Liver toxicity -where to look online

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Increasingly physicians as well as families gather medical information online.  Physicians, like patients, benefit when they know that a website is highly regarded by experts in the field.  This month’s Hepatology (2013: 57: 873-74) provides an introduction to the website LiverTox (www.livertox.nih.gov) (Search Livertox Database).

This website provides comprehensive and “evidence-based information on drug, dietary supplement, and herbal-induced liver injury that is freely accessible to physicians, researchers, and the public.”  The website includes about 650 different medications, supplements, and herbals; more than 12,000 annotated references are available.  In addition, the website allows clinicians to submit a case report as well as allow submission to the FDA Adverse Event Reporting System (AERS).

Related blog entry:

Childhood Obesity and Consensus Recommendations

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Everyday pediatric gastroenterologists care for obese children; in fact, the prevalence is approximately 17% in the United States (JAMA 2010; 303: 242-9).  The types of problems include the entire spectrum of pediatric gastroenterology, though some problems like encopresis and gastroesophageal reflux are more prevalent in this population.  Whether during visits for other problems or at clinic visits focused on obesity, there may be opportunities to improve the health of these patients.

A recent consensus statement provides some guidance on the problems and treatment approaches (JPGN 2013; 56: 99-109).

After reviewing epidemiology and etiology, the consensus reviews common comorbidities which include

  • NAFLD/NASH
  • Cardiovascular: Hypertension, Hyperlipidemia   Screen: Blood pressure, fasting lipids
  • Pulmonary: Obstructive sleep apnea  Screen: assess snoring
  • Psychiatric: Depression, Bullying   Screen: assess clinically
  • Orthopedic: Blount disease (pain at medial aspect of knee) and difference in leg length, SCFE
  • Endocrine: Diabetes/insulin resistance, Polycystic ovarian syndrome  Screen: look for acanthosis nigricans, fasting glucose, hemoglobin A1c.  For PCOS, inquire about oligo/amenorrhea, look for hyperandrogenism, consider pelvic ultrasound

Besides looking for these comorbid conditions, the authors discuss treatment.  “Overall, multidisciplinary, behavior-based programs should be used when lifestyle modification counseling has not worked.”  Also, the authors recommend motivational interviewing, lifestyle interventions (healthy activity and diet =”mainstay of weight management”), possibly using Orlistat, and possibly bariatric surgery.

These consensus recommendations are sensible.  Will they make a difference?

Related posts:

Malnutrition Redefined

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Defining malnutrition accurately is the focus of a new report (JPEN 2013; DOI: 10.1177/0148507113479972). Thanks to Kipp Ellsworth for this article.

The Pediatric Malnutrition Definitions Workgroup was formed in April 2010 and makes numerous relevant contributions to precisely defining malnutrition.  The reasons for this workgroup and report are to promote the following:

  • early identification of those at risk for malnutrition
  • allow better comparison of malnutrition prevalence & collect meaningful data
  • develop uniform screening tools
  • develop thresholds for intervention
  • improve assessment of outcomes

“Pediatric malnutrition (undernutrition) is defined as an imbalance between nutrient requirement and intake, resulting in cumulative deficits of energy, protein, or micronutrients that may negatively affect growth, development, or other relevant outcomes.”

First, malnutrition is subdivided into two categories: illness-related malnutrition and non-illness-related malnutrition.  Illness-related malnutrition refers to malnutrition caused by chronic conditions, burns, and surgery.  It is the predominant cause in developed countries.  Non-illness-related malnutrition refers to malnutrition caused by environmental or behavioral factors (including food aversions or anorexia).

Illness-related malnutrition occurs due to nutrient loss, increased energy expenditure, decreased nutrient intake, or altered nutrient utilization.

In brief, patients need to be assessed in five domains: anthropometrics, growth charts, chronicity, etiology/pathogenesis, and functional status.

Summary of recommendations:

  1. Record anthropometric variables on admission and serially.  These measurements include weight, height, BMI, mid-upper arm circumference (MUAC) and consider triceps skin fold (TSF) and mid-arm muscle circumference.  Obtain head circumference if younger than 2 years.
  2. In infants/children <2 years, measure length with recumbent board. In older patients unable to stand, consider alternative measurement like tibia length or knee height for a height proxy.
  3. Use the 2006 World Health Organization growth charts in patients younger than 2 years and the CBC 2000 growth charts for children 2-20 years. In addition, use corrected age (number of weeks/months premature + chronological age) for preterm infants until they are 3 years old.
  4. Use a decline in z score for individual anthropometric measurements as the indication of faltering growth.
  5. Use 3 months as a cutoff to classify as acute or chronic.
  6. Include description of predominant mechanism of malnutrition: decreased intake, increased requirements, excessive losses, or failure to assimilate/malabsorption.
  7. Recognize the role of inflammation on nutrition status.
  8. Assess impact of malnutrition: consider developmental assessment, lean body mass measurements, and measures of muscle strength.

