Looking better or feeling better in EoE?

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When seeing a new diagnosis of eosinophilic esophagitis (EoE), I often try to explain that there are two potential goals of treatment: clinical remission (improvