Explaining Differences in Disease Severity for Alagille Syndrome

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A recent study (DOI: http://dx.doi.org/10.1016/j.jcmgh.2016.05.013) has shown a gene which may help explain the difference in disease severity in Alagille syndrome.

Here’s a link to full text: THBS2 is a Candidate Modifier of Liver Disease Severity in Alagille Syndrome

Here’s the abstract:

Background & Aims

Alagille syndrome is an autosomal-dominant, multisystem disorder caused primarily by mutations in JAG1, resulting in bile duct paucity, cholestasis, cardiac disease, and other features. Liver disease severity in Alagille syndrome is highly variable, however, factors influencing the hepatic phenotype are unknown. We hypothesized that genetic modifiers may contribute to the variable expressivity of this disorder.

Methods

We performed a genome-wide association study in a cohort of Caucasian subjects with known pathogenic JAG1 mutations, comparing patients with mild vs severe liver disease, followed by functional characterization of a candidate locus.

Results

We identified a locus that reached suggestive genome-level significance upstream of the thrombospondin 2 (THBS2) gene. THBS2 codes for a secreted matricellular protein that regulates cell proliferation, apoptosis, and angiogenesis, and has been shown to affect Notch signaling. By using a reporter mouse line, we detected thrombospondin 2 expression in bile ducts and periportal regions of the mouse liver. Examination of Thbs2-null mouse livers showed increased microvessels in the portal regions of adult mice. We also showed that thrombospondin 2 interacts with NOTCH1 and NOTCH2 and can inhibit JAG1–NOTCH2 interactions.

Conclusions

Based on the genome-wide association study results, thrombospondin 2 localization within bile ducts, and demonstration of interactions of thrombospondin 2 with JAG1 and NOTCH2, we propose that changes in thrombospondin 2 expression may further perturb JAG1–NOTCH2 signaling in patients harboring a JAG1mutation and lead to a more severe liver phenotype. These results implicate THBS2 as a plausible candidate genetic modifier of liver disease severity in Alagille syndrome.

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Fatty Liver Improved with Exercise

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A recent study (LA Orci et al. Clin Gastroenterol Hepatol 2016; 14: 1398-1411) analyzed data from 28 randomized trials (>1600 patients) and performed a meta-analysis regarding the utility of exercise for nonalcoholic fatty liver disease (NAFLD).

Key finding:

  • Physical activity, independently from diet change, was associated with improvement in intrahepatic lipid content (-0.69) and with reduction in alanine aminotransferase.

The authors note that the effects of lipid reduction due to exercise is considered moderate-to-large.  In several trials, another effect of exercise that was measured was a reduction in insulin resistance.

Limitations:

  • The duration of the effect of exercise is not known and there is not a clear “dose” of exercise.
  • Lack of histologic data (only 2 studies had histology data)

My take: This study suggests that exercise by improving metabolic status is important in improving NAFLD; thus, a fatty liver is not just about being fat.

Bar Harbor at Sunset

Bar Harbor at Sunset

Is It Time To Start Testing HBsAg Levels in Hep B Patients?

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Two recent studies show that HBsAg levels may help determine therapeutic decisions:

  • WP Brower et al. Clin Gastroenterol Hepatol 2016; 14: 1481-89
  • Y-C Hsu et al. Clin Gastroenterol Hepatol 2016; 14: 1490-98.

The first study was a retrospective study of 292 HBeAg-negative patients with chronic hepatitis B virus (HBV) infection.  This cohort had normal ALT values and HBV DNA <20,000 IU/mL.  Patients were considered to be carriers of inactive HBV if their HBV DNA was <2000 IU/mL and serum levels of ALT remained normal.

Key findings with regard to likelihood of having inactive HBV at following year:

  • “odds were 97% for initial level of HBsAg <100 IU/mL”
  • “odds were 85% for patients with initial levels 100-1000 IU/mL and 76% for patients with initial levels >1000 IU/mL”

Also, “patients with HBV activity who had levels of HBV DNA <5000 IU/mL and decreases in HBsAg of 0.5 log IU/mL or more for 1 year had a high probability of becoming carriers of inactive HBV in the next year.” Figure 2 in an easy graphic form shows cumulative probabilities of becoming inactive or active HBV over the three-year period.

In the second study, Hsu et al performed a prospective study of 161 consecutive patients with undetectable HBV DNA following 3 or more years of entecavir.  After stopping therapy, patients were monitored for relapse.

Key findings;

  • 49.2% of patients had a clinical relapse (defined by elevation of both HBV DNA >2000 IU/mL and by elevated ALT >2-fold ULN)
  • 81.7% had virological relapse (HBV DNA >2000 IU/mL).
  • All patients with HBeAg-positivity had clinical relapse and were retreated.
  • For HBeAg negative patients at end of treatment, 39.2% had a clinical relapse & 77.4% had a virological relapse.
  • Serum HBsAg level predicted relapse among HBeAg-negative patients: 11 patients with HBsAg <10 IU/mL did not relapse. The lower the serum level of HBsAg at the end of treatment, the lower the rate of clinical relapse (see Figure 1).  Of those with HBsAg 100-1000, there was ~25% clinical relapse at 30 months f/u and more than 50% virological relapse.