By having a better established uniform definition of malnutrition, impact on outcomes will be easier to assess. In addition to the potential outcomes noted above (#8), others that will need to be examined in relation to malnutrition include length of hospital stay, wound healing, frequency of infections, behavioral problems, and disease-specific resource utilization.

This article also reviews previous definitions and potential problems with their usage.  For example, Waterlow criteria rely on percentiles and standard deviations and are used widely.  In hospitalized children, accurate serial weights and heights can be challenging due to fluid retention and poor mobility.

The authors note that malnutrition is likely underdiagnosed and inadequately treated.  Some recent estimates indicate that malnutrition is present “in 40% of patients with neurologic conditions, 34.5% in those with infectious diseases, 33.3% of those with cystic fibrosis, 28.6% in those with cardiovascular disease, 27.3% in oncology patients, and 23.6% in those with GI diseases. Patients with multiple diagnoses are most likely to be malnourished (43.8%).”

Bottomline: A lot of patients are malnourished.  Recognition of malnutrition (defining what is malnutrition) should improve outcomes.

Related blog posts:

There must be a reason for intractable vomiting

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There are cases when patients are clearly ill and the potential explanations are quite unsatisfactory.  Most patients with intractable nausea and vomiting have a specific etiology for this.  A disorder, rarely seen by gastroenterologists, has been identified that provides a detailed reason for a few patients with an “idiopathic vomiting” diagnosis (Clin Gastroenterol Hepatol 2013; 11: 240-5).

The authors examined a database of patients who presented with vomiting for autoantibodies to aquaporin-4 (AQP4).

Background: These autoantibodies are sensitive and specific for neuromyelitis optica (NMO).  In fact, finding these autoantibodies in serum or spinal fluid allows distinction of NMO spectrum disorders (NMOSDs) from multiple sclerosis.

In patients with NMOSDs, there are typical brain MRI findings in AQP4-enriched areas, including the fourth ventricle floor which contains the chemosenisitve nausea and vomiting center (area postrema).  AQP4 is the principal water channel in the central nervous system.

Design: The authors reviewed their database of 70 NMOSD patients to determine how many presented with vomiting.  In addition, they tested serum samples from patients who presented with idiopathic nausea and vomiting for AQP4-IgG from the gastroparesis research registry.  This included 318 patients with gastroparesis and 117 patients without gastroparesis.

Results:  Ten patients (14% of NMOSD database) presented with intractable vomiting. The youngest patient in this group was 26 years old.  All of these patients had a noncyclic pattern of vomiting.  Four had associated hiccups.  No control patients from the gastroparesis database was identified as having AQP4-IgG.

Why this is important: Early diagnosis allows initiation of immunosuppressant therapy which may modify the disease course. AQP4-IgG positivity predicts a high likelihood of relapsing attacks of optic neuritis and transverse myelitis.

How effective are aminosalicylates for pediatric UC?

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In a prospective, multicenter, inception cohort study (JPGN 2013; 56: 12-18) with 213 newly diagnosed ulcerative colitis (UC) patients, oral aminosalicylate (5-ASA) therapy was effective in 86 (40%).  That is, 40% were considered to be in corticosteroid-free remission at 1 year using 5-ASA as primary maintenance therapy.

This study took place between 2002-2010.  Of 1669 children enrolled in the registry from 32 sites, 440 (26%) were diagnosed with UC.  Of this group, 353 had followup >1 year and 213 met inclusion/exclusion criteria; all patients had to be treated with only 5-ASA or corticosteroids in the initial 30 days following diagnosis.  Most of those excluded had other therapies.  Among those with primary oral 5-ASA treatment, only 98 started treatment without a steroid induction.

