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MicroRNA signature for eosinophilic esophagitis

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In a previous post discussing MicroRNAs (miRNAs) (MicroRNAs and biliary atresia), I stated that “Despite this intriguing research, it not clear whether or when miRNAs will have an important role in bedside management.”  Well, as more articles emerge on miRNAs, it is becoming clear that miRNAs will have a role in clinical medicine; the questions are when and what cost.

The latest study (J Allergy Clin Immunol 2012; 129: 1064-75) by Lu et al from Cincinnati shows how this technique can identify a specific signature for eosinophilic esophagitis (EoE) and how miRNAs can serve as a biomarker for disease response.  The investigators took plasma and esophageal biopsy specimens from patients with EoE, reflux esophagitis, and healthy controls; they used an array comprising 677 miRNAs.  254 miRNAs were expressed at greater than background levels, but 21 upregulated miRNAs and 11 downregulated miRNAs were markedly different.

To quickly understand how useful this technology could become requires a glance at the “heat maps” showing the expression profile of the 21 upregulated miRNAs and the 11 downregulated miRNAs, comparing EoE with healthy controls (Figures 1 & 3).  In addition, in Figure 3, it is readily apparent that the expression pattern is completely different from reflux esophagitis.  Furthermore, this figure demonstrates visually a normal-appearing pattern in patients who respond to fluticasone.

Other figures in the article and in the appendix demonstrate the complex relationships between these specific miRNAs and target genes.

Key points:

  • miRNAs from tissue or blood could serve as biomarkers for the presence of EoE and response to therapy
  • Of the identified miRNAs, miR-21 and miR-223 strongly correlate with esophageal eosinophilia as well as previously described EoE transcriptome
  • Plasma miRNAs that are most differentiated in EoE include miR-146a, miR-146b, and miR-223.

Related posts:

Guidelines for Eosinophilic Esophagitis

Eosinophilic Esophagitis -Six Food Group Diet

The undiscovered country

Magnet ingestion –urgent removal needed

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This month’s Gastroenterology has an interesting picture of magnet(s) ingestion (Gastroenterology 2012; 142: 701, 1044).  This case report describes an ingestion by a 3-year-old boy who had swallowed 5 ball-shaped magnets.  The authors considered this an emergency even though it appeared that all 5 balls were in the stomach. As it turns out, a gastric mucosa fold was trapped in between the balls.  By taking the child for emergency removal, the authors averted a gastric perforation.

When multiple magnets are ingested, they may attract each other and cause pressure and subsequent damage. Magnet ingestion has become an important ingestion with case reports that have even included a death secondary to sepsis as well as perforations, fistulas, and volvulus.  Due to the potential for severe harm, they should be retrieved when possible ASAP.

Additional references:

Treatment for rumination and belching

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Treatment options for rumination and for belching are limited.  Baclofen improves symptoms and decreases events in both of these disorders (Clin Gastroenterol Hepatol 2012; 10: 379-84).

Rumination is characterized by effortless regurgitation of recently ingested food into the mouth (or beyond). It is easily mistaken for vomiting disorders and motility disturbances.  With rumination, patients have retrograde flow of gastric contents into the esophagus through voluntary, though unintentional, abdominal muscle contractions with increased intragastric pressure increases.

Supragastric belching occurs when air is sucked into the esophagus by decreasing the intrathoracic pressure or by contracting pharyngeal muscles.

Baclofen is an agonist of the γ-aminobutyric acid B (GABA) receptor which results in increased lower esophageal sphincter (LES) pressures and reduced swallowing rates. Baclofen has been shown to improve reflux, mainly by reducing transient LES relaxations (TLESRs) but also by increasing basal LES pressures.

