Genetics of Autoimmune Hepatitis

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Briefly noted:

Recently, the first genome-wide association identified mutations associated with type 1 autoimmune hepatitis (AIH1) (Gastroenterol 2014; 147: 443-52).

Cohort: 649 Dutch adults with AIH1 and 13,436 controls

Findings: prominent association with rs2187668 (associated with variants in the major histocompatibility complex region) and with variants of SH2B3 (rs3184504) and CARD10 (rs6000782)

Interpretation (from authors): “These findings support a complex genetic basis for AIH pathogenesis and indicate that part of the genetic susceptibility overlaps with that for other immune-mediated liver diseases.”

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Adalimumab Gains FDA Approval for Use in Children

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Medications used in pediatrics often do not have a “pediatric indication” on their FDA-approved labeling.  Until recently, one of those medications included adalimumab (Humira).

Sept 25, 2014 (From MSN Money):  The Food and Drug Administration cleared Humira as a treatment for moderate to severe Crohn’s disease in children ages 6 and older when those children haven’t been helped by other treatments, AbbVie said. The North Chicago, Illinois, company said Humira can be administered at home, unlike similar drugs used to treat the condition. During the second quarter, revenue from Humira jumped 26 percent to $3.29 billion.

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NASPGHAN “Best Practices Cleanout Regimens”

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The authors of a recent report (JPGN 2014; 59: 409-16) acknowledge that “bowel regimens vary significantly” and “few clinical studies in pediatrics have evaluated the use of various bowel preparation regimens.” Furthermore, “pediatric studies did not have a common efficacy measure.”

Nevertheless, they provide a “NASPGHAN best practices cleanout regimens.”  According to Table 7:

  • Option 1: PEG-3350 (eg. Miralax) -1-day cleanout:  If less than 50 kg, then 4 g/kg/day + bisacodyl 5 mg.  If >50 kg, then 238 g in 1.5 L sports drink + bisacodyl 10 mg.   PEG-3350 administered over 4-6 hours.
  • Option 2: PEG-3350 -2-day cleanout: If <50 kg, then 2 g/kg/day + bisacodyl 5 mg; if >50 kg, then 2 g/kg/day + bisacodyl 10 mg.
  • Option 3: NG cleanout: PEG-ELS (eg. Nulytely) 25 mL/kg/h (max 450 mL/h).  NG cleanouts mainly in those with history of failed preps or other adherence problems (eg. vomiting).
  • Option 4: non-PEG cleanout: Magnesium citrate 4-6 mL/kg/day + bisacodyl 5-10 mg.

My personal opinion is that Table 7 could drop the words “best practices” since the report states “alternative dosing regimens may be entirely reasonable” and the data are quite limited.

With regard to split dosing preparations which are now recommended in adults, their role in pediatrics is a “potential area for future research.” For adults, the U.S. Multi-Society Task Force Consensus Statement on Adequate Bowel Cleansing for Colonoscopy (Johnson DA et al. Optimizing Adequacy of Bowel Cleansing for Colonoscopy: Recommendations from the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology 2014; 147(4):903-924) recommends:

  • Use of a split-dose bowel cleansing regimen is strongly recommended for elective colonoscopy, meaning roughly half of the bowel cleansing dose is given the day of the colonoscopy.
  • The second dose of split preparation ideally should begin four to six hours before the time of colonoscopy with completion of the last dose at least two hours before the procedure time.
  • During a split-dose bowel cleansing regimen, diet recommendations can include either low-residue or full liquids until the evening on the day before colonoscopy. 

Take-home message: This NASPGHAN report summarizes the literature and provides recommendations for effective bowel preparations.

