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.

Challenges with primary sclerosing cholangitis

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Although primary sclerosing cholangitis (PSC) is an infrequent liver problem in pediatrics, it remains important.  PSC accounts for 2-3% of pediatric liver transplant cases.  A recent report updates some of the challenges for pediatric hepatologists (Shneider BL. Liver Transplantation 2012: 18: 277-81).

First the article examines some of the salient differences between children and adults.  The approach in adults may not apply well to children.  Some inherited diseases and immunologic defects may produce a similar clinical picture.   Specific differences include the following:

  • Defects in the adenosine triphosphate-binding cassette B4 (ABCB4 gene) (multidrug resistance protein 3) may cause a number of small-duct PSC in children
  • Cystic fibrosis can have a similar appearance
  • Overlap syndrome with autoimmune hepatitis is more common in children
  • Children with PSC often have higher alanine aminotransferase enzyme values than adults
  • Cholangiocarcinoma is rare in childhood, with 17 being the youngest reported case

Diagnosis usually requires, in addition to blood tests, cholangiography (eg MRCP), liver biopsy or both.  ERCP may not be needed depending on MRCP results.

Management: Pruritus may be managed with ursodeoxycholic acid (UDCA), bile acid binding resins, and rifampin.  Bone disease needs to be monitored along with fat soluble vitamin status.

  • While pruritus may improve with UDCA, high-dose UDCA (28-30mg/kg/day) has been associated with increased likelihood of negative endpoints.  It is not clear whether there may be detrimental effects at lower doses.
  • What about immunosuppression?  This (corticosteroids/thiopurines) is accepted in cases with AIH overlap.  Of course, what constitutes overlap is not certain.  So, in many cases, a trial of corticosteroids is considered.
  • Antibiotics?  Oral vancomycin has been tried in a small number with preliminary success.

As noted above, liver transplantation is a needed treatment in some cases. One concern with this approach has been recurrent PSC in about 10% at an average of 18 months after liver transplantation.

Additional references:

  • -Am J Gastro 2011; 106: 1638.  Use of high dose Urso increases risk of colonic neoplasia. n=150.
  • -Hepatology 2011; 54: 1842.  Guidelines on surveillance for PSC.  IF IBD yearly scope.  **Yearly U/S + CA 19-9 or yearly MRI.
  • -Liver Transplantation 201; 17: 925-933.  n=79 pediatric pts.  49% w IBD prior to OLT (46% w UC, 3%) & 9.8% developed IBD p OLT.  1 & 5yr survival for OLT 99% & 87%.  Recurrence in 9.8%.
  • -Clin Gastro & Hepatology 2011; 9: 434.  37% of PSC pts with CA 19-9 >129U/mL do NOT have cholangiocarcinoma.  n=7.
  • -Hepatology 2010; 51: 660-678.  update on dx/mgt.
  • -Gastroenterology 2010; 138: 1102.  genome associations with PSC.
  • -Hepatology 2009; 50: 808, 671 (ed).  Use of urso ~30/kg associated w WORSE outcome @5yrs. n=76 (& 74 controls)
  • -Clin Gastro & Hep 2009; 7:239. n=47 children w PSC.  59% w IBD, 25% w overlap syndrome
  • -JPGN 2008; 47: 61.  Use of oral vancomycin, 50mg/kg/day in patients with PSC/IBD was effective. n=14.
  • -Liver Tx 2008; 14: 735.  Review.  5 yr OLT survival 85%  ReTx rate higher (9.6% vs 4.9%).
  • -Hepatology 2008; 47: 9494-57.  Asymptomatic PSC common in AIH –might be higher than 10%.
  • -Gastroenterology 2008; 134: 975.  Natural hx/o small duct PSC in 83 pts (compared to controls).  Not likely increase in cholangiocarcinoma unless also large duct involvement.
  • -Gastroenterology 2008; 134: 706.  IAC is similar; IAC=IGG4 Associated Cholangitis
  • -Hepatology 2008; 47: 949.  8/79 w AIH also had PSC.
  • -J Pediatr 2007; 151: 255, 230.  association of CFTR mutations in PSC (26%); also present in disease control group with IBD (43%).
  • -Clin Gastro & Hep 2007; 5: 32.  Review vis-a-vis possible cholangiocarcinoma.
  • -Hepatology 2006; 44: 1063.  Review along w secondary causes.
  • -Liver Transplantation 2006; 12: 1813.  Recurrence post Tx 22% AIH, 18% PBC, 11% PSC.  (Review of 43 studies).
  • -Gastroenterology 2005; 129:1464.  High-dose actigall ineffective in 5 yr randomized controlled study.
  • -Gastroenterology 2003; 125: 1364.  Incidence of PSC.
  • -JPGN 2003; 37: 345 (57A). Use of vanco 50/kg/day x 4-6weeks in PSC, n=10, (56A) some pts c normal cholangiograms.
  • -Gastroenterology 2003; 124: 889. Urso prevents colon ca.
  • -Am J Gastro 2001; 96: 1558-62.  High dose UDCA, 25-30/kg/day may help long-term outlook
  • -JPGN 2001; 33:296. PSC-IBD.
  • -NEJM 2002; 346: 271-277.  case c Crohn’s.  PSC assoc c UC, celiac dz, pancreatic insufficiency.
  • -Ann Intern Med 2001; 134: 89-95.  Urso decreases colonic neoplasia in pts c UC & PSC.
    -NEJM 1997; 336: 691. Ursodeoxycolic acid & PSC.
  • -Gregorio et al. Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study. Hepatology 2001;33:544-553

