Category Archives: Pediatric Gastroenterology Liver Disease

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

Curing Hepatitis C without interferon

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In the face of increasing morbidity and mortality, better therapies for Hepatitis C have emerged which if applied broadly have an opportunity to change the outcome.  Recently, several articles have highlighted the possibility of treating individuals without interferon.

  • Lok et al. NEJM 2012; 366: 216-224
  • Chayam et al. Hepatology 2012; 55: 742-48
  • Zeuzem et al. Hepatology 2012; 55: 749-58.

In the Lok study, 21 null responders (patients who failed to achieve ≥2log10 decline in HCV RNA after ≥12 weeks of peginterferon and ribavirin) were divided into two groups. In Group A, 36% of patients were able to achieve SVR12 using a combination direct-acting antivirals (DAAs) with non-overlapping resistance profiles — without the use of interferon. Group A patients received BMS-790052 (an oral, first-in-class, NS5A replication complex inhibitor) and BMS-650032 (an oral NS3 protease inhibitor). In Group B which included peginterferon and ribavirin the SVR12 was 100%. There were no serious adverse events, or discontinuations.  The most common side effects were diarrhea, fatigue, headache, and nausea.

In the Chayam study, the combination of BMS-790052 (now called daclatasvir) and BMS-650032 (now called asunaprevir) examined this combination of DAAs in null HCV responders with genotype 1B (in Japan).  Ten patients received both drugs for 24 weeks. All nine who completed treatment had an SVR.  One patient stopped the medication due to elevated bilirubin and lymphopenia which occurred following an apparent infectious gastroenteritis.

In the Zeuzem study, tegobuvir (a nonnucleoside polymerase inhibitor) and GS 9256 (an NS3 serine protease inhibitor) with RBV (n=15), with PEG/RBV (n=15) and without ribavirin (n=16) were administered in three arms for 4 weeks, followed by dual therapy with PEG and RBV.  The primary end point was rapid virologic response (RVR), defined as HCV RNA <25 IU/mL.  Reductions (mean) for HCV RNA were -4.1 log10 IU/mL for dual therapy, -5.1 log10 IU/mL for triple therapy, and -5.7 log10 IU/mL for quadruple therapy.  RVR was noted in 7% of dual Rx, 38% of triple therapy, and 100% of quadruple therapy.

These studies indicate that even for difficult to treat HCV patients that new oral medications are on the horizon that will increase cure rates and may allow effective regimens that do not include interferon.  This is good news because until recently regimens with interferon were more likely to provoke adverse reactions that to guarantee a cure.

Links to relevant blog entries on HCV:

HCV now more deadly than HIV

The cost of progress in treating Hepatitis C

Looking for trouble

More on PNAC

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In a previous blog entry (PNAC, PNALD, and IFAC), reduction in intralipids was shown to improve parenteral nutrition associated cholestasis (PNAC).  This change in the use of parenteral nutrition (PN) and others are emphasized in a review article by the American Pediatric Surgical Association (J Ped Surg 2012; 47: 225-40).

This review tries to provide evidence-based guidelines for PNAC with ratings of the evidence for each of their recommendations.

A summary of their findings is given in Figure 1 of the article.  Key points:

  • PN duration is a significant predictor for cholestasis
  • NEC & sepsis both play a role in the development of PNAC
  • Insufficient data to determine if antibiotics used to decrease bacterial translocation/hepatocyte damage may be beneficial
  • Fat emulsion restriction may reduce PNAC without detriment to growth
  • Fish-oil based lipid emulsions are safe and effective for PNAC.  “Despite the promise of Omegaven…the literature is insufficient to provide a recommendation higher than grade C.”  (Grade C= “possibly effective, ineffective, or harmful;” requires at least 2 convincing class III studies [class III studies generally are non-randomized non-blinded studies]).  Information to obtain Omegaven:

http://www.oley.org/documents/How_Physicians_Can_Obtain_Omegaven.pdf
http://www.oley.org/lifeline/PN_Liver_Disease.html

