Tofacitinib –a JAK Inhibitor for UC

There are definitely a lot of new therapies on the horizon for inflammatory bowel disease.  One of these agents is likely to be tofacitinib which has shown efficacy for active ulcerative colitis (NEJM 2012; 367: 616-24).

Background: Tofacitinib is a selective oral inhibitor of Janus kinase (JAK) which mediates activity for multiple cytokines, including interleukins 2, 4, 7, 9, 15, and 21.  Blockage of a common signaling molecule by these cytokines “should result in suppression of both T and B cells while maintaining regulatory T-cell function.  It has shown efficacy for organ allograft rejection, rheumatoid arthritis, and psoriasis.”  A previous small study by these investigators did not demonstrate efficacy in Crohn’s disease (Gastroenterology 2011; 140: Suppl: S124 Abstract).

Design: In this study which began as a double-blind, placebo-controlled, phase 2 trial, tofacitinib or placebo was given to 194 adult patients (from 51 centers in 17 countries) with moderate-to-severe active ulcerative colitis. Dosing for tofacitinib included groups receiving 0.5 mg, 3 mg, 10 mg, or 15 mg (all BID).  “The primary outcome was a clinical response at 8 weeks, defined as an absolute decrease from baseline in the score on the Mayo scoring system.”  Most of these patients had failed conventional therapy, including mesalamine, corticosteroids, immunosuppressants, and anti-TNF agents.

Results: At 8 weeks, the primary outcome with the highest doses (10 mg & 15 mg) of tofacitinib had clinical response rates of 61% (p=0.1) and 78% (p<0.001) respectively compared with a 42% placebo response.  Clinical remission (Mayo score ≤ 2) occurred in 48% and 41% respectively (both p<0.001) compared with 10% in placebo group.  Endoscopic remission was noted in 30% and 27% respectively (both p<0.001) compared with 2% of placebo group.

In addition, tofacitinib administration improved CRP values and fecal calprotectin concentrations (Figure 2 of article).

Potential adverse effects included the following

  • neutropenia (ANC 1000-1500) observed in three treated patients
  • two tofacitinib patients (10 mg group) developed abscesses
  • mild increases in LDL and HDL were noted and dose-related (these changes have been seen in rheumatoid arthritis patients as well)

Additional reference:

  • N Engl J Med 2012; 367:495-507 | August 9, 2012.  Tofacitinib for rheumatoid arthritis

NEC and thickening agents

Last year the FDA issued a warning regarding food thickeners and necrotizing enterocolitis (FDA: Do not feed SimplyThick to premature infants).  More details are now available (J Pediatr 2012; 161: 354-6).

This information was derived from a series of cases of NEC with a common antecedent, the use of SimplyThick.  After excluding infants with multiple episodes of NEC prior to use of this thickening agent, 22 infants met the case definition and were included in the report.

16 infants started SimplyThick >37 weeks post-menstrual age (PMA).  19 infants developed NEC >37 weeks PMA.  14 cases required surgery and 7 patients died.  The number of days of SimplyThick exposure:

  • 9 patients  –1-10 days
  • 7 patients –11-20 days
  • 6 patients –>20 days
  • Median –13 days

Since most cases of NEC occur in the hospital and are associated with extreme prematurity, these cases are unusual & likely causally related to the use of SimplyThick.  Delayed NEC can also occur with congenital heart disease.  Also, NEC often develops shortly after the introduction of enteral feedings; in this series, patients had been receiving enteral feeds for a median of 43 days prior to NEC onset.  As a consequence, 50% of patients were at home when NEC developed.

The authors postulated that an increased production of short-chain fatty acids by breakdown of xanthan gum component was the mechanism for SimplyThick to increase the risk of NEC.

In a brief commentary on the article, Alan Jobe states that “Neonatologists seem determined to treat the poorly defined reflux that frequently occurs in preterm infants with something –preferably drugs that are off-label and have no proven efficacy…Perhaps clinicians should restrain their enthusiasm for other thickeners for the feeding of preterm infants as well.  The proven treatments for reflux in otherwise normal preterm infants are time and patience.”