In the majority of patients, the mainstay of treatment has been behavioral which use diaphragmatic breathing to compete/extinguish these behaviors.  There are a shortage of therapists familiar with this approach.  As such, alternative treatments are needed.  In this study, high-resolution manometry-impendance recordings were taken from 16 patients (10 women; mean age 43 years; range 18-89 years); eight of the patients had rumination.  Only 12 patients were included in the final analysis; four patients refused repeat manometry.  Manometry was performed before and after treatment along with recording symptoms.  Both symptoms and manometry recordings improved with Baclofen therapy.  This was a one-week open-label study.  Baclofen was dosed at 10 mg TID.  At baseline the total number of “flow events” was 473; after treatment, this was reduced to 282 events.  In total, rumination events decreased by 68% during treatment.   This improvement correlated with increased LES pressures.

Four of the 12 patients reported mild side effects mainly sleepiness and difficulty concentrating.

Additional references:

  • -Clin Gastroenterol & Hep 2007; 5:772. Review. Supragastric belching usually due to aerophagia and is very frequen (up to 20/hr)t. GERD related belching is less infrequent, has sour taste, usually less loud & after meals. Gum chewing, excessive beverage drinks, rapid eating or drinking,  smoking or using straw for drinking may increase air in the stomach and lead to burping which can be behavioural problem as well.
  • -“Behavioral Treatment of Chronic Belching Due to Aerophagia in a  Normal Adult” Behav Modif 2006; 30; 341
  • -JPGN 2011; 52: 414. Mgt of severe rumination @ Columbus Ohio. n=5. Definitive dx established with AD manometry with typical r-wave pattern (when regurgitates after a meal)
  • -JPGN 2010; 50: 103. Rumination occurring in NL intelligent adolescents. May start with regurgitation and progress to inability to swallow saliva.
  • -Clin Gastro & Hep 2006; 4: 1314. Review of management of rumination/case presentation
  • -Chitkara et al: Teaching diaphragmatic breathing for rumination syndrome. Am J Gastroenterol. 2006 Nov;101(11):2449-52. Review. Can use behavioral interventions such as deep breathing exercises/ diaphragmatic breathing to break the spasms..
  • -Gastroenterology 2006; 130: 1527-28. Review and criteria of rumination.
  • -Pediatrics 2003; 111: 158-62. Review of rumination dx, Rx, & prognosis.
  • -Clin Persp in Gastro 2000; 3 (5): 277.

Additional Baclofen references:

  • -J Pediatr 2006; 149: 436, 468. Baclofen reduces GER. 0.5mg/kg/day
  • -JPGN 2004; 38: 317. Effectiveness of baclofen in neurologically-impaired children w GER. (0.7/kg/day), n=8.
  • -Gastroenterology 2000; 118: 7-13. Use of baclofen to reduce TLESR.
  • -Aliment Pharm Ther 2003; 17: 243-51. Baclofen reduced GER (acid & nonacid). side effects -N, V, dizzy. dose: in adults, start at 5mg tid, increase c 5mg increments every 4th day to 10-20mg tid.

Guidelines for Eosinophilic Esophagitis

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For a little while, I’ve meant to complete a post on the EoE guidelines published last fall (J Allergy Clin Immunol 2011; 128: 3-20).  This article, based on the input of 33 physicians with EoE expertise, provides a lot of depth to this unfolding area in pediatric gastroenterology.

Diagnosis of EoE. The authors caution that this diagnosis is not a histologic diagnosis as a number of entities can cause esophageal eosinophilia; at the same time, a minimum number of eosinophils, 15/hpf, is a necessary diagnostic threshold.  A small number of patients may have EoE with fewer than 15/hpf, including PPI-responsive EoE, inadequate biopsy sampling, seasonal variation, or partial treatment (eg. patient on corticosteroids).

How many biopsies?  In one cited study in the article, 2, 3, and 6 biopsies had sensitivity of 84%, 97%, and 100% respectively.  Endoscopic biopsies remain the only reliable diagnostic test.

Why are there a subset of PPI-responsive EoE patients?  Potential explanations include improvement in immune-activation after healing of esophageal mucosa, inherent anti-inflammatory property of PPIs, or due to pitfalls in current diagnostic testing.  Due to recognition of this disorder, pH testing may be needed in many patients with suspected EoE.  Even still, the authors note that “PPI responsiveness or diagnostic testing (pH monitoring) might not adequately distinguish GERD and EoE.”

