. At one point, elevated ALT was evident in 74% and radiographic evidence of steatosis in 55%.

The authors conclude that “liver biopsy specimens from children with NAFLD with normal or mildly elevated ALT levels show significant histological abnormalities, including advanced fibrosis…measurement of ALT may underestimate liver injury in NAFLD.” Yet, while it is true that ALT values may not have adequate sensitivity for liver injury, the authors deploy some circular logic; when one understands the selection of these patients, it comes as no surprise that some had advanced liver findings on biopsy.  If one identifies an abnormal liver on ultrasound and confirms this on liver biopsy, this is targeting a population whose findings are not generalizable.

Outside of a research study, how does one decide which patients will benefit from a liver biopsy? This study does not offer any clarity.

And, if one identifies more cases of NAFLD, what is one to do?  Besides weight loss (which should be recommended already in the majority), there are no other proven treatments.  The associated editorial (pgs 684-86) reminds the reader to use appropriate normative values for ALT (<25.8 U/L for boys and <22.1 U/L for girls).  In the study’s discussion, the lack of consensus among expert recommendations is acknowledged.  Furthermore, in those who have recommended frequent screening with ALT values in obese children, the authors note that “evidence of the utility and cost-effectiveness of this approach is still lacking.”

Another study in the same issue (J Pediatr 2014; 164: 699-706) suggests a possible link between obstructive sleep apnea (OSA) and more advanced liver histology in NAFLD.  This was a cross-sectional study with only 25 patients (88% Hispanic, mean age 12.8 years).  The authors speculate that nighttime hypoxemia triggers oxidative stress and may induce further liver injury.  53% of those with OSA had stage 2 or higher fibrosis compared with only 10% of those without OSA.

Bottomline: NAFLD occurs in a lot of children and a normal or mildly elevated ALT does not exclude more severe disease.  OSA may be either an epiphenomenon or a causative factor for more severe NAFLD findings.

Related blog posts:

Will Lubiprostone Help Children with Functional Constipation?

Posted on by

A recent open-label study of lubiprostone examined its use in children younger than 18 years (2007-2008) at 22 U.S. centers (JPGN 2014; 58: 283-91).

Lubiprostone (Amitiza) activates chloride-channel protein-2 in the gastrointestinal epithelium and promotes secretion of chloride ions and fluid.  This results in more frequent bowel movements (BMs) and improved motility.  To determine its safety and effectiveness in the pediatric population, the investigators enrolled 127 patients (124 were treated and analyzed and 109 completed the 4-week study).  After a 2-week observation period, several doses of lubiprostone were compared: 12 μg QD, 12 μg BID, 24 μg BID.  There was no placebo group.  The mean age of the participants was 10.2 years.

Results:

  • Mean spontaneous BM frequency increased from baseline: 3.1/week versus 1.5/week.  Overall, at each week in treatment ≥ 43% achieved ≥ 3 spontaneous BMs/week.
  • 62% experienced a spontaneous BM within 48 hours of starting treatment.
  • Common adverse reactions: Nausea (18.5%), vomiting (12.1%), diarrhea (8.1%), abdominal pain (7.3%) and headache (5.6%). Overall, 65% of patients experienced ≥ 1 adverse effect and this was highest (78%) in the subset of patients receiving the highest dosage

Bottomline: Current guidelines recommend osmotic agents like polyethylene glycol (PEG) (Miralax) as first-line treatment.  This short-term study shows lubiprostone may be an alternative in nonresponders, though more data on long-term outcomes are needed.

Related blog posts:

Is There a Link Between Maternal Iron Supplementation and Celiac Disease?

Posted on by

According to a recent study, maternal iron supplementation may increase the risk of celiac disease in children (Clin Gastroenterol Hepatol 2014; 12: 624-31).