While Dr. Jobe makes some helpful points, SimplyThick has been used primarily for swallow dysfunction rather than reflux.  Nevertheless, any thickeners as well as reflux medications can increase the risk of NEC and should be used cautiously.

Related posts:

Avoid ranitidine (acid suppression) in neonates

Do medicines work for GERD infants?

Closer followup for Celiac disease & pediatric guidelines

Data from the Mayo clinic indicate that Celiac patients are not followed up adequately (Clin Gastroenterol Hepatol 2012; 10: 893-99).

Data was extracted on 122 patients from Olmsted County.  Due to the Rochester Epidemiology Project, a comprehensive medical record is available for the entire county population (since 1966).

Results:

  • At 1 year following diagnosis, 41% of patients had followup visits; 89% within 5 years.
  • At followup visits, gluten-fee diet compliance was assessed in 33.6% and 79.8% respectively at 1 and 5 years.
  • The minority met with a dietician: 3.3% and 15.8% respectively at 1 and 5 years.
  • Serological followup was performed in 22.1% and 65.6% respectively at 1 and 5 years.

The related editorial (pages 900-901) makes the point that quality follow-up and outcomes would be aided by clear guidelines.  General guidelines in our practice are noted below.

When I review lists of patients with specific diagnoses, I am often surprised by the lack of follow-up for a number of conditions, not just celiac disease.  Developing a system to remind patients about follow-up for a wide range of conditions would be a worthwhile goal for pediatric practices.

Additional references/blog entries:

General Guidelines in our practice (developed by Dr. Jeff Lewis in 2009)
1. Who to test
There is a wide spectrum of clinical presentation from the classical malabsorption to a number of non-GI presentations.  Some studies suggest that the frequency of celiac in a peds GI clinic is as high as 1:40 (general population is 1:130).  Presentations that are common other than diarrhea, distention or FTT include constipation, anemia, abdominal pain, intussception, vomiting, short stature abnormal LFT’s, pancreatitis, and asymptomatic detection upon screening.  30% of newly diagnosed patients are overweight.  There is about a 5% risk in 1st and 2nd degree relatives, patients with type I DM, Down syndrome, and thyroiditis.  In 300 pediatric patients over 9 years, 10% presented with diarrhea, 20% abdominal pain, 23% as a result of screening, 5% with constipation, and 26% with growth issues.  Rates in family members include 1st degree relative 5 – 10%, MZ twins – 75% concordance rate, DZ twins – 10% concordance rate and HLA identical sibs – 30% concordance rate.

Recommend: Think about celiac disease with a variety of GI symptoms including those present in overweight patients.  Screen asymptomatic patients with Down’s, William’s syndrome, Type I DM, Thyroiditis, and in patients who are family members of celiac patients.

2. How to Test

Serology: Under age 3 years (some say 2 years) there is consensus that to consider including antigliadin IgA and AGA IgG along with anti-TTG and quantitative IgA.  Over age 3, anti-TTG and quantitative IgA should suffice but many are recommending also ordering EMA.  There is good evidence that anti-TTG assays vary from lab to lab.  There is also good evidence that anti-TTG in an individual may fluctuate over time.  Patients in the Teddy study (The Environmental Determinants of Diabetes in the Young (TEDDY …) have had abnormal anti-TTG followed by normal levels on the next blood draw.  17/82 had a positive anti-TTG convert to a negative on a regular diet and remain negative at all follow-ups.  For purposes of the Teddy study, two consecutive abnormal anti-TTG over 0.5 should be the threshold for EGD.  EGD after one abnormal TTG in the asymptomatic screened individual, may be too soon and lead to a false sense of security.  In a patient on a GF diet, testing serology may still be useful if the GF diet is less than 6 months.  HLA typing may help rule out celiac in patients on GF diet.

Gluten exposure prior to biopsy: There is no consensus on how long a patient needs to be back on gluten before testing but most experts suggest at least a month and some 2 or more months.