NASPGHAN 2010 Pointers:
I. -“STOPSC criteria”: 2 of 3 diagnostic criteria needed:
1) elev GGT or alk phos
2) intra and/or extrahepatic bile duct irregularities on cholangiography (i.e. PTC, MRCP, ERCP) c/w PSC
3) liver biopsy abnormalities c/w chronic biliary injury

AND no evidence of a secondary cause of sclerosing cholangitis

 

II. SUMMARY OF KEY CLINICAL FEATURES:

 

  • -Sclerosing cholangitis  is associated with IBD, autoimmune and connective tissue disorders, abnormalities of immune function (i.e. immunodeficiencies, GvHD), infiltrative disorders (i.e. Langerhans cell histiocytosis, lymphoma).
  • -PSC may sometimes affect only small intrahepatic bile duct (“small duct PSC”), which may have a better outcome based on adult studies
  • -PSC may have overlapping features of AIH  (“autoimmune sclerosing cholangitis”)
  • -IgG4 –associated cholangitis: patients appear to have PSC with elev IgG4.  They seem to respond very well to steroid therapy in adult studies
  • -No therapy of proven benefit for PSC (ursodiol, antibiotics), some case series have suggested antibiotics may help PSC
  • -5 times higher rate of Colorectal Ca when UC pt has PSC.  Consider yearly endoscopy

 

Preventing Cancer in patients with Barrett’s Esophagus

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Though Barrett’s esophagus is rare in pediatric gastroenterology, concerns about esophageal cancer are fairly frequent.  In addition, some conditions that increase the risk of esophageal adenocarcinoma start in childhood.

One way to lessen the risk of Barrett’s esophagus in adults is through the use of medications (Gastroenterology 2012; 142: 442-52).  This study was a pooled analysis of six population-based trials with a total of 1226 esophageal adenocarcinoma (EAC) patients and 1140 esophagogastric junctional adenocarcinoma (EGJA) patients.  NSAIDs (aspirin and nonaspirin) lowered the risk of both EAC and EGJA, with OR of 0.68 and 0.83 respectively.

Although this study suggests a possible role for NSAIDs in preventing cancer in patients with Barrett’s esophagus, the risks and benefits for this intervention need to be individualized.

Related previous blog post: More bad news for smokers

Additional references:

  • -Gastroenterology 2011; 141: 2000. Lower risk of Barrett’s in pts taking NSAIDs & statins. n=570.
  • -Gastroenterology 2011; 141: 1179. Overall, patients with BE and LGD have a low annual incidence of EAC, similar to nondysplastic BE. There are no risk factors for progression and there is significant interobserver variation in diagnosis, even among expert pathologists.
  • -NEJM 2011; 365: 1375. Large Danish study, n=11028. Lower incidence of Barrett’s than previous estimates. Relative risk of 11.3 compared to general population for adenoca of Esophagus with absolute annual risk of 0.12%. Barrett’s patients have the same life expectancy as general population (ed. pg 1437). Detecting cancer only ~1 in 1460 scopes with screening whereas Barrett’s detected in 10% of pts.
  • -Gastroenterology 2011; 141: 417, 460. Durable effects of ablation, n=127..
  • -Gastroenterology 2011; 140: 1084. AGA statement on Barrett’s . Recs screening only in those with multiple risk factors (age 50, male, chronic GERD, white, incr BMI)
  • -Clin Gastro & Hep 2010; 8: 565. Guidelines suggest that screening for Barrett’s is not justified w/o alarm symptoms (dysphagia, odynophagia, wt loss, anemia, hematemesis)
  • -Gastroenterology 2010; 138: 2260. n=11,823. Decrease risk of esophageal adenoCa in patients taking NSAIDs & statins.
  • -Gastroenterology 2010; 138: 854. Nice review.
  • -Gastroenterology 2010; 138: 5. Survival equivalent to general population according to Mayo study, n=366. In Barrett’s patients, leading cause of death was cardiovascular (28%). Esophageal cancer resulted in 7% of deaths. Study presented at ACG Oct 26, 2009.
  • -Clin Gastro & Hepatology 2009; 7: 1266. no benefit from surgery for Barrett’s & unclear if chemoprevention works.
  • -Gastroenterology 2009; 137: 763. Suggests surveillance with Barrett’s is not beneficial.
  • -NEJM 2009; 360: 2277, 2353.. Radiofrequency ablation can be effective.
  • -Gut 2008; 57: 1200-06. Utility of endoscopic Rx.
  • -Clin Gastro & Hep 2008; 6: 1206; editorials: 1180, 1181, 1183.. n=2107 with Barrett’s. 79 w surgery and 80 w endoscopic Rx.
  • -Gastro & Hep 2006; 2: 468. 2-8% of pts in general population have Barrett’s. >90% of ptsc Barretts will never develop cancer. Screening has not been proven to be effective in lowering rate of death from cancer. ~40% of US population has heartburn; only 8000-9000/yr develop esoph adenoCa. Also, the presence of Barrett esophagus does not decrease life expectancy.
  • -Gastroenterology 2005; 129: 1825-31. 1.6% incidence of BE in adult Swedish population. Alcohol, smoking increase risk.