  • Strong evidence that higher initial protein load does not increase the risk of PNAC
  • Strong evidence that trophic feeds are beneficial to reduce PNAC
  • Weak/conflicting evidence that there is any benefit of Aminosyn over Trophamine
  • Weak evidence to support the routine removal of copper or manganese from PN as a prophylactic strategy to prevent PNAC
  • Weak evidence to support prophylactic cycling of PN to reduce PNAC.  There are also concerns about the development of hypoglycemia in preterm infants off of PN
  • Use of CCK is not recommended
  • Oral bile acids may result in improvement
  • Erythromycin may promote motility and facilitate enteral feeds, thereby reducing PNAC

PNAC, PNALD, and IFAC

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Intravenous lipids may cause parenteral nutrition associated cholestasis (PNAC), parenteral nutrition associated liver disease (PNALD), or intestinal failure associated cholestasis (IFAC) (J Pediatr 2012; 160: 421-7 & editorial 361-2).  PNAC refers to cholestasis due to parenteral nutrition and PNALD refers to PNAC that has progressed to liver dysfunction or permanent liver injury.

In a previous blog (Four advances for intestinal failure), one of the advances for intestinal failure that was noted was the reduction of lipid infusions with parenteral nutrition which reduces IFAC.  This study adds additional information to this area.  In this prospective study, 31 patients were enrolled in a reduced IV fat emulsion group and compared with a matched historical control group.  The reduced fat group received 1gm/kg of a standard soybean-based lipid emulsion (liposyn 20%) twice weekly.  Patients were eligible if they received PN for >2 weeks and had a direct bilirubin >2.5 mg/dL.

Outcomes:

  • Total bilirubins dropped 0.73 mg/dL each week in the reduced fat group; in the control group, the bilirubin increased 0.29 mg/dL each week
  • Growth was similar in both groups
  • Essential fatty acid deficiency (biochemical not clinical features) was identified in 13 of 31 infants among the restricted IV fat emulsion group.

Essential fatty acid deficiency was defined as having a triene: tetraene ratio >0.05 (mild), >0.2 (moderate) or >0.4 (severe).

Limitations:

  • Historical control group & small study population
  • Fat-restricted group received enteral antibiotics which may have helped reduce cholestasis
  • Majority of patients with relatively short duration of TPN: 18 of 31 for less than one month

The reasons why lipids may contribute to PNAC/PNALD/IFAC include the presence of phytosterols.  This in turn may damage hepatocytes via the farnesoid X receptor.  One other aspect of the study was that the fat-restricted cohort had a higher mortality.  This was thought to be related to the cohort being sicker rather than to any nutritional effect.  Specific causes of death included respiratory failure in a patient with an abdominal wall defect, chylothorax/sepsis in a patient with a congenital diaphragmatic hernia, and cardiopulmonary failure in a patient with pulmonary hypoplasia.

The article does throw into question whether the use of a fish oil lipid preparation is needed to improve cholestasis.  In studies supporting fish oil preparations, a confounder was that the total lipid administered was reduced to 1 gm/kg/day in comparison to soybean lipids which were administered at 2-3 gm/kg/day.  This study suggests that reducing the total amount of lipid infusion is the more important factor.

The accompanying editorial makes a couple of useful points:

  • Increasing enteral feeds (>50%) is as effective as using less intravenous lipids
  • Use of standard lipids at 1gm/kg/day decreased IFAC from 15% to 4% in their intestinal failure patient population
  • Drastic reductions in lipids lead to essential fatty acid deficiency and should be avoided.
  • Use of Omegaven has not been shown to prevent liver fibrosis even with resolution of cholestasis; similarly, these studies do not inform fully on the long-term liver effects of reducing standard lipids
  • Neurologic followup will be important
  • Explains “Morton’s fork.”  John Morton was a 16th century Archbishop who wanted to increase taxes on people who were living lavishly.  In addition, he wanted to increase taxes on those living modestly (must be hiding wealth).

Additional references:

  • -NEJM 2010; 362: 181.  Letter to editor describes use of fish oil in (n=125) Boston pediatric patients.
  • -JPGN 2009; 48: 209. n=12. SBS.  9/12 improved with Omegaven. 3 had transplant (L-ITx). No controls.
  • -Pediatrics 2008; 121: e678-86. n=18.  Use of fish oil improved cholestasis compared to historical controls.
  • -Pediatrics 2006; 118: e197-e201.  Reversal of TPN-AC c IV omega-3 fatty acids (fish oil-derived) instead of intralipids

Another life-threatening complication of HCV

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Epidemiological studies have shown a causal relationship between B-cell non-Hodgkin lymphoma (B-NHL) and hepatitis C virus (HCV) (Hepatology 2012; 55: 634-641).  This is not simply an association but a cause and effect.