Biopsy is still considered essential in confirming the diagnosis.  Some studies suggest that some patients (2 to 3% of kids and perhaps adults) may show abnormalities in the bulb but not in the 2nd or 3rd portion of the duodenum.

Recommend:  anti-TTG and IgA will catch most patients with celiac.  Under age 3, consider obtaining AGA IgG and AGA IgA.  Addition of EMA may increase sensitivity of the anti-TTG.  Biopsy is still considered by celiac experts to be essential for the diagnosis.  At least 6 duodenal biopsies are recommended.  Some recommend 4 additional biopsies from the duodenal bulb. HLA testing has a role (mostly in excluding the possibility of celiac) though there are rare patients (about 1 in 100 celiac patients though some report much less) that are DQ2 and DQ8 negative.  Not all labs test for the beta chain and this can lead to a false negative HLA DQ2.

3. When might scoping not be necessary?

There is no expert consensus on this. If serology and symptoms are highly suggestive of celiac in a patient with a first degree relative with celiac disease, it is reasonable to make a diagnosis without endoscopic exam.  To confirm diagnosis, it is helpful to see the antibody levels fall on a GF diet (usually retest after 6 months).  Some studies have shown lower compliance rates in patients without biopsy proven celiac.

Recommend:  It is a personal MD:patient:parent decision as to diagnosing celiac without a scope.  If you do diagnose without biopsy, make sure that serology improves on a GF diet.  Celiac centers standard of care still includes biopsy all newly diagnosed patients.
4.Treatment once the diagnosis is made

NIH consensus conference on celiac recommends:1) treatment include referral to a trained dietician (Atlantametroceliacs.com lists nutritionists for adults)  2) availability of a community support group – georgiarock.org or email to celiacgroup@ccdhc.org 3) follow-up with an MD experienced with celiac. 3) lifelong adherence to gluten-free diet 4) identification and treatment of nutritional deficiencies 4) follow-up with an MD familiar with celiac ideally as part of a multidisciplinary team (primarily in partnership with nutritionist).

Recommend:  All newly diagnosed patients or those struggling with compliance should see a specially trained dietician.  You can also refer to the ROCK group – georgiarock.org or celiacgroup@ccdhc.org  You should see the patient in follow-up after diagnosis.
5. Follow-up

Follow up frequency varies widely from every 3 months after initial diagnosis with a nutritionist and an MD to lesser intervals.  Once well controlled, many experts recommend annual visits, some every 2 years.  At diagnosis it is often recommended to look for deficiencies in iron, folate, vitamin D and B12.  Patients are also at risk for other fat soluble vitamin deficiencies and zinc deficiency.  Bone mineral density is often performed one year after diagnosis with abnormalities referred to endocrinology – recommendations in pediatrics are still in debate.  As patients with celiac are at substantial risk for other autoimmune disorders, it is worth considering thryoid problems (eg. check TSH and free T4) early on after diagnosis and once every 1 to 2 years though this practice is of debatable cost effectiveness.  It can take up to a year for the anti-TTG to normalize but it should be coming down significantly in 6 months.

Recommend:  At time of diagnosis, usually a CBC should be obtained to allow you to look for clues about iron, folate, and B12.  It is not unreasonable to check 25 OH Vitamin D levels as well.  At least yearly follow-up labs should include an anti-TTG but may also include TSH, free T4, Vitamin D and a CBC.  Screening for folate, B12, and iron deficiency may also be considered.  Follow up closely after diagnosis can be helpful in dealing with the stress of a major life change and to ensure compliance and understanding of the disease.

6. Testing family members

It is clear that 1st and 2nd degree family members – with and without symptoms are at high risk.  Offering to screen siblings and parents once a diagnosis is made is reasonable due to risks associated with celiac disease.  If an at risk patient screens negative with serology, it does not mean that they can not get celiac disease in the future.  Some experts recommend retesting every few years or sooner if there are symptoms.  It is important to document that you recommended screening to 1st degree relatives.