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Difficult Boundaries in Patient Care

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An interesting article in the NEJM (here’s link to full text: No Appointment Necessary?) explores the ethical and practical challenges of being asked to help in the care of friends and families.  These issues are definitely not abstract.  I would be surprised if most physicians have not received multiple requests for advice or for prescriptions.  Some of the potential problems listed include the following:

  • feeling pressured to practice outside their area of expertise
  • lack of complete information about the problem
  • not asking for sensitive information
  • emotional investment/loss of perspective
  • conflict of interest
  • potential for guilt/remorse if clinical error
  • poor documentation

The article notes that “the very first code of medical ethics drafted by the American Medical Association (AMA) in 1847 recommended against physicians treating family members, stating that “the natural anxiety and solicitude which he [the physician] experiences at the sickness of a wife, a child . . . tend to obscure his judgment, and produce timidity and irresolution in his practice.”

Yet, in practice, “a 1991 study showed that 99% of surveyed physicians reported having received requests from family members for medical advice, diagnosis, or treatment, and 83% had prescribed medications for relatives.6  Physicians cite convenience as a key reason to provide this care, but other explanations have included a wish to save the relative money as well as a belief that ‘I provide the best care.’”

Take-home message (from the authors): It is our hope that providers will think through the potential ethical conflicts before offering informal care. We also urge providers who are involved in medical education to help trainees understand the ethical boundaries of care as part of their professional role and encourage them to refrain from treating friends, family members, and themselves.

 

Brave New World: Psychotropic Manipulation & Pediatric Functional GI Disorders

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A recent review (JPGN 2014; 59: 280-87) provides helpful advice for the use of psychotropic medications in pediatric functional GI disorders.  That being said, a couple key caveats need to be stated first and foremost:

  • “A minority of psychotropic drugs has been studied in children and safety data remain inadequate.  Psychotropic drugs used for gastrointestinal symptoms in pediatric patients will be off-label for the foreseeable future.”
  • “Descriptions of individual drugs in the present review are too brief to provide accurate guidance to someone who is not already familiar with them.”

Given the limited data, the authors, in my opinion, bravely state recommendations regarding these medications.  Despite their common usage, providing explicit recommendations is quite uncommon.  The title of the blog references Aldous Huxley’s book which discusses psychological manipulation.  This book in turn is titled after a line from Shakespeare’s The Tempest, Act V, Scene I (from Wikipedia):

“O wonder!
How many goodly creatures are there here!
How beauteous mankind is! O brave new world,
That has such people in’s.”

Back to the review of psychotropic medications, the authors provide a rationale/pathophysiologic mechanism for the use of these drugs mainly for recurrent abdominal pain and chronic nausea/dyspepsia.  Table 1 lists the authors’ specific suggestions regarding first to fourth choices:

  • For abdominal pain, first choice was amitriptyline, followed by gabapentin, clonidine patch, and SSRI.
  • For nausea/dyspepsia,  first choice was amitriptyline, followed by mirtazapine, buspirone, and clonazepam.
  • For d-IBS,  first choice was amitriptyline, followed by alosetron [not a psychotropic], clonidine patch, and SSRI.
  • For c-IBS (along with polyethylene glycol),  first choice was imipramine, followed by lubiprostone [not a psychotropic], gabapentin, and SSRI.

Table 2 provides dosing suggestions, and common adverse effects.  For example, with amitriptyline, suggested dose is 10-50 mg qhs and “best to begin low dose…titrate up by response.” Other suggestions:

  • SSRIs: “should begin with low dose; titrate up by response.  With SSRIs, benefit is usually apparent after 4 to 6 wk.  Most GI adverse effects disappear in 1 to 2 wk.”
  • Mirtazapine: 7.5 mg dosing for sleep, 15-30 mg qAM for nausea/dyspepsia (higher dose is usually not sedating.  “Few drug interactions; safer than TCAs.” Weight gain is common.
  • Buspirone: 10-60 mg/day, divided twice daily; “may start with half dose in the morning.” Avoid grapefruit juice. Can “used alone or in combination with SSRIs or TCAs.”
  • Gabapentin (100 mg BID to 800 mg TID). “Rare adverse effects include drowsiness and blurred vision…Safe but only effective in about one-third of patients.”
  • Recommends that second-generation antipsychotics (quetiapine, risperidone, and olanzapine) be used only in collaboration with child psychiatry (Figure 2)

Additional pointers:

TCAs:“In RCTs, among children with functional abdominal pain, both amitriptyline and placebo were associated with an excellent therapeutic response.”  It is interesting to note the authors lack of critical comments regarding this statement.  “The usual dose of amitriptyline for chronic functional pain is 1 mg/kg/day up to a maximum of 50 mg/day.”