Some interesting aspects of the study group:

  • 82% had pancolitis
  • 62% had moderate/severe disease at diagnosis based on physician global assessment
  • No laboratory or clinical features were associated with a higher likelihood of response
  • Mean daily dosage of 5-ASA was 52 mg/kg/day; 23% had a dose >60 mg/kg/day

The authors note that improved patient adherence and possibly higher 5-ASA dosing schedules may improve response to 5-ASA treatment.

Related blog entry:

Once daily Mesalamine | gutsandgrowth

Increasing prevalence of pediatric NAFLD

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A recent study shows that the prevalence of nonalcoholic fatty liver disease (NAFLD) in adolescents has increased over a 20 year period in the U.S. (J Pediatr 2013; 162: 496-500).

Using a cross-sectional data from 12,714 adolescents, aged 12-19, from the National Health and Examination survey, the prevalence of suspected NAFLD has more than doubled over the past 20 years and currently affects nearly 11% of adolescents.  Approximately one-half (48%) of obese males have NAFLD.

Suspected NAFLD was defined as elevated ALT in an overweight or obese child.  Specific ALT values were chosen using sex-specific cut points (>25.8 U/L for boys and >22.1 for girls).

  • Besides increased NAFLD, the prevalence of obese BMI (≥95%) and severe obesity (BMI ≥99%) also increased steadily.  Between 1988-1994, obese BMI accounted for 11.2% and severe obese BMI 1.5%.  By 2007-2010, these increased to 20.% and 5.5% respectively.
  • For suspected NAFLD, in 1988-94 compared to 2007-2010, the prevalence went from 3.9% to 10.7%.

Probably the biggest limitation of this study was considering “suspected NAFLD” only in overweight or obese children.  The authors chose to do this to increase the specificity of their diagnosis and avoid overestimating the prevalence of NAFLD.

Related blog posts:

NAFLD Guidelines 2012 | gutsandgrowth

Pediatric NAFLD histology score | gutsandgrowth

Expert review: Celiac disease

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A recent article gives a concise expert update on Celiac disease (NEJM 2012; 367: 2419-26).

As this is an area that has been covered several times by this blog and is familiar to most of the followers, I will comment on a few issues that were particularly interesting to me.  Though, the review is thorough and a helpful reference on most aspects of celiac disease..

What is the gluten threshold?  In patients with celiac disease, a minimal degree of gluten contamination is difficult to avoid.  “The lowest amount of daily gluten that causes damage to the celiac intestinal mucosa over (the gluten threshold) is 10 to 50 mg per day (a 25-g slice of bread contains approximately 1.6 g of gluten).”  New regulations propose that foods which are labeled as gluten free have less than 20 ppm of gluten contamination.

When are intraepithelial lymphocytes increased in the duodenum?  The abnormal threshold is considered >25 per 100 enterocytes.

What proportion of celiac disease patients have been diagnosed?  According to a recent European study, only a small proportion (21%) of celiac patients are clinically recognized.

Best screening test currently? Anti-tissue transglutaminase (TTG) IgA antibody –both sensitivity and specificity are >95%.  Consider TTG IgG in patients with IgA deficieny or possibly deamidated gliadin IgG.

Potential complications of untreated celiac disease? Osteoporosis, impaired splenic function, neurologic disorders, infertility or recurrent abortion, ulcerative jejunoileitis, and cancer.

Biopsy needed? Usually, “although recent guidelines suggest that biopsy may not be necessary in selected children with strong clinical and serologic evidence of celiac disease.”

Population-based screening or case-finding?  At this time, population-based screening is not recommended.  Case-finding based on symptoms and screening of at-risk groups is recommended though this is likely to miss >50% of cases.

Related blog posts:

A-OK for Accutane

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Another article has reaffirmed that isotretinoin (Accutane) does not increase the risk of IBD (JAMA Dermatol 2013; 149: 216-20).  Thanks to Mike Hart for this reference. However, this data will not reverse the millions of dollars that have been lost in litigation (Isotretinoin – Wikipedia, the free encyclopedia).

Using a large U.S. health claims database (68 million patients), the authors examined women ages 18-46 years who had received at least one oral contraceptive prescription between 2001-2009.  For each patient with IBD, 20 controls were identified in a nested case-control study design.

In total, 2159 IBD cases (1056 UC, 1103 CD) were matched with 43,180 controls.  Only 10 patients with IBD were exposed to isotretinoin compared with 191 controls.  The adjusted relative risk (RR) for IBD was 0.99; for ulcerative colitis the RR was 1.1 (confidence intervals 0.44-2.7) and for Crohn’s disease the RR was 0.91 (confidence interval 0.91).  For the meta-analysis which was a secondary part of this study, the RR for IBD with 5 studies was 0.94.