Recommend:  Strongly recommend that symptomatic first degree relatives be screened for celiac disease.  It is reasonable and helpful to offer to do the screening of parents and siblings yourself.  There is good data that it is important to screen asymptomatic people at risk as there are increased risks in adults of developing cancers, auto-immune conditions, anemia, and osteoporosis in untreated celiac disease.  There are no good recommendations for retesting at risk individuals who initially test negative. HLA typing, if negative, can be useful in eliminating the need for routine rescreening.

7. Feeding infant siblings

A multicenter trial is underway to try to determine the best time to introduce gluten to genetically at risk individuals.  There is good evidence that breast-feeding can be protective.  There is good evidence that introducing small amounts of gluten while still breast-feeding may be protective.  There is good evidence that introduction of gluten before four months of age may increase the risk of developing celiac.  Some evidence exists that the best practice is to give a teaspoon of a gluten containing cereal a few time a week between 4 and 6 months of age (Scandinavian data and prospective data out of the Denver diabetes trial).  Fassano suggests that there may be benefit in keeping the infant gluten-free for the 1st year of life and introduce while still brest feeding after a year of age.  Final answer is still pending.  Gluten can be found intact in human breast milk but not cow’s milk.  No recommendations regarding mother’s diet while breastfeeding a patient with or at risk of getting celiac are available.

Recommend: Do not introduce gluten to at risk infants before 4 moths of age.  Support breast-feeding as something that may delay or even prevent the development of celiac disease.  There is some data to suggest that tolerance may be more likely of small amounts (1 tsp a day) of gluten containing food are introduced between 4 and 6 months of age.  During breast-feeding, a mother who does not have celiac may eat gluten during the pregnancy and throughout infancy.

Fat soluble vitamin deficiency -sometimes the rule rather than the exception

While it is well-known that cholestasis predisposes individuals to develop fat-soluble vitamin (FSV) deficiencies, the exact frequency is not clear.

A recent prospective multi center study of infants with biliary atresia (BA) indicates that FSV deficiency is quite frequent –thanks to Kipp Ellsworth for forwarding this article (DOI: 10.1542/peds.2011-1423; http://pediatrics.aappublications.org/content/early/2012/08/08/peds.2011-1423).  “Infants with BA are at risk for malabsorption of dietary lipid and fat-soluble vitamins (FSVs) due to insufficient intraluminal bile acid concentrations.”

To determine the frequency of FSV deficiencies, this study examined 92 infants with BA who were enrolled in a randomized double-blinded, placebo-controlled trial of corticosteroid therapy after hepatoportoenterostomy (HPE).  This study was conducted by the Biliary Atresia Research Consortium (BARC) between 2005-2008.

All infants were treated with a standardized dose of a liquid multiple FSV/d-α tocopheryl polyethylene glycol-1000 succinate (TPGS; a micelle forming water-soluble form of vitamin E).  Infants received initially ADEKs; later in the study, ∼32 months after start, participants were changed to AquADEKs due to a manufacturer’s change.  In addition, all infants received supplemental vitamin K, initially 2.5 mg three times per week.  As noted in supplement to article, the two study multivitamins have particularly low amounts of vitamin D (800 units) and vitamin E (80-100 units) compared to frequent dosing in clinical practice for severe cholestasis (see below).

TABLE 1 from study: Target FSV Levels and Replacement Regimens

  • Vitamin A (retinol)

Target:  19–77 mg/dL retinol:RBP molar ratio >0.8

Supplement strategy:  Increments of 5000 IU (up to 25–50 000 IU/d) orally or monthly intramuscular administration of 50 000 IU

  • D (25-hydroxy vitamin D)

Target: 15–45 ng/mL

Supplement: Increments of 1200 to 8000 IU orally daily of cholecalciferol or ergocalciferol; alternatively calcitriol at 0.05 to 0.20 mg/kg per day

  • E (α tocopherol) 

Target: 3.8–20.3 mg/mL & vitamin E:total serum lipids ratio >0.6 mg/g

Supplement: Increments of 25 IU/kg of TPGS orally daily (to 100 IU/kg per d)