The cited reference reviews several aspects of this relationship including the mechanisms of lymphoproliferation, the epidemiology, the clinical manifestations, the treatment, the prognosis, and preventive measures.

  • With regard to epidemiology, the odds ratios are between 2.4 and 5.2.  This is a small risk compared to hepatocellular carcinoma.
  • Management: Lymphoma may regress with HCV treatment, indicating a role for HCV in pathogenesis.   HCV treatment may prevent the occurrence of B-NHLs as well.  For aggressive lymphomas, patients require systemic treatment with rituximab-based regimens (1st line treatment).
B-NHLs are not nearly as important as cirrhosis and hepatocellular carcinoma in terms of mortality and morbidity in patients with HCV.  It is nevertheless quite significant considering the number of infected persons worldwide.
Other related posts on HCV:

Additional references:

  • -Gastroenterology 2011; 140: 1182. Increasing HCC/Cirrhosis in HCV pts.
  • -Clinical Gastro & Hep 2008; 6: 451. HCV associated with increased risk of non-Hodgkins lymphoma. OR was 1.8 among n=4784 cases of NHL/n=6269 controls
  • -Clinical Gastro & Hep 2008; 6: 459. Overweight & obesity increase risk of HCC. n=1431 chronic HCV patients; 36% developed HCC over 10 year f/u. OR 1.9 of HCC if overweight & 3.1 OR of HCC if obese.
  • -NEJM 2002; 347: 89-95. regression of splenic lymphoma w HCV treatment.

HCV now more deadly than HIV

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Hepatitis C virus (HCV) now kills more people in the United States than HIV (Ann Intern Med 2012; 156: 271-78).  Data from the CDC followed the mortality burden of Hepatitis B (HBV), HCV, and HIV from 1999 to 2007.    The data were derived from death certificates & a limitation was that these are often completed by individuals other than the primary physician.  Sometimes the exact cause is difficult to discern.  However, this is more likely to result in underreports of deaths from viral hepatitis compared with those from HIV.

In total, 21.8 million death certificates were analyzed.

  • HBV death rate stayed relatively constant –in 2007: 1815 deaths*
  • HCV death rate increased steadily –in 2007: 15106 deaths*
  • HIV death rate improved –in 2007: 12734 deaths*

*When infection was cause or underlying contributor of death

One in 33 baby boomers are infected with HCV; most do not know they are infected.  Three-fourths of the deaths for HCV are in this age group as well.  In addition, it is expected that mortality from HCV will grow over the next 10-15 years without a major intervention. http://www.ajc.com/health/hepatitis-c-deaths-up-1356460.html

Given the increasing HCV disease burden, this strengthens the rationale for more aggressive case finding and the use of more effective & more expensive therapies (see previous blog: The cost of progress in treating Hepatitis C.  Among patients with HCV with advanced disease/cirrhosis, monitoring for HCC is important (Looking for trouble).

Additional references:

  • -Hepatology 2011; 54: 1547. Excess mortality (6x gen population) in those who achieve SVR
  • -Gastroenterology 2010; 138: 513. Predicts peak cirrhosis due to HCV in year 2020; peak HCV prevalence was year 2000.
  • -Clin Gastro Hep 2010; 8: 924. Epidemiology 2010.
  • -Hepatology 2010; 52: 1543. Visceral adiposity is associated with increased histological findings and higher viral loads.
  • -Gastroenterology 2010; 138: 136. Predicting clinical outcomes: plt<99, Alb <3.5, AST/ALT ratio >1.2, & TB>2 all assoc with 40-50% risk of developing ‘clinical outcome’ in next 3.5yrs. Outcomes: ascites, variceal hemorrhage, decompensation according to CTP (66%), peritonitis, death (2%), encephalopathy
  • -Hepatology 2009; 49: 729. 5-yr f/u after successful HCV RX, n=150. 2 developed HCC.
  • -Gastroenterology 2009; 136: 138, 39(ed). HCC occurring c HCV ~1%/yr in HALT-C study. prolonged Rx -not helpful. n=1005
  • -Hepatology 2008; 47: 1128. Increasing mortality of HCV between 1995-2004. Due to aging of infected individuals.
  • -Hepatology 2008; 47: 1371. Genotype 4 review.
  • -Hepatology 2008; 47: 836. 2/121 bx of children had cirrhosis.
  • -J Pediatr 2007; 150: 168. n=60. Looked at two populations: look back after transfusion and referrals. mean age at infection 7 months, mean time with infection 13yrs. 12% developed significant fibrosis.
  • -Hepatology 2007; 45: 1076. Large study: Lancet 2006; 368: 938. 39,109 c HBV, 75,834 c HCV, 2,604 c both. death rate: 3.2%, 5.3%, 7.1% respecively. Increased rate of dying c HCV due to drug use rather than liver dz.
  • -Clin Gastro & Hep 2006; 4: 1190-1191, 1271-78, 1278-1282. slow progression of HCV in 184 untreated women infected in 1977 (mean 27 years) — 2.1% developed cirrhosis. genotype 1B ALT values correlated with change in histology.
  • -JPGN 2006; 43: 209. Review of 91 cases; 7 c cirrhosis at presentation (mean 11.7yrs)
  • -Clin Gastro & Hep 2005; 3: 910. cirrhosis in 71% after 60 years in Asian patients; 25% in Caucasian pts 61-80 who presumably had disease for shorter interval.
  • -Gastroenterology 2003; 125: 1695. obesity/insulin resistance worsens fibrosis in HCV
  • -Gastroenterology 2002; 123: 483-491. IFN Rx improved survival; n=2889. retrospective study.
  • -JPGN 2001;33: 22A. spontaneous clearance in 30% during short f/u; n=145.
  • -Hepatology 2000; 32: 91-96. Low likelihood of progression in cohort followed for 20yrs.

Sarcopenia, fatigue, and nutrition in chronic liver disease

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Several articles from a recent Clinical Gastroenterology and Hepatology have addressed nutritional aspects of chronic liver disease.

1. Sarcopenia?  This term refers to generalized loss of skeletal muscle.  It does not equate to malnutrition though there is significant overlap.  (Clinical Gastroenterology and Hepatology 2012; 10: 166-73 & editorial 100).  In this study, 112 adults with cirrhosis had CT scans which examined skeletal muscle at the L3 level; 40% had sarcopenia. Sarcopenia was independently associated with mortality and was not reflected in MELD score.  Patients had increased risk of death from sepsis and liver failure (HR 2.18).  Thus, sarcopenia joins hyponatremia, refractory ascites, hepatic encephalopathy as additional factors which add prognostic information to MELD score.

2. Fatigue in cirrhosis. (Clinical Gastroenterology and Hepatology 2012; 10: 174-81 & editorial 103).  Fatigue is common in cirrhosis and is multifactorial.  In this prospective study, 108 patients were evaluated with a fatigue impact scale. Fatigue improved after liver transplantation. Fatigue can be peripheral due to muscle weakness and dysfunction. And, fatigue can be central due to difficulty performing physical and mental activities.  Central fatigue is associated with an increased perceived effort for tasks and often related to depression; this type of fatigue is much more common with cirrhosis.  Although improved, fatigue often does not completely resolve with liver transplantation.

3. Nutrition recommendations. (Clinical Gastroenterology and Hepatology 2012; 10: 117-25).  A summary of nutrition recommendations in adults  with chronic liver disease is given in this article.  One common misconception is protein restriction.  This is not beneficial.  Protein recommendations are for adult patients with cirrhosis to receive 1-1.5 g/kg/day.  This amount is higher than for healthy individuals.  Protein restriction leads to protein catabolism, muscle breakdown and increases the likelihood of hepatic encephalopathy.

Additional references:

  • -Age Ageing 2010; 39: 412-23.  Sarcopenia consensus definitions in older people.
  • -Gastroenterology 2008; 134: 1741. Evaluation and management of end-stage liver disease in children. Recs vaccines due to functional asplenia/portal hypertension at age 2 for Neisseria (MCV4) or polysaccharide (MPSV4); at 6 weeks of age for pneumococcal conjugate vaccines. Reviews nutrition, varices, ascites, encephalopathy….
  • -Liver Transplant 2008; 14: 585-591. Poor growth often due to growth hormone resistance. Chronic malnutrition is a factor, but children with advanced liver dz may not grow despite adequate calories. Recs: for chronic liver dz: 130-150% of RDA based on ideal body wt; in infants 120-150 cal/kg/day. Increase MCT either thru formula or supplemental MCT.
  • -Liver Transplant 2006; 12: 1310. Review article on nutrition for OLTx patient.
  • -JPGN 2000; 30: 361. nutrition review and chronic liver disease.