Conclusion: The study results do not suggest an increase risk of IBD with isotretinoin use.

Why did previous studies suggest a link between IBD and isotretinoin? The authors note that this is the first study to adjust for two main confounders, mainly a diagnosis of acne and use of oral tetracycline antibiotics.  Oral antibiotics, including tetracyclines, have been associated with IBD previously.  In addition, the design limits the confounding of contraceptive usage.

Limitations of this study:

  • Only women were studied; however, there are no known biologic factors that would make isotretinoin more problematic for males.
  • Other risk factors were not examined: smoking, ethnicity, diet, IBD family history

Additional references:

  • -Am J Gastroenterol 2009; 104: 2774-78.  Population-based study in Winnipeg, <40yrs.  n=1960 cases and 19,419 controls.  No differences in the proportions of IBD cases taking isotretinoin vs controls.  1.2% of IBD cases received isotretinoin prior to IBD diagnosis (n=25) compared with 1.1% of controls (n=213).  Mean # of days prior to IBD dx was 1102.  Thus, isotretinoin unlikely to be causally-associated with idiopathic IBD.
  • -IBD 2009; 12: Supplement -abstract O -0002  Increased risk of UC after isotretinoin.  OR 4.36 for developing UC
  • -Am J Gastroenterol 2009; 104: 2387-93.  7 country study found no causal association between isotretinoin & colitis.

CCFA IBD Update -Conference Notes (part 2)

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As noted in previous blog post, I wanted to share some notes from recent Atlanta CCFA talk.

The fourth lecture by Jeffry Katz discussed optimizing biologic therapy.  Overall this was an excellent review.  He discussed his general preference for combination therapy since the publication of the SONIC study. Also, he highlighted a smaller study that showed better efficacy with combination therapy in ulcerative colitis as well (DDW 2011, Abstract #835).

With regard to withdrawal of therapy when doing well on combination treatment, he indicated that he sometimes reduces (or stops) dosage of immunomodulator after 1 year but tries to avoid stopping anti-TNF agents.  Relapse rates after stopping infliximab in Crohn’s disease are approximately 50% at 1 year and 75% at 5 years.

His talk reviewed antibodies to infliximab and low therapeutic levels. This has been discussed on this blog previously:

He reviewed risks of the IBD medications.  With regard to psoriasis reactions, he stated that developing skin lesions occur in about 5% and this necessitates drug withdrawal in 1%.  As these skin reactions are often a ‘class effect,’ use of an alternative may be needed.  He stated that he had used ustekinumab in this setting (“but this entails a fight with the insurance company”).

The 5th talk by Doug Wolf reviewed pregnancy in IBD.  Much of the information has also been discussed in this blog recently: Anti-TNFs and Pregnancy | gutsandgrowth

His key points:

  • Probably stop infliximab at gestational week 32
  • Likely give adalimumab up until week 34-36
  • If patient in remission, consider stopping stopping drugs earlier
  • In PIANO registry (n=1000), use of anti-TNFs and immunomodulators was not associated with any complication, including prematurity, spontaneous abortion, intrauterine growth retardation or specific birth defects.  However, there was a significant increase in infant infections up to 12 months of life in the combination therapy group.
  • No live virus vaccines (eg. rotavirus) for first 6 months for infants exposed to infliximab

The last talk that I attended was a pediatric case presentation from Cary Sauer. He presented a teenage boy who had mild disease based on bloodwork and endoscopy who had more severe and extensive disease on magnetic resonance enterography (MRE) (More imaging needed? | gutsandgrowth) and video capsule endoscopy.  He argued that small bowel assessment is worthwhile in every patient at the time of diagnosis as more severe findings could influence the choice to start with top-down therapy.

The final aspect worth mentioning were some of the patient-related information:

1. A pediatric, adolescent, and parent support group will have its first meeting April 23rd 6-7:30 pm at Scottish Rite Children’s Hospital (Main auditorium).  Followup meetings are scheduled for August 27, and October 22. All meetings are free.  Contact CCFA mball@ccfa.org or 646-623-4869 (cell) for more information.

2. CCFA also has “Power of Two.”  This contacts patients/parents with peer mentors.  Interested patients can contact mball@ccfa.org or 404-982-0616.