  • K (phytonadione)

Target: INR ≤1.2

Supplementation Strategy:

  • <1.2-1.5  INR:  2.5 mg vitamin K orally daily
  • 1.5-1.8  INR: 1.8  2.0–5.0 mg vitamin K intramuscular and 2.5 mg vitamin K orally daily
  • >1.8 INR:  2.0–5.0 mg vitamin K intramuscular and 5.0 mg vitamin K orally daily

Results: FSV was common in infants with total bilirubin (TB) ≥2 mg/dL. At three months post HPE, only 3 infants with this degree of cholestasis were sufficient for all four vitamins.; at 6 months post HPE, all 24 infants with TB ≥2 mg/dL had at least one FSV deficiency: “100%, 79%, 50%, and 46%, respectively, for vitamins A, D, E, and K .”   Also, the incidence of vitamin D deficiency would be higher if the authors had chosen a higher target.

Take-home points:

  • FSV deficiencies are common particularly in patients with TB > 2mg/dL; thus careful monitoring is worthwhile
  • There is no current multivitamin that is adequate.  A better strategy is to individualize the dosing for each vitamin and consider injection (except for vitamin E) if needed

Initial individualized dosing of FSV supplementation in clinical practice for severe cholestasis (prior to deficiencies):

Vitamin A: start with ~5000 units daily.

Vitamin D: See previous posts for more information on dosing.  Two options include: Drisdol® (8000 IU/ml) 0.125ml/kg/day (=1000 IU/kg/day) and Bio-D-Mulsion Forte® http://www.bioticsresearch.com/node/1570 -each drop = 2,000 IU (also inexpensive)

Vitamin E (Liqui-E®/Nutr-E sol®26.6 IU/ml) 1ml/kg/day
with tocopherol polyethylene glycol succinate.  Alternative is AquaE®(Yasoo -www.yasooproducts.com/aqua-e/).

Vitamin K (phytonadione) 2.5mg QOD

Related posts:

Diagnosing biliary atresia earlier

Common to be “D-ficient”

Outcomes of Biliary Atresia

MicroRNAs and biliary atresia

Bleeding due to vitamin K deficiency

What is the GRADE of GM-CSF in IBD?

I was not familiar with the acronym “GRADE” which refers to an analysis by Cochrane review:

Grading of Recommendations Assessment, Development and Evaluation.

With regard to Sargramostim (GM-CSF), GRADE analysis indicates that GM-CSF does not appear more effective than placebo for Crohn’s disease (Inflamm Bowel Dis 2012; 18: 1333-39).

Three randomized studies were examined with 537 patients.  Clinical remission was achieved in 25.3% of GM-CSF patients compared with 17.5% of placebo-treated patients (p=0.17).  Clinical response (100-point CDAI score drop) was noted in 38.3% of GM-CSF group compared with 24.8% of placebo group (p=0.06).  Adverse effects were not statistically different either.

In my view, there are probably populations of IBD patients who will be benefit from GM-CSF.  The difficulty is identifying which groups.

Additional references:

  • -Gastroenterology 2011; 141: 28, 208.  GM-CSF receptor (CD116) defective expression & function in 85% of IBD pts. n=52.
  • -NEJM 2005; 352: 2193. Leukine decreased Crohn’s dz severity: 48% c decrease in CDAI of >100 (vs 26% placebo). injection & bone pain -common; 3 pts (n=81 in leukine group) c serious rxns- migraine, weakness/lethargy, R-sided weakness (?demyelinating d/o)
  • -Lancet 2002; 360: 1478-1481. use of GM-CSF for Crohn’s.

What is resistin?

Resistin is a cysteine-rich protein which is often elevated in chronic renal disease and has been associated with increased risk for cardiovascular disease (CVD) (J Pediatr 2012; 161: 276-80).  It is expressed primarily in macrophages and stimulates the production of interleukin 6, and tumor necrosis factor α (TNF-α).