Methotrexate and liver toxicity

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There are drawbacks with all of the therapies for inflammatory bowel disease; however, usually the inflammatory bowel disease is worse than any of the medications. One of the therapies that  has started to see increased usage in Crohn’s disease is methotrexate (MTX), both as an alternative to thiopurines and as an adjunct to Remicade.  There are a number of side effects; a patient handout is available at the following: http://www.ccdhc.org/diseases/MethotrexateLetter.pdf

One of the concerns with MTX has been liver toxicity, in part because of descriptions in the rheumatology literature with long-term usage.  In Crohn’s disease patients, it appears that the risk is much lower (Inflamm Bowel Dis 2012; 18: 359-67).  This study found 13 trials for their meta-analysis.  A total of 632 participants were included: 373 MTX, 131 thiopurines, 128 placebo.  In the MTX group, elevated hepatic aminotransferases occurred in 1.4 per 100 person-months.  The rate of elevation more than 2-fold the upper limit of normal was 0.9 per 100 person-months.  Thus, of the initial 373 patients, 39 had an abnormal aminotransferase.  26 of these 39 had spontaneous resolution, 3 improved with dose reduction & 10 withdrew from MTX treatment (0.8 per 100 person-months).  Seven of these withdrawals were from one of the earlier studies (Feagan et al. NEJM 1995; 332: 292-97). Besides the low likelihood of needing to stop MTX due to liver toxicity, the other observation was that the liver toxicity was mostly dependent on the dose; therefore, dosage reduction would likely be effective if needed.

In my practice, when considering MTX treatment, I usually recommend the following:

  • Monitoring: Baseline: CXR, CBC, Amylase, Renal, LFTs, urine HCG & then Q2-4 weeks initially, then Q3months
  • Give Folate during therapy.
  • Use zofran if needed for nausea
  • Avoid NSAIDs during treatment due to renal toxicity
  • Contraindicated with pregnancy (MTX=teratogen) -females should see gynecology
  • Families warned in writing that this medication is given once a week; more often can be deadly

Additional references:

  • -IBD 2011; 17: 2521. ~25% remission at 1yr, 16% at 2yrs.. n=93.
  • -JPGN 2011;53: 389. n=64. Supports use of zofran for 1st few months to prevent nausea.
  • -JPGN 2010; 51: 714. Use of MTX after thiopurines. n=27. 48% in remission at 6 months.
  • -JPGN 2009; 48: 526. Use in pediatric CD, n=25. 64% response
  • -JPGN 2009; 48 suppl 2: S111. MTX may be effective for UC.
  • -NEJM 2008; 359: 2790. Similar safety of AZA and MTX in vasculitis patients. AZA may be safer.
  • -IBD 2008; 14: 756. MTX in Crohn’s. n=39. 71% remission (20% steroid-free).
  • -J Clin Pharm & Therapeutics 2007; 32: 327-31.
  • -Am J Health Syst Pharm 2004; 61: 1380-84. review of MTX errors -FDA reported
  • http://www.npsa.nhs.uk/patientsafety/alerrts-and-directives/alerts/oral-methotrexate/
  • -Am J Gastro 2007; 102: 2804-2812. n=60 pediatric patients. ~42% in remission with MTX & ~50% improved. 13% (8) had to stop due to increased LFTs or sepsis.
  • -IBD 2006; 12: 1053. n=61. MTX for AZA nonresponders/breakthroughs: 80% with improvement/ 45% with long-term response; 10% discontinued due to side effects. Steroids stopped in 36.
  • -JPGN 2005; 40: 445. Oral MTX works as well as IM/SC.
  • -JPGN 2003; 37: 392 (194A) 0.4 mg/kg/weekly. 91% response at 2 mo, most still needed remicade
  • -Gastroenterology 2003; 124: suppl 1, A-41 (305) 11/12 responded – able to stop remicade
  • -Feagan et al. NEJM 1995; 332: 292-97.
  • -J Pediatr 1999: 134: 47. Hepatotoxic risk factors. (enzymes & obesity). Consider bx if serial enzymes increased >40% of the time over 1 year
  • -Arthritis Rheum 1997; 40: 2226.

What to make of FODMAPs

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Consumption of FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) may trigger irritable bowel syndrome (IBS) symptoms.  Some research indicates that a diet low on FODMAPs may be beneficial (J Hum Nutr Diet 2011; 24: 487-95).  This study tried to assess whether a low FODMAPs diet which had been reported from a single center in Australia would be effective for IBS.

In this study, consecutive patients with IBS were divided into two groups.  39 received standard dietary advice based on UK National Institute for Health and Clinical Excellence (NICE) guidelines.  43 patients were placed on a low FODMAP dietary advice.  Patients were selected into each group consecutively (not randomized). This study reported a 76% satisfactory symptom response in the FODMAP group vs a 54% response in the control group (p=0.038).  Overall, 86% of FODMAP group had improved composite score compared with 49% of standard treatment group. Specific improvements were noted in bloating, abdominal pain, and flatulence.  The average age of the study population was 38 and 71% were females.  60% had diarrhea-predominant IBS.

NICE guidelines for IBS:

  • Healthy eating principles: regular eating, taking time to eat
  • Limit high fat foods and fizzy drinks
  • Limit insoluble fiber for diarrhea and gradually increase for constipation
  • Limit sugar-free sweets and foods with sorbitol
  • Limit fruit to 3 portions/day
  • Avoiding ‘resistant’ starch may be useful (eg. sweetcorn, green bananas, part-baked and reheated bread)
  • Addition of oats and linseeds may be helpful

Low FODMAP diet

  • Reduce high fructan foods (eg wheat and onion)
  • Reduction in high galactooligosaccharide foods (eg chickpeas, lentils)
  • Reduce high polyol foods and polyol-sweetened sources.  Replace with suitable fruits and vegetables
  • In patients with lactose malabsorption, reduce high lactose foods (eg milk, yoghurt) to smaller volumes or substitute lactose-free products
  • In those with fructose malabsorption, decrease excess fructose

Of course, reading the author’s description of a low FODMAP diet is confusing.  Translation:

Include more bananas, blueberries, lettuce, potatoes, gluten-free breads or cereals, rice, oats, hard cheeses, lactose-free milk, sugar, molasses, and artificial sweeteners that do not end in “ol.”

Avoid/eliminate apples, pears, canned fruits in natural juices, high-fructose corn syrup, cows’ milk (due to lactose), soft cheese, broccoli, cabbage, pasta, bread, baked goods from wheat/rye, mushrooms, and sweeteners like sorbitol or others that end in “ol.”

Since this diet has attracted more widespread attention, basic familiarity is important for all physicians who treat IBS.  A useful resource to explain this diet is the Wall Street Journal:

http://online.wsj.com/article/SB10001424052970204554204577023880581820726.html

This link has a good table illustrating the recommended dietary choices.

Whether FODMAPs will be superior to other dietary advice for IBS is still uncertain.  Though, given the limited number of effective treatments for IBS, this small study is a promising development.

Additional references:

  • -Clin Gastro & Hep 2009; 7: 706. n=17. 13 responded to very low carb diet (<20g/day)
  • -Clin Gastro & Hep 2008; 6: 765. Dietary triggers for IBS include fructose/fructans: honey, high fructose corn syrup, wheat, fruits.
  • -IBD 2006; 13: 91. Dietary guidelines for IBS.
  • -Clin Gastro Hepatol 2005; 10: 992-996. Obesity increases IBS symptoms; diet with low fat, high fruit/fiber have fewer symptoms
  • -Gut 2004; 53: 1459-1464. Food elimination based on IgG antibodies. Patients did better on diet with implicated foods than with control diet (diet was blinded/randomized).
  • -Am J Gastro 2011; 106: 508-514. randomized, double-blind trial showing efficacy of GFD for non-celiacs.  60% vs 32& placebo response.
  • -Nutr Clin Pract. 2011;26:294-299.  GFD for non-celiacs.
  • -Gastroenterology 2011; 141: 1941./Am J Gastro 2011; 106: 915.  Exercise improves IBS symptoms.