CCFA IBD Update -Conference Notes (part 1)

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I wanted to share some notes from the Atlanta CCFA “Update in Inflammatory Bowel Disease” conference which was held March 23, 2013.

The first talk by Gil Melmed reviewed immunization issues in IBD.  One of the best quotes of the conference was on his first slide:  “The single most important thing a [rheumatologist] can do to optimize care for a [lupus] patient is to act as their internist, yet that is the last thing most [rheumatologists] wish to or feel qualified to do.” (Wallace DJ. Lupus 2008 (17) 91-2.

While trying to manage all aspects of the health care of our patients with chronic disease is an ideal, he also noted that 20-30% of adult IBD doctors do not understand the importance of avoiding live-virus vaccines (a list of these are noted in previous blog: Protecting the most vulnerable | gutsandgrowth).

One of the take-home points from this talk for me was to avoid use of rotavirus vaccine in newborn patients if their mother is receiving Infliximab or Adalimumab.  Another useful point would be to remind family members of immunosuppressed IBD patients to receive the influenza vaccine rather than the live-virus vaccine (flumist).

The second talk by Wallace Crandall focused on improving health care delivery.  The best quote of the day was from his first slide: “Every system is perfectly designed to achieve exactly the results it gets.”  (Donald Berwick).  One of his slides that I found intriguing showed 2007 data on immunomodulator use within the first 3 months of diagnosis from 10 different centers.  The rate varied from 30% to 98%.  He didn’t try to answer how frequent immunomodulator use in this time period should occur but there was no valid reason for this degree of variation.

In Columbus (Ohio), he stated that they are working to transform chronic care from 15-30 minute visits every 3-6 months to a more continuous process.  “Patients receive only 60% of recommended care.” With a better health care delivery system, this could be improved and potentially improve outcomes.

Another obstacle is the lack of evidence to guide decisions.  Recent “ECCO” guidelines for pediatric ulcerative colitis had 48% of recommendations based on level D evidence.

The third talk by Douglas Drossman was probably the most helpful.  He discussed pain management in IBD.  He reviewed a lot of recent data on irritable bowel syndrome (IBS) and discussed similarities between post-infectious IBS and many patients with treated IBD.

He also discussed central pain aspects and alluded to changes in the brain that happen with chronic treatment (Pain changes brain | gutsandgrowth).  He noted that antidepressants have the potential to reverse brain changes due to chronic pain but that regrowth of neurons can take a long time.  As such, he noted that agents like imipramine are needed for at least one year. Use of imipramine, he noted, has been shown to improve cognitive function in mice with traumatic brain injury (J Neurotrauma 2011; 28: 995).

With regard to IBD, Dr. Drossman noted a wide variability in pain response among patients.  Some who have very significant mucosal disease do not experience significant pain, likely due to downregulation of some central pathways.  He outlined his treatment model for pain in IBD.

  1. Effective communication improves clinical outcomes
  2. Just as there is a “treatment pyramid” for IBD, with IBS the treatment pyramid ncludes the following: motility agents, antispasmodics, antidepressants, psychological intervention, and central augmentation.
  3. With regard to antidepressants, he highlighted the differences between tricyclics, SSRIs, and SNRIs. He noted that SSRIs like citalopram, escitalopram, fluoxetine, paroxetine, and sertraline are not effective at reducing pain but can help anxiety/depression.
  4. Tricyclic antidepressants are effective at reducing pain and are inexpensive.  Side effects can include sedation, dry mouth, dizziness, and constipation.  Desipramine and nortriptyline have fewer side effects.
  5. SNRIs including duloxetine, venlafaxine, desvenlafaxine, and minacipran are effective at reducing pain and fewer side effects.  However, they are considerably more expensive.  Nausea, though, is not infrequent.
  6. Psychologic treatments: cognitive behavioral, psychotherapy, hypnosis, and relaxation training.  When to refer? moderate-severe symptoms, maladaptive coping (eg. “catastrophizing”), and motivated patient.
  7. What is central augmentation? If an antidepressant is not effective, augmentation is adding an agent that may target a different brain receptor.  Potential augmenters include pharmacologic and non-pharmacologic approaches.  Pharmacologics could include added gabapentin, added atypical antipsychotic (e.g.. quetiapine [Ability]), added clonidine, added buspirone, or added mirtazepine (e.g. remeron).  Most practitioners will need the help of a psychiatrist to manage these medications.