How useful are genotypic features?  Clinical  use of genotypes is not feasible at this time.  However, it is anticipated that esophageal gene expression will emerge as one way to differentiate EoE from other conditions and to determine optimal treatments.

What type of allergy evaluation? The majority of EoE patients have concurrent atopic diseases, including rhinitis, asthma, and eczema.  Thorough evaluation by an allergist (or immunologist) is recommended.  Specific recommendations: skin prick testing (SPT), serum IgE for immediate-type food allergy.  Atopy patch testing (APT) has high negative predictive values, >90%, except for milk which is ~50%.  APT needs to “be standardized and validated.”

Biomarkers? “Insufficient evidence to support any peripheral marker” including cytokines, and IgE (total).

Treatment –PPI: PPIs are useful to distinguish GERD as well as PPI-responsive EoE from EoE requiring other treatments.  They also help with symptomatic treatment in some patients who have secondary GERD.  Recommended dose in children 1 mg/kg/dose BID.

Treatment –Dietary: Three dietary regimens have potential effectiveness: 1) selective food diet based on allergy testing, 2) dietary restriction of the most likely food antigens (eg. six food group diet elimination) and 3) strict amino acid based diet.  Tolerance of foods that have been shown previously to provoke EoE is unlikely to develop in the majority of EoE patients.

Treatment –Corticosteroids: Corticosteroids are effective but when discontinued EoE almost always recurs.  Systemic corticosteroids can be particularly useful when severe dysphagia is present.  With severe endoscopic findings, a course of corticosteroids may help reduce the need for dilatation or lessen the risk.  Long-term use of systemic steroids is not recommended.  Topical steroids should be considered in all patients with EoE.  Recommended doses are given.

  • For fluticasone:  88-440 μg 2-4 times per day (max 880 μg BID)
  • For budesonide: 1mg daily (<10 y) and 2 mg daily (≥10 y)
Treatment –Dilation:  Dilation can provide relief of dysphagia.  In most cases, medical or dietary therapy should be attempted prior to use of dilation.  Goal of 15-18 mm.  Practical advice (not validated in studies): Limit dilation progression per session to 3 mm or less after resistance has been encountered.
Treatment –Alternatives:  Cromolyn, leukotriene receptor antagonists, or immunosuppressive agents (eg azathioprine, 6-mercaptopurine) are “not recommended.”
Complications: Perforations (spontaneous & procedure-related), food impactions, strictures, and narrow caliber esophagus.  There has not been evidence of an increased esophageal cancer risk in EoE patients to date.
Unresolved issues: Despite the extensive consensus on many of these issues, the conclusions inform the reader of how far we need to go.  Some of the unresolved questions include such basic problems:
  • “Importance of treating asymptomatic patients”
  • “Natural history of EoE and rates and predictive indexes of complications”
  • “Accuracy of skin prick and patch testing”
  • “Optimal end points of treatment”

Previous related blog posts:

The undiscovered country

Eosinophilic Esophagitis -Six Food Group Diet

Practical information on EoE for families:

http://www.ccdhc.org/diseases/EoE.html

Biomarkers identify patients who benefit and how

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Fecal calprotectin and serum CRP levels are helping to identify which patients benefit most from biologic therapies, how frequently to dose individuals and how well inflammation correlates with changes in CDAI.  Several abstracts from ACG highlight these issues:

Abstract #1175: Fecal calprotectin concentration and clinical remission in patients with active Crohn’s disease treated with certolizumab pegol: results from PRECiSE 1 (Sandborn W et al).

Abstract #1164: Baseline C-reactive protein is associated with disease progression in  patients with Crohn’s disease (Colmbel J-F et al).