My take: HBsAg level is becoming important in truly determining who has inactive HBV and reflects the likely natural history.  It is expected that using HBsAg levels will be increasingly used to determine management of HBeAg-negative HBV.

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cligastroocthbv

Pushback on AAP SIDS -Sleeping Guidelines

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Recently, this blog summarized AAP SIDS recommendations.  These recommendations have been reviewed in a NY Times commentary: Should Your Baby Really Sleep in the Same Room as You?

This opinion piece provides a good background on the issue os whether having a baby sleep in the same room is beneficial and explains some of the flaws in the studies behind the recommendations.  Here’s an excerpt:

So when the American Academy of Pediatrics recently issued new infant sleep guidelines — highlighting a recommendation that babies sleep in their parents’ rooms for at least six months but ideally a full year — some parents despaired…

Yet the recommendation drew skepticism from some doctors, who argued that a close look at the evidence showed that the benefits of room-sharing didn’t always justify its costs to parents, who would have to sacrifice privacy, sex and, above all, sleep…

Depriving parents of good sleep can also endanger babies. Sleep-deprived people can have decreased empathy. Sleep deprivation is associated with anincrease in car accidents (which are a top killer of older children). It stresses marriages and families and is significantly associated with an increased riskof postpartum depression.

And with regard to the studies:

The first thing to note is that they all collected data in the 1990s, when SIDS was much more common than it is today. The academy said room-sharing “decreases the risk of SIDS by as much as 50 percent,” but that was before the significant improvement in SIDS rates. It’s not clear that sharing a bedroom would make as much of a difference today as it did then.

The second is these were all studies in Europe, where room-sharing is much more common. Only about 20 percent to 41 percent of infants in the control group slept in their own rooms. That makes it hard to pinpoint the reason they survived, and to generalize the findings to the United States.

My take: While the risk of SIDS may improve when infants sleep in the same room, this article makes a compelling argument that it may cause more harm than benefit.

 

Salivary Pepsin Doesn’t Pass Muster for Evaluation of Reflux

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For quite a long time, I thought the expression was “Pass Mustard”.

A recent study (F Dy et al. J Pediatr 2016; 177: 53-8) shows that testing salivary pepsin is probably a waste of time in assessing for extraesophageal reflux disease. The authors prospectively recruited 50 children who underwent multiple studies including 24-hour pH-MII testing. The idea of pepsin as a biomarker has some plausibility since it is produced in the stomach and its presence in the oropharynx (or airway) would be unexpected.  Since salivary pepsin does not require invasive diagnostic testing, it would be useful if it had adequate sensitivity and specificity.

Key findings:

  • 21 of 50 (42%) were salivary pepsin-positive with a median concentration of 10 ng/mL.  Pepsin was detected in 6 of 21 with abnormal impedance testing and 8 of 21 with abnormal pH results (per Table 1 –the discussion used a denominator of 11 for each of these results)

  • There was no significant correlation between salivary pepsin-positivity compared with salivary pepsin-negative for reflux episodes, acid reflux, nonacid reflux or any other reflux variable.

  • The authors also reiterate in the discussion that clinical trials, evaluating reflux and chronic cough, “have failed to find a consistent relationship between measure dreflux and clinical response.”
  • The authors note that bronchoscopy pepsin correlation with esophageal reflux monitoring was similarly low in sensitivity
  • The authors note that “one-third of healthy asymptomatic adults have pepsin detected in their saliva.”  In this study, 38% (15 of 39) of children had pepsin detected despite normal impedance results.

My take:  While this study mainly shows that pepsin detected in the saliva has no practical use in correlation with reflux, the bigger picture is the uncertain relationship of reflux as a causal association with chronic cough.

Any of the reflux-esophageal gurus care to comment?

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Carriage Road in Acadia National Park

Carriage Road in Acadia National Park

 

Big Progress with Smoking

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A remarkable public health advance is happening and has not received much attention.  A recent commentary (MC Fiore. NEJM 2016; 375: 1410-12) highlights the substantial and accelerating progress in lowering the use of tobacco/smoking.

The author notes that the rate of decline in smoking is now about 0.78 percentage points per year during the Obama administration which is more than double the rate during the prior 16 years.  This decline, if continued, could mean that the current rate of smoking of 15.3% of U.S. adults could be zero by around 2035.

The author notes that the current administration likely deserves some of the credit for this progress due to legislative acts and leadership.  Legislation has included increases in federal cigarette excise taxes, more FDA oversight of thousands of tobacco products, and better insurance coverage of smoking cessation through the Affordable Care Act. Leadership has involved the CDC, FDA and HHS.  This has led to comprehensive strategic plans which have developed effective educational campaigns, including “Tips from Former Smokers” and “The Real Cost.” More steps to build on this progress has been outlined in the 50th-annisversary of the Surgeon General’s report, The Health Consequences of Smoking (2014).