The cited study examined whether resistin was associated with renal function and inflammatory markers in 319 children from the Chronic Kidney Disease in Children (CKiD) cohort.  The CKiD study is a longitudinal observational study from 46 pediatric nephrology centers in North America.  For this study, the glomerular filtration rate (GFR) had to between 30-90 mL/min/1.73 m-squared.

Findings:

  • Serum resistin was significantly associated with elevated inflammatory cytokines IL-6, IL-10, and tumor necrosis factor.
  • Resistin levels were negatively correlated with GFR.  The authors state that decreased clearance may not be the only reason for higher resistin levels as chronic kidney disease is a state of chronic inflammation and resistin may be involved in these processes.
  • Resistin also was independently associated with pubertal status

String test for EoE

Gut Online First, published on August 15, 2012 as 10.1136/gutjnl-2012-303171  Furuta GT et al.  “The oesophageal string test: a novel, minimally invasive method measures mucosal inflammation in eosinophilic oesophagitis”

This study examined an esophageal string test (EST) in 41 children; 14 with active EoE, 8 with EoE remission, 4 with gastroesophageal reflux, and 15 controls.  The goal of this study was to measure eosinophil-derived proteins with an EST with a hypothesis that these proteins would correlate with mucosal inflammation as determined by biopsies.

Methods: Using a FDA approved device, Enterotest, patients were instructed to swallow  a capsule attached to a string.  Luminal secretion samples from the string were used for the EST.  The esophageal portions of the string were aided by the use of pH indicator sticks.  Patients were between 7 and 20 years of age.  The EST was placed overnight in the esophagus.  The EST was removed at the time of an endoscopy the following day.

The measured proteins included the following:

  • Eosinophil secondary granule proteins: major basic protein-1(MBP-1), eosinophil-derived neurotoxin (EDN), eosinophil cationic protein (ECP), and eosinophilic peroxidase (EPX).
  • Charcot-Leyden crystal protein/galectin-10 (CLC/Gal-10)

When looking at Figure 1 in the results (full text link below), there is a striking difference in the measurement of these EoE proteins in the active group compared with the other groups.  The remission EoE group also had modest elevation of EoE proteins, particularly ECP and EDN, relative to the GERD and control groups.

Conclusions:

  • Measurement of these proteins did correlate with peak and mean eosinophil counts and distinguished active EoE from the other groups
  • EST could serve as a minimally invasive marker of for EoE activity and response to therapy.  EST would be less expensive, quicker and safer than endoscopy

Technical issues will need to be addressed to improve the applicability of EST.  For example, shorter incubation time could make the test more feasible.  Also, for younger patients, swallowing an EST/capsule will remain problematic.

Full text: http://gut.bmj.com/content/early/2012/08/14/gutjnl-2012-303171.full.pdf+html

Previous related blog entries:

Choosing topical therapy for EoE

Guidelines for Eosinophilic Esophagitis

Looking better or feeling better in EoE?

Look of improvement on an EoE diet

Eosinophilic Esophagitis -Six Food Group Diet

MicroRNA signature for eosinophilic esophagitis

The undiscovered country

Is it possible to avoid allergic food reactions?

In subjects with known food reactions, avoiding food ingestions is quite difficult (Pediatrics 2012; 130: e26-e32).

This study enrolled 512 children at ages 3-15 months and followed them for a median of 35.5 months.  Patients had to have positive skin prick test to milk or egg in addition to either a history consistent with an IgE-mediated food reaction to milk or egg or a history of moderate-to-severe atopic dermatitis.

Key findings:

  • High rate of reactions: 1171 reactions reported in 367 (72%) of subjects.
  • Most reactions were attributed to lack of vigilance, like not checking ingredients
  • Parents most frequently were the providers at time of incident (36%); however, about half of all allergic reactions were attributed to other providers (eg. grandparents, teachers)
  • Of severe reactions (n=134, 11%), only 30% were treated with epinephrine. Almost all severe reactions were due to ingestions (95%) rather than skin or inhalation exposures.

Bottom line: More work is needed to prevent these reactions and to improve the treatment when they occur.