Abstract #1165: Association of baseline C-reactive protein with maintenance of remission in patients with moderate to severe Crohn’s disease treated with adalimumab (Sandborn W et al)

Abstract 1175 uses a post hoc analysis of patients with active Crohn’s disease (CD) who were treated with certolizumab or placebo for 26 weeks.  Baseline calprotectin concentrations were higher in patients who achieved remission.  Another interesting finding of this study was that placebo patients did not have improvement in calprotectin levels.  So, even though some patients  had improvement in CDAI scores, indicating subjective improvement, inflammatory activity did not decline.  This is another indicator of how flawed a CDAI is for indicating the effectiveness of an IBD therapy.

Abstract 1164 looked at 238 patients with moderate to severe CD who were randomized to placebo arm in the CHARM study.  These patients were given open-label adalimumab for induction (80 mg week 0, 40 mg week 2) followed by blinded weekly placebo treatment from weeks 4-56 with a switch to open-label adalimumab after week 12 for a disease flare.  Higher baseline CRP levels in patients with moderate or severe CD were associated with higher disease scores after four weeks and after one year.  This suggests that a patient with higher CRP is more likely to have disease progression without adequate treatment.

Abstract 1165 examined the relationship between CRP and remission in CHARM patients. In the high baseline CRP group, 39 patients received adalimumab every other week, 28 weekly, and 34 received placebo.  In the low baseline CRP group, there were 42 every other week patients, 33 weekly, and 39 placebo patients.  In the high baseline CRP group, remission rates were 50% higher in the weekly treatment group compared to the every other week group.  Patients with low baseline CRP had similar results when treated weekly versus every other week.  Thus, patients with high baseline CRP are more likely to benefit from dose escalation and low CRP patients are more likely to have coexistent issues contributing to their symptoms (eg. IBS).

One other caveat: CRP production is geneticallly-determined and some patients do not make CRP in spite of active inflammation.

Related blog entries:

Food as medicine

Speed matters

Additional calprotectin references:

  • -IBD 2010; 16: 482. Calprotectin correlated with inflammation of ileum after pouch creation in children.
  • -IBD 2009; 12: 1851. Calprotectin was the only marker to correlate with endoscopic activity; n=134.
  • -JPGN 2009; 48: 48. Good sensitivity/specificity of calprotectin & lactoferrin. Up to 96% sensitivity & specificity.
  • -Clin Gastro & Hep 2008; 6: 1218. Lack of correlation between clinical symptoms and fecal biomarkers. However, biomarkers do correlate with mucosal/endoscopic disease. n=164.
  • -IBD 2008; 14: 1392. Monitoring IBD activity level c calprotectin & lactoferrin; n=15.
  • -IBD 2008; 14: 1229. Clinical utility in assessing histological relapse in kids. n=73 over 8yrs…may allow avoidance of invasive tests; cut off of 275mcg/gm had 97% sensitivity/neg pred value 85% pos pred value/specificity at predicting relapse.
  • -IBD 2008; 14: 669. Fecal calprotectin good at predicting relapse in pediatric IBD w cutoff of 400.

C-reactive protein references:

  • -J Pediatr 2011; 159: 340. CRP helps identify IBD.
  • -Clin Gastro & Hepatology 2011; 9: 421. CRP predicts response to IFX. n=718. those with high CRP had 91% response vs 83% in pts with NL CRP.
  • -Gastro 2004; 126: 1574-81. Crohn’s review. High CRP suggests likely response to anti-TNFα treatment.
  • -JPGN 2004; 38: 509-12. CRP more reliable than ESR for IBD.
  • -NEJM 1999; 340: 448. Review on acute phase reactants. CRP better than ESR as ESR is an indirect measure (resistance of plasma, due to fibrinogen, to the falling of RBCs) & broader range for CRP.

Magnetic resonance enterography for Crohn’s disease

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Magnetic resonance enterography (MRE) has increasingly been recognized as an effective way to characterize small bowel disease in Crohn’s disease (Inflamm Bowel Dis 2012; 18: 520-28).

In this retrospective pediatric study, 95 patients with Crohn’s disease underwent MRE from 2006-2009.  As expected, terminal ileal disease was the most common site of involvement with 54%; this was followed by ileum with 19%, and jejunum with 17%.  Other findings included solitary jejunal inflammation (3.7%), small bowel stenosis (1.9%) fistula (1%), and abscess (1%).  Specific evidence of inflammation included contrast enhancement, bowel wall thickening or derangement of bowel wall shape.  The images in the article are excellent.