Potential Further Actions:

  • Further increases in cigarette excise taxes
  • Sustain high-impact national media campaigns
  • Public housing mandates to make smoke-free
  • Federal legislation to ban any tobacco products to persons younger than 21 years
  • Extend smoke-free indoor-air protections to all Americans

My take: This is great news.  Hopefully, there will be a big drop from >36 million Americans who smoke to many fewer in coming years.  This can reduce premature deaths which are expected for about half of people who continue to smoke.

New Family Member: Charlie!

New Family Member: Charlie!

What Happens When Infliximab Is Stopped in Patients with Ulcerative Colitis Remission

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‘If it ain’t broke, don’t fix it’

Perhaps, the above sentiment is needed for patients with ulcerative colitis who are doing well with infliximab therapy according to a recent study (G Fiorino et al. Clin Gastroenterol Hepatol 2016; 14: 1426-32).

In this multicenter retrospective cohort study, 111 patients with ulcerative colitis who had been in remission (>12 months) were followed after stopping infliximab (IFX) and compared with 82 controls who remained on therapy.  Here’s what happened (see Figure 1 in study):

  • Among those who discontinued IFX, 53 patients (47.7%) relapsed in the followup period.  This corresponded to an incidence of 23.3 per 100 person-years and with a median time to relapse of 3.6 years.
  • In comparison, for those who remained on IFX, 14 relapses (17.1%) occurred which corresponded to an incidence of 7.2 per 100 person-years at risk and with a median time to relapse of 7.6 years.
  • Thiopurine use after stopping IFX seemed to diminish the risk of relapse: 15.0 per 100 person-years compared with 31.2 per 100 person-years for those taking an aminosalicylate alone.
  • For those who restarted IFX, 77.1% had a response and 51.4% returned to remission; however, 17.1% had infusion reactions.

My take: In a real-life experience, stopping IFX in patients with ulcerative colitis who had been in sustained clinical remission resulted in a higher relapse rate.  This finding is consistent with other studies.

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The Lawn at University of Virginia

The Lawn at University of Virginia

Advice on Abdominal Pain for Everyone Who Cares for Children

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A recent editorial (MK Farrell. J Pediatr 2016; 177: 16-17) provides many useful pointers from a master clinician along with commentary on an epidemiology study of recurrent abdominal pain (ML Lewis et al. J Pediatr 2016; 177: 39-43).

The main finding of the study which used an internet survey of mothers (children 4-18) was that 23% of US children met the Rome III criteria for a functional GI disorder.  Constipation was the most common.

Key points in commentary:

  • John Apley’s monograph The Child with Abdominal Pains “should be read by all who care for children.”
  • Worldwide prevalence of functional GI disorders has been estimated to be 13%. Peak ages were 4-6 years and early adolescence with a greater prevalence in females
  • “A variety of phamacologic and nonpharmacologic treatments have been proposed, but none have been consistently effective except perhaps cognitive behavioral therapy and hypnotherapy.”
  • “Negative studies are not reassuring” [to families]

Pithy observations from Apley:

  • “The more time the doctor spends on the history, the less time he is likely to spend on treatment.”
  • “Doctors who treat the symptoms tend to file a prescription. Doctors who treat the patient are more likely to offer guidance.”
  • “It is a fallacy that a physical symptoms always has a physical cause and needs a physical treatment.”
  • “Anxiety like courage is contagious.”

My take: Dr. Farrell urges more research focus on interventions (diet, behavioral, alternative therapies, medical treatments) to improve outcomes and less focus on epidemiology.

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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.

The Lawn, University of Virginia

The Lawn, University of Virginia

 

Topamax and Amitriptyline Did Not Work for Pediatric Migraines

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A recent study (SW Powers et al. NEJM 2016; DOI: 10.1056/NEJMoa1610384) showed that neither topamax nor amitriptyline were more effective than placebo.

Excerpt of summary from NY Times: Two Drugs for Adult Migraines May Not Help Children

Neither of the two drugs used most frequently to prevent migraines in children is more effective than a sugar pill, according to a study published on Thursday in The New England Journal of Medicine.

Researchers stopped the large trial early, saying the evidence was clear even though the drugs — the antidepressant amitriptyline and the epilepsy drug topiramate — had been shown to prevent migraines in adults…

At 31 sites nationwide, 328 migraine sufferers aged 8 to 17 were randomly assigned to take amitriptyline, topiramate or a placebo pill for 24 weeks. Patients with episodic migraines (fewer than 15 headache days a month) and chronic migraines (15 or more headache days a month) were included…

As it turned out, there was no significant difference among the groups: 61 percent of the placebo group reduced their headache days by 50 percent or more, compared with 52 percent of the children given amitriptyline and 55 percent of those who took topiramate. And there was no significant difference among the three groups in reducing the school days or other activities missed…

One child on topiramate attempted suicide. Three taking amitriptyline had mood changes; one told his mother he wanted to hurt himself, while another wrote suicide notes at school and was hospitalized.

My take: Given the overlapping features between migraines and abdominal pain, how (in)effective are these types of medications for abdominal pain?  Also, does someone know where I can buy stock in whoever makes placebo -it performed pretty well.

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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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