TCAs and EKGs: “at doses <1 mg/kg/day used to treat chronic pain and nausea, there have been no reports of death or cardiac arrhythmias in >60 years.  An EKG before starting a TCA is unnecessary in otherwise healthy children and adolescents, but may be advisable in those with a personal or family history of corrected QT interval prolongation or heart disease, or in children requiring a dose >50 mg/day.”

TCAs: some tricyclics may be less sedating and constipating including imipramine, doxepin, and nortriptyline.  The later two also come in liquid formulations.

SSRIs: “may be used in combination with TCAs in teens and adolescents…using them simultaneously may increase serum concentrations of both.” “In children there was a single RCT showing citalopram superior to placebo in IBS. Some clinicians obtain an EKG assessing corrected QT interval before initiating citalopram doses >20 mg daily.”

Clonidine has “improved diarrhea-predominant IBS…Common adverse effects include dry mouth, drowsiness, dizziness, and tiredness…checking blood pressure at each clinic visit [is recommended].” It is available as a patch (0.1-0.3 mg/wk).

Melatonin: dosed 3- to 10-mg at bedtime can promote sleep.

Take-home message: This article provides practical advice for the use of these agents.  Discussion with patients and parents regarding the role of these medications in targeting CNS arousal which perpetuates disabling chronic symptoms is crucial as well.  More studies are needed to determine conclusively their effectiveness.

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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.

 

Podcast on Vedolizumab Efficacy for Crohn’s Disease

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According to AGA Journals blog, one may need to wait up to 10 weeks to determine whether vedolizumab is effective for Crohn’s disease. Here’s the link: Vedolizumab for Crohn’s.

Here’s an excerpt: (re: Bruce Sands’ article in the September issue of Gastroenterology)

Sands et al. report that vedolizumab, an antibody against the integrin α4β7, is no more effective than placebo in inducing clinical remission at week 6 in patients with Crohn’s disease in whom previous treatment with tumor necrosis factor antagonists had failed.

However, at week 10, a higher proportion of patients given vedolizumab were in remission (26.6%) than of those given placebo (12.1%)… Adverse events were similar between groups.

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On the Merits of Moderation: Salt, Cholesterol, and Vitamins

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At excellent overview from NY Times that explains that strict reductions in salt and cholesterol may be detrimental and that additional vitamins may be harmful. Here’s the link: Dash of Salt Does No Harm

Here’s an excerpt:

The second New England Journal of Medicine study did just that. In addition to looking at high sodium diets, it also compared the health outcomes of those who had very low sodium diets. What they found was worrisome. When compared with those who consumed 3-6 grams per day, people who consumed less than 3 grams of sodium per day had an even higher risk of death or cardiovascular incidents than those who consumed more than 7 grams per day.

This result would be shocking if we in the medical community hadn’t seen it before. But we have. In 2011, researchers published a study in the Journal of the American Medical Asssociation after following 3,681 people over almost a decade. They, too, found that excessive salt intake was associated with high blood pressure. They also found that a low-sodium diet was associated with higher mortality from cardiovascular causes….

Why experts and organizations feel the need to go from one extreme to the other is unclear. But it’s unfortunately something we do far too often in medicine.

Take cholesterol. Initially, people believed that the evidence was pretty compelling that high cholesterol was bad for you…Eggs were shunned. But later research showed us that egg consumption had no relationship to cardiovascular disease for most people. In fact, a majority of people’s serum cholesterol level has little to do with how much cholesterol is in their diet. Today we use medications to lower our cholesterol levels. Once again, though, our sights keep shifting lower…

We have to learn that when one extreme is detrimental, it doesn’t mean the opposite is our safest course.