The main advantage of MRE over CT enterography (CTE) is the lack of ionizing radiation.  In addition, MRE can better detect soft tissue contrast suggestive of bowel wall edema.  This helps distinguish acute from chronic inflammation.  Obtaining an MRE is technically more challenging and more costly.  The youngest patient in the study was seven; though the authors note that the youngest patient they have performed MRE was six.

Additional references:

  • More imaging needed?
  • -JPGN 2010; 51: 603.  MRE for suspected IBD.  Useful in pediatric Crohn’s disease.
  • -IBD 2009; 15: 1635. U/S compared favorably with endoscopy in correlating postoperative recurrence with Crohn’s.
  • -Clin Gastro Hepatol 2006; 3: 1221. MRI as accurate in evaluating ileocolonic disease with flareups as endoscopy.
  • -IBD 2004; 10: 452-61. U/S was very helpful in identifying disease and complications.

Drug levels for inflammatory bowel disease

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In many conditions, drug levels are helpful to make sure the patient receives an adequate dose for the indication.  When we treat infections or seizures, drug levels predict the effectiveness of the medication and allow dosing adjustments to improve responses as well as to lower toxicity. Drug levels are helpful in inflammatory bowel disease (IBD) as well.  Drug levels may help with thiopurine dosing and with infliximab (IFX) dosing.

Infliximab (IFX) levels can guide therapy (Scand J Gastroeneterol 2011; 46: 310-18). This study examined 106 patients (85 with CD and 21 with UC) over a ten-year period. In this cohort, patients received concurrent hydrocortisone, acetaminophen, and cetirizine to prevent acute reactions and to try to limit anti-infliximab antibodies (ATI), also called anti-human antichimeric antibodies (HACA).  Infusion intervals ranged from 4-12 weeks.

69% of Crohn’s patients maintained response to IFX and 48% of UC patients.  Infliximab trough levels were significantly increased among patients who maintained their response.  A cutoff value of 0.5 μg/mL was defined as clinically relevant for IFX trough concentrations for Crohn’s patients and for UC the cutoff was 0.8 μg/mL .  Trough levels below this cutoff were 86% sensitive and 85% specific for identifying loss of response.  The overall accuracy for the test was 87% in identifying loss of response.

Also, ATIs were significantly higher in CD patients who had lost response to infliximab.  Patients who had been “re-treated,” were significantly more likely to have developed ATIs.  “Re-treated” was defined as having interruption of IFX treatment more than 6 months.

These specific cutoff values apply to the radioimmunoassay technique for measuring IFX and ATI.  These values may not extrapolate to ELISA assays.  At the same time, the findings suggest a practical approach in patients with symptoms while receiving IFX:

  • Check IFX level (at trough or at 4 weeks)
  • If low level and no ATI, likely to respond to dose escalation
  • If low level but positive for ATI, not likely to respond to dose escalation
  • Do not assume symptoms are due to drug failure; reassess with imaging &/or scope. Consider alternate etiologies (eg infections, stricture, celiac, IBS).
  • Cotherapy with an immunomodulator reduces ATIs and boosts levels of IFX.
More usage of IFX and ATI levels is likely; however, cost issues preclude frequent measurements.

Additional references:

  • Only one chance to make first impression.  Previous blog entry on use of infliximab.
  • -Clin Gastro & Hepatology 2011; 9: 395. Do not assume symptoms are due to drug failure -reassess with imaging &/or scope. Consider alternate etiologies (eg infections, stricture, celiac, IBS). Check IFX level –if >12 @ 4weeks or >1.4 mcg/mL at trough –>predicts good response.  If +HACA, ~90% response with alternative TNF.  In those with low level, 86% responded to dose escalation.
  • -DDW 2011, Abstract #772. If loss of response to IFX, **confirm active dz (labs, scope) & not due to CDT. **check HACA –if +, only 10-20% chance of responding to dose escalation; better chance of responding to similar agent **check IFX week 4 level, if low (& neg HACA) then 90% respond to dose escalation
  • -NEJM 2010; 362:1383-1395. SONIC study.  Patients with moderate-to-severe Crohn’s disease who were treated with infliximab plus azathioprine or infliximab monotherapy were more likely to have a corticosteroid-free clinical remission than those receiving azathioprine monotherapy.
  • -Gut 2010; 59: 49-54. Trough IFX levels in UC. n=115. Antibody status can only be measured at trough levels. Undetectable trough level (<1.4 mcg/mL) associated with lower remission (15% vs 69%) and lower endoscopic response (28% vs 76%) & higher colectomy rate (55% vs. 7%).
  • -Gastroenterology 2010; 139: 344 (review of above Gut article). Similar to Crohn’s disease: 82% remission with detectable trough vs 6% w/o detectable level.
  • –Lancet 354 (9194): 1932–9. doi:10.1016/S0140-6736(99)05246-0. PMID 10622295.”Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group”.
  • -Am J Gastroenterol 2010; 105: 1133-39. If lack/loss of response, may need dose escalation with humira or Cimzia (q2weeks):
  • -IBD 2011; 17: 141-51. Loss of response to biologics.
  • -Gastro & Hep 2008; 4: 12. “primary nonresponse can be determined after 2 doses” in table reiterating AGA consensus guidelines. 85% of responders show benefit by 2weeks & all responders benefit c/in 6 weeks (Am J Gastro 2001; 96: S303). Worsening Sx despite infliximab indicates need to look for stricture, infxn, etc.
  • -Clin Gastro & Hep 2006; 4: 1248. Clinical remission associated with measurable infliximab troughs; thus, if no measurable trough, increase dose or shorten interval. If level detected & no response, unlikely to respnd to TNF class. Also, concurrent immunomodulators were not helpful.
  • -Am J Gastro 2010; 105: 2617 (Oussalah et al). 2-3yrs 41% IFX failure in UC. withdrawal of AZA increase loss of response –7x more likely
  • -Am J Gastro ; 105: 1133-40. n=155. 23% ATI -92% respond to med change, 17% respond to dose change. Level <12 @ 4weeks, 86% respond to dose change
  • -Gut 2010; 59: 1363. n=121. Co-treatment helped reduce complications & flares relative to monotherapy (& azathioprine appeared to be more effective than methotrexate).

Vitamin D, IBD, and Causality

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The importance of vitamin D has been noted in this blog previously (Common to be “D-ficient” ).  Now a study implicates vitamin D as a risk factor for developing inflammatory bowel disease, especially for Crohn’s disease (Gastroenterology 2012: 142: 482-89).  It is known that vitamin D influences innate immunity.  As such, it may play a role in the susceptibility to Crohn’s disease (CD) and Ulcerative colitis (UC).

This prospective study included 72,719 women (age 40-73) enrolled in the Nurses’ Health Study.  Research subjects completed an assessment of diet and lifestyle along with 25-hydroxy vitamin D [25(OH)D] levels.  The 25(OH)D levels were predicted; this prediction was based on a validated model which included vitamin D intake, sun exposure, race, and body mass index (J Natl Cancer Inst 2006; 98: 451-9).  This model was validated against directly measured 25(OH)D levels.

During nearly 1.5 million person-years of followup, 122 incident cases of CD and 123 cases of UC occurred.  The adjusted hazard ratio (HR) for the highest quartile of 25(OH)D was 0.54 for CD and 0.65 for UC compared to the lowest quartile.  Compared with a level less than 20, the highest quartile HR was 0.38 for CD and 0.57 for UC.

In addition, the authors identified a significant inverse association between dietary supplemental vitamin D and UC; an insignificant reduction in CD risk was noted with dietary intake.  Although it is difficult to determine causality, these data convincingly show that ‘healthy’ levels of vitamin D are associated with a lower risk of IBD.

Proven treatments for mitochondrial disorders

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The title is misleading; the most frequent treatments are unproven and not tailored well to the numerous disorders lumped under the term ‘mitochondrial disease.’  A nice review on what’s up-to-date with ‘mito’ disorders is in a recent NEJM (NEJM 2012; 366; 1132-41).

The first part of the review details the structure and function of the mitochondria including those pesky pathways for the production of ATP: glucose –>pyruvate through glycolysis.  In turn, pyruvate –>lactate –>acetyl coenzyme A (CoA).  Acetyl CoA generates NADH & flavin via tricarboxylic acid cycle.  Fatty acids and glutamine can also serve as substrates.  NADH & FADH2 fuel oxidative phosphorylation through five coupled mitochondria protein complexes.  Coenzyme Q10 helps transport electrons across the complexes.

Primary and secondary mitochodrial disorders.

  • 1000 genes encoding mitochondrial proteins have been identified in humans
  • 228 mutations of protein-encoding nuclear DNA (nDNA) and 13 mitoDNA (mtDNA) have been linked to human disorders
  • Secondary mito disorders include mito dysfunction due to viral infections and ‘off-target’ drug effects.  Specific drugs include valproic acid, statins, halothane, doxorubicin, and aspirin
  • Mito dysfunction is seen in a number of other diseases including Alzheimer’s, Parkinson’s, cancers, cardiac disease, diabetes, and obesity

Diagnosis:  Biopsy specimens from patients can be studied to assess cellular and mitochondrial physiology in comparison to healthy samples.  This review does not discuss molecular testing for mutations; however, an extensive list of genes associated with mitochondrial disorders (mtDNA & nDNA) is listed in Figure 2; a supplementary online appendix to the article explains these mutations in more depth.

Four potential treatments –all with a goal of increasing ATP production:

  • genetic therapy
  • small molecule treatment
  • metabolic manipulation
  • diet/exercise

Previous Cochrane review (2006) has not found evidence to support the use of any therapeutic interventions.  More recent trials have shown limited positive effects on clinical or biochemical end points but have not led to a New Drug Application with the FDA.  A few specific disorders that have treatments include the following:

  • Idebenone (a CoQ10 variant) for Friedreich’s ataxia & Leber’s hereditary optic neuropathy
  • Ketogenic diet for improving seizures in children with electron-transport defects
  • Cyclosporin A for secondary mito dysfunction in Ulrich’s congenital muscular dystrophy & Bethlem’s myopathy
  • Overview of current trials: http://www.clinicaltrials.gov/ct2/results?term-mitochondrial+disease

As one of my colleagues (LS) has said, making a diagnosis of a mitochondrial disorder is like getting the license plate of the bus that ran you over.  Until treatments improve, this is pretty much the case.

Additional reference:

  • -Mitochondrion 2011; 11: 679-85. Why are there no proven therapies for genetic mitochondrial diseases?
  • -J Pediatr 2011; 158: 802.  Developing liver toxicity with VPA is a contraindication to OLTx (even in the absence of documented mitochondrial dz).  Rx with carnitine and d/c VPA.  82% of 17 children died w/in 1 yr of OLTx.  POLG1 mutations are associated with Alpers syndrome.
  • -Pediatrics 2007; 120: 1326. Diagnosis and complications of mitochondrial disease.
  • -Pediatrics 2007; 119: 722. long-term outcome of mito dz –variable.
  • -NEJM 2003; 348: 2656. Review

Ivacaftor for Cystic Fibrosis

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Recent FDA approval of Ivacaftor (Kalydeco) is a promising step for a subset of patients with cystic fibrosis who have the G551D mutation.  This drug enhances the cystic fibrosis transmembrane regulator (CFTR) gene in these patients; only ~4% of CF patients or about 1200 patients in the US have this genetic defect.

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm289633.htm

Additional references:

-NEJM 2011; 365: 1663. Effect of VX-770 -a CFTR potentiator -mild improvement in study of 167 pts. (Ivacaftor).
-NEJM 2010; 363: 1991. Effect of VX-770 -a CFTR potentiator -mild improvement in study of 39 adults.