Using the Norwegian Mother and Child cohort study (1999-2008) which included data for 78,846 children, the authors analyzed the risk of developing celiac disease by examining prospectively collected questionnaires regarding iron supplements, diet, and anemia.  Questionnaires were obtained 3 times during pregnancy, then at age 18 months, 6 years, 7 years and 8 years.

Key Results:

  • 4.65 of 1000 children whose mothers took iron supplements while pregnant developed celiac disease compared to 3.15 of 1000 whose mothers did not.
  • After adjustment for multiple variables, the OR was 1.33 for children developing celiac disease if their mother took iron supplementation during pregnancy.
  • The authors note that maternal anemia was not associated with celiac disease in offspring nor was iron supplementation in childhood.

While these findings are intriguing, the associated editorial (pg 632-35) notes that unmeasured confounding variables could explain the findings.  For example, undiagnosed maternal celiac disease which could increase the likelihood of iron exposure could increase the risk of celiac disease in the offspring and account for the increased association with iron supplementation.

Take-home message (from the editorial): “it is premature to argue that iron supplementation during pregnancy should be avoided in individuals with celiac disease…the observed effect (an absolute risk increase of 0.15%) is modest in magnitude. This exposure is not driving the slow, ongoing epidemic of celiac disease.”

Related blog links:

Brief Updates on Colorectal Cancer

Posted on by

“Low-Dose Aspirin Use After Diagnosis of Colorectal Cancer Does Not Increase Survival: A Case-Control Analysis of a Population-Based Cohort”  Gastroenterol 2014; 146: 700-08.  The authors performed a nested case-control analysis of a cohort of 4794 patients diagnosed with colorectal cancer.  “There was no association between low-dose aspirin usage and colon cancer-specific mortality.”  These study findings contradict previous studies.  More trials are underway.

“Reduced Risk of Colorectal Cancer Up to 10 Years After Screening, Surveillance, or Diagnostic Colonoscopy” Gastroenterol 2014; 146: 709-17.  Conclusion: “In a population-based case-control study, the risk of CRC was strongly reduced up to 10 years after colonoscopy for any indication. Risk was particularly low after screening colonoscopy, even for cancer in the right colon.”  The odds ratio for CRC after screening colonoscopy was 0.09.

NEJM 2014; 370: 1287-97.  Multitarget Stool DNA Testing for Colorectal-Cancer Screening.  Among 9989 average-risk participants, this stool DNA assay identified more cancers than a fecal immunochemical test (FIT) but had more false positives.

Related blog posts:

Keeping Track of HCV Trials -Three More

Posted on by

Recently three more trials of all oral regimens for HCV have been published in the NEJM.  A useful summary of their effectiveness is available in the associated editorial.  Here’s the link and an excerpt:

http://nej.md/1hhae91 

Welcomed and exciting results from three large, controlled trials of different regimens of oral antiviral agents for chronic hepatitis C, genotype 1, have now been published in the Journal.1-3 The regimens all included the combination of ledipasvir and sofosbuvir, two new direct-acting antiviral agents with potent activity against hepatitis C virus (HCV). The two drugs were given as a single tablet once daily for 8, 12, or 24 weeks, with or without ribavirin. The results were consistent and striking: the various regimens yielded rates of sustained virologic response of 93% to 99%. The combination of ledipasvir and sofosbuvir alone (without ribavirin) for 12 weeks was associated with response rates of 94% in the ION-2 study and 99% in the ION-1 study.1,2 Extending therapy to 24 weeks increased the rate minimally (to 98% and 99%, respectively). In contrast, adding ribavirin provided no further benefit, regardless of duration. In previously untreated patients without cirrhosis, shortening the duration of therapy (without ribavirin) to 8 weeks did not lessen the rate of response (94%, vs. 95% with 12 weeks of therapy in the ION-1 study).3 Importantly, the single-tablet regimen was easy to administer and had few side effects; among the 539 patients who received ledipasvir and sofosbuvir alone for 12 weeks in these three trials, only 2 stopped therapy early because of adverse events.