IBS Subtypes in Pediatrics

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A recent study (Clin Gastroenterol Hepatol 2014; 12: 1468-73) examined irritable bowel syndrome (IBS) subtypes among 129 subjects ages 7 to 18 who met Pediatric Rome III IBS criteria.  These children were part of larger studies of functional gastrointestinal disorders and recruited from primary and tertiary care centers.  Participants completed pain and stool diaries.

Key finding:

  • IBS with constipation (IBS-C) was the most common subtype (58.1%); in the other categories IBS unsubtyped (IBS-U) was next at 34.1%, then IBS with diarrhea (IBS-D) at 5.4%, and least common was mixed IBS (IBS-M) at 2.3%

The authors note that in adults with IBS studies tend to yield a more even distribution among the subtypes IBS-C, IBS-D, and IBS-U along with smaller numbers in IBS-M.

Take-home message: IBS with constipation is common in pediatrics.  Among patients who have been labelled as having isolated constipation, many in fact have IBS-C and may have persistent gastrointestinal symptoms despite the use of laxatives.

Related blog post:

Mechanisms of irritable bowel syndrome | gutsandgrowth

Liver Masses -Helpful Reference

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A recent review (Clin Gastroenterol Hepatol 2014; 12: 1414-29) is a good reference for liver masses.

Topics include hepatocellular carcinoma, focal nodular hyperplasia, hepatic adenoma, cholangiocarcoma, hemangioma, hepatic abscess, liver imaging, and management advice.

More Lessons in TNF Therapy (Part 2)

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Another useful study (Clin Gastroenterol Hepatol 2014; 12: 1474-81, editorial 1482-84 [podcast available: http://www.gastro.org/cghpodcast%5D) on infliximab (IFX) usage addresses the issue of reinitiating IFX therapy after a “drug holiday.”

The authors conducted their retrospective single-center study in Belgium.  This detail is important as interruption of therapy is more common in Europe where agents like IFX are often stopped when patients are doing well.  In the U.S. stopping IFX occurs more commonly when there are antibodies to infliximab (ATIs) or increased clinical symptoms.  In this particularly study, 22% were restarted on IFX after loss of response (despite dose optimization) and the remainder had been stopped either due to remission, pregnancy or patient decision. Also, in their center, patients do not receive IFX unless they were allergic or refractory to steroids and/or immunomodulators for a minimum of 3 months.

In total there were 128 patients (105 with Crohn’s and 23 with ulcerative colitis).

Key findings:

  • Reintroduction of IFX resulted in a clinical response in 84.5% at week 14, 70% at 1 year, and 61% at more than 4 years.
  • Higher response was noted in those who discontinued because of remission: 90% at week 14, 77.5% at 1 year, and 66.6% at more than 4 years.
  • In patients with prior loss of response, 45% had response to reintroduction of IFX at 1 year.
  • 15 patients had acute infusion reactions, seven of these were severe.
  • ATI-positivity was associated with a higher risk of infusion reaction, though most ATI-positive patients did not develop a reaction.  Particularly in ATI-positive patients, the editorial recommends a “slow infusion protocol and possibly steroids before administration of the drug.”
  • The editorial states: “it seems reasonable to check drug levels and antibodies before the second infliximab dose.” Trough levels >2 mcg/mL and undetectable ATIs early after restarting the drug were associated with good responses. “For patients with high ATIs (≥9.1 U/mL), another drug should be considered.”
  • Among those with detectable ATIs, response at 1 year was noted in 54.8%.
  • Immunomodulator cotherapy had a beneficial effect.

Bottomline: This study provides useful insights for patients who need to reinitiate IFX treatment.  In addition, some IFX failures may be able to resume IFX after a drug holiday.

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