Disruption of KLF4 is the real villain for gastric cancer

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The only reason I’m posting this article is the word “Villin” in the title of the article (Gastroenterology 2012; 142: 531-42); I wondered what this was.  In this study, the authors show that “disruption of KLF4 in villin-positive gastric progenitor cells promotes the formation and progression of tumors in the antrum of mice.”  For the uninitiated,  an editorial on pages 424-27 of the same issue explains the entire article and the significance of the findings.

Kruppel-like factor 4 (KLF4) is a protein in multiple tissues that is important in cell differentiation, inflammation, and carcinogenesis.  Villin is an actin-bundling protein found in the apical brush border of absorptive tissue.  Villin-expressing gastric progenitor cells are typically quiescent but undergo division during inflammatory insults.

This is important in understanding gastric cancer because for a long time it was unclear why cancer would develop in the stomach where there is frequent turnover of the mucosa.  It is likely that more quiescent cells live long enough to accumulate cancer-promoting mutations/changes.  This study adds support to this hypothesis, at least in mice.

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).

Breastfed babies less likely to develop fatty liver

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In a study presented at AASLD meeting (San Francisco, November 4, 2011), Ayonrinde et al followed 1170 children in Australia (www.rainstudy.org.au) from birth to age 17. Anthropometric measurements were followed regularly and a liver ultrasound was obtained at age 17.  Patients who reported consuming alcohol were excluded.

By age 17, 16% of girls and 10% of boys had developed nonalcoholic fatty liver disease (NAFLD). Breastfeeding was highly protective.  Infants breastfed for more than 6 months were less than half as likely to develop NAFLD.

As noted in this blog recently (A liver disease tsunami), fatty liver disease is a huge problem.  While this study may not influence the choice to breastfeed in many cases, it highlights yet another advantage of breastfeeding. 

Previous post on breastfeeding:

More evidence that breastfeeding improves cognitive development

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

GCSF for acute-on-chronic liver failure

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When chronic liver patients decompensate, there are a number of considerations, including concerns about spontaneous bacterial peritonitis, GI bleeding, and renal insufficiency.  A new study looks at another treatment to improve the outcome of these patients.  Consecutive patients with acute-on-chronic liver failure (ACLF) were randomly assigned to granulocyte colony-stimulating factor (GCSF) therapy (n=23), 5 μg/kg subcutaneously, or placebo (n=24) (Gastroenterology 2012; 142: 505-12).

The average age in this study was 40 years with the most common etiology being liver disease related to alcohol. The GCSF group, treated with 12 doses over 1 month, had higher leukocyte and platelet counts at 1 week.  More importantly, at day 60, the GCSF had higher survival, 70% vs 29%.  In addition, therapy was associated with lower Child-Turcotte-Pugh (CTP), model for end-stage liver disease (MELD) and sequential organ failure assessment (SOFA) scores.

GCSF has been shown to improve results in animal models and has been used in chronic liver disease.  The mechanism for improvement following GCSF is not clear.  One role could be in the prevention of sepsis due to increased neutrophils; patients on GCSF had less multi-organ failure which is often precipitated by sepsis.  Another factor could be an element of hepatic regeneration induced by GCSF.  It was noted that CD34 cell population increased in the liver tissue after 4 weeks of GCSF protocol.

Additional reference:

  • -Dig Liver Dis 2007; 39: 1071-76.  Use of GCSF for 5 days was not effective for acute -on-liver disease