Save a life with free allergy education

www.cofargroup.org

A double whammy –obesity and GERD

“A double whammy is when something causes two problems at the same time, or when two setbacks occur at the same time.”  Double whammy – Idiom Definition – UsingEnglish.com

Obesity probably doesn’t fit this definition strictly because it causes a lot more than two setbacks.  However, obesity clearly causes its own set of problems and, even in childhood, contributes to the development of gastroesophageal reflux disease (GERD) (JPGN 2012; 55: 72-75).

This study consisted of 153 healthy children from a well-child clinic; among this group 31 were obese and 122 were nonobese.  All caregivers completed a reflux questionnaire.  The reflux symptomatic score was significantly higher in children with waist circumference (WC) >90th percentile compared with those <75th percentile.  Furthermore, the rise in GERD symptoms (heartburn, epigastric pain, and regurgitation) was shown to rise progressively with increasing BMI and WC.

One of the shortcomings of the study was the use of a questionnaire that has not been validated for assessment of reflux symptoms in children (according to the authors, none are available in children); though, this questionnaire has been used in a few prior publications.

More references on GERD and obesity:

  • -Gastroenterology 2010; 139: 1902, 1823.. Abdominal visceral adipose tissue increases risk for Erosive esophagitis.
  • -Ann Intern Med 2005; 143: 199-211. Pooled studies showed GERD symptoms with ORs of 1.43 c BMI 25-30 & 1.94 for > 30. OR for esophagitis was 1.76 for BMI>25 & increased risk of adenoca of 1.68-2.02
  • -Gastroenterology 2006; 130: 1925-6.  Obese youth have more reflux symptoms as with adults.

Previous post on GERD and asthma:

Treating reflux does not help asthma

Optimizing lipids to minimize cholestasis

As discussed in previous blog entries (PNAC, PNALD, and IFAC, More on PNAC, Four advances for intestinal failure), the right amount of lipid and the type of lipid both can contribute to parenteral nutrition associated cholestasis (PNAC).  More information about SMOFlipid which is a complex mixed-type lipid emulsion derived from soybean, coconut, olive, and fish oils is available (JPGN 2012; 54: 797-802).  SMOF contains 30% soybean oil, 30% MCT, 25% monounsaturated fatty acids, and 15% fish oil.

This study had a retrospective cohort comparison design & examined serum bilirubin over 6 months in children with PN-associated cholestasis (PNAC).  In one cohort, 8 patients received the SMOFlipid and the other 9 patients continued on Intralipid (IL).

The SMOF cohort was receiving 81% of caloric needs as PN at entry whereas the IL cohort was receiving 92%.  Six months later, SMOF cohort was receiving 68% of caloric needs as PN compared with 50% for IL cohort.  Nevertheless, the SMOF group had improved cholestasis with a median bilirubin drop of 99 μmol/L compared with an increase of 79 μmol/L among IL patients.  Overall, 5 of 8 children in the SMOF group had resolution of jaundice compared with 2 of 9 in the IL group.

While the authors state that SMOF may have important properties to prevent PNALD, the study has limited ability to draw any firm conclusions.

The authors state that no other treatment innovations were introduced; however, the authors overlook the large discrepancy in lipid volume administered.  The IL group was receiving much more lipid both before and during study.  Prior to entry of study, the IL group was receiving about 3.1 g/kg/day whereas the SMOF group about 2 g/kg/day; the SMOF group continued initially at the same lipid dosing with the new formulation.  This is one of the problems with historical controls.  While the authors might believe that the cholestasis improved because of the lipid content, the key factor may in fact be the amount of lipid given.

In the same issue (JPGN 2012; 54: 803-11), specific plant sterols (PS) were elevated among neonates with intestinal failure-associated liver disease (IFALD).  This study looked at 28 neonates and 11 children from Finland who required PN for more than 28 days.  Specific markedly-elevated PS included stigmasterol, sitosterol, avenasterol and campesterol (Table 4 in study).  Some of these PS in the neonates were more than 20-fold higher than healthy controls.