The rates of response to ledipasvir and sofosbuvir were virtually the same in all subgroups of patients, regardless of patients’ age, sex, race, liver-enzyme levels, HCV genotype (1a vs. 1b), preexisting antiviral resistance variants, or host genetic factors. Even in the difficult-to-treat patients who had not had a sustained response to a previous course of the most effective interferon-based therapies,4 the response rate at post-treatment week 12 was 94%. In this group of patients, the presence of cirrhosis was associated with a slightly lower response rate (88%, vs. 95% without cirrhosis), but with the longer course of treatment (24 weeks), these differences disappeared (100% in both groups).2 Preliminary studies with interferon-free drug combinations in patients with other HCV genotypes (2 or 3) suggest that high rates of response can be expected with those HCV strains as well.5

The combined results of the three trials include 1952 patients, of whom 97% had a sustained virologic response. Among the 3% who did not have a response, almost half were lost to follow-up or withdrew consent… Relapses were more common with shorter courses of therapy: 5% of patients who received 8 weeks of treatment had a relapse, as did 2% of those who received 12 weeks and 0.2% of those who received 24 weeks of treatment…

Ledipasvir and sofosbuvir are not the only promising antiviral agents for hepatitis C on the near horizon. Several other all-oral antiviral regimens have performed similarly in phase 2 studies, with sustained response rates in the range of 90% or higher.6,7 Thus, there are likely to be several options for oral therapy of hepatitis C within the next year.

  1. The availability of effective, oral regimens of therapy for hepatitis C will lead to major changes in the management of this disease and probably affect both its morbidity and its mortality…The limitations and medical barriers to treatment, however, may now largely disappear. The ease of administration, short duration of treatment, and minimal side effects of all-oral regimens will probably mean that most persons will qualify for therapy. Collectively, these regimens promise to transform hepatitis C from a condition requiring complex, unsatisfactory therapies and specialist care to one that can be effectively treated and easily managed by a general physician with few contraindications and side effects.
  2. Unfortunately, not all barriers to treatment will be lifted. The major limitation remaining will be economic. The current cost of a 12-week regimen of sofosbuvir alone is $84,000, or $1,000 per tablet.11 The addition of ledipasvir will add to the costs, and these estimates do not include expenses for diagnostic assays, monitoring, and physician visits…

Costs alone cast a pall over the stunning success in achieving the long-hoped-for goal of a safe and effective therapy for hepatitis C.

References:

  1. Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. DOI: 10.1056/NEJMoa1316366.
  2. Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. DOI: 10.1056/NEJMoa1402454.
  3. Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. DOI: 10.1056/NEJMoa1402355.

Related tweets (with links to abstracts/full text) from NEJM twitter feed:

  • ION-1: Sofosbuvir and ledipasvir (12 or 24 wks) achieved high (98 or 99%) SVR rates in untreated pts w/ HCV.
  • ION-2: Sofosbuvir and ledipasvir (12 or 24 wks) achieved high SVR rates in pts w/ HCV who failed prior Tx. 
  • TURQUOISE II: SVR achieved at 12 wks in 92% of pts w/ HCV and cirrhosis, and in 96% at 24 wks.

Head-to-Head: Capsule Endoscopy versus Colonoscopy

Posted on by

A recent study shows how useful capsule endoscopy (CE) can be in diagnosing Crohn disease (Clin Gastroenterol Hepatol 2014; 12: 609-15).  Congratulations to one of my partners, Dr. Stan Cohen, who is one of the authors.

This prospective study examined 80 patients with signs and/or symptoms of small-bowel Crohn disease (age, 10-65 years) who underwent CE, small-bowel follow-through (SBFT), and colonoscopy.

Presenting suggestive features included the following:

  • Diarrhea >6 weeks but less than 3 years
  • Abdominal pain >6 weeks but less than 3 years
  • Extraintestinal IBD manifestations: pyoderma gangrenosum, erythema nodosum, perianal disease, arthritis, aphthous stomatitis, and uveitis
  • Along with abnormal laboratory/clinical finding:
  1. positive inflammatory marker: sedimentation rate, C-reactive protein, calprotectin/lactoferrin
  2. unexplained iron deficiency
  3. hypoalbuminemia
  4. positive IBD serology (eg. anti-Saccharomyces cerevisiae antibodies)
  5. or other clinical findings: recurrent fevers, GI bleeding, growth failure, abnormal radiologic study

Results:

  • CE/colonoscopy in combination detected 107 of 110 inflammatory lesions (97.3%)
  • SBFT/colonoscopy detected 63 lesions (57.3%)
  • “The diagnostic yield of CE compared with colonoscopy was not different.”
  • Of the 80 patients with suspected Crohn disease, 25 (31.3%) had the diagnosis confirmed. 9 patients had diagnostic findings on at least 2 of the 3 modalities.  11 were diagnosed with CE alone and 5 by colonoscopy alone.

The authors conclude that colonoscopy remains the initial diagnostic test of choice.  However, “CE is safe and can establish the diagnosis of Crohn’s disease in patients when ileocolonoscopy results are negative or the terminal ileum cannot be evaluated.”

Take-home message: in patients with symptoms suggestive of Crohn disease, a negative colonoscopy is not sufficient to exclude the disease.  Other modalities like CE or MRE may be needed.

Related post:

Pediatric Capsule Endoscopy Experience

It is Hard to Keep Track…

Posted on by

of all the new Hepatitis C virus (HCV) studies that are being published.  A recent study shows that the combination of sofusbuvir with either ledipasvir or GS-9669 was effective for HCV genotype 1 infections (Gastroenterol 2014; 146: 736-43).

Two years ago publication of this study would have been met with incredible enthusiasm.  However, now this study, while important, is part of a big trend showing that oral HCV therapies are going to make the treatment of HCV easier, safer, and expensive.  Ledipasvir (LDV) is a NS5A inhibitor and  GS-9669 is a NS5B non-nucleoside inhibitor.

The particulars of this study:  113 patients were enrolled.  All patients received sofusbuvir (400 mg daily).  LDV was dosed at 90 mg daily and GS-9669 at 500 mg daily.  Three of the four treatment arms used ribavirin (RBV) with 1000 mg for those patients <75 kg and 1200 mg for those patients >75 kg.

Four arms:

  1. SOF/LDV/RBV 12 weeks–n=25 treatment-naive (TN)/n=9 null responders (NR)
  2. SOF/GS-9669/RBV 12 weeks –n=25 TN/10 NR
  3. SOF/LDV or SOF/LDV/RBV 12 weeks–n=19 NR with cirrhosis
  4. SOF/LDV/RBV for 6 weeks –n=25 TN (noncirrhotic)

Key Results:

  • Group 1 had SVR12 of 100%, group 2 had SVR 12 of 92%, and group 4 (6 week Rx) had SVR12 of 68%.
  • Among cirrhotic NR, SVR12 was achieved in 9 (100%) of those with triple therapy (SOF/LDV/RBV) and 7 (70%) of those with SOF/LDV dual therapy.

Take home message: Oral direct-acting agents in combination are effective in all groups of patients affected by HCV, included those with cirrhosis and prior null responders.

An editorial (Clin Gastroenterol Hepatol 2014; 12: 533-36) titled “The End of Hepatitis C” indicates that “interferon-free treatment is likely to become the new standard of care within the next 12-18 months.”  However, the potential price tag for treating 3.2 million infected individuals in the U.S. would be about $270 billion in drug costs alone.

A related NEJM article: (link) “Curing Chronic Hepatitis C –The Arc of a Medical Triumph.”  And another study, (link) Sapphire II, showed the effectiveness of other oral agents for HCV.  This study examined ombitasvir, ritonavir, and dasabuvir in 394 patients.

More HCV study results will be reviewed later this week on this blog.

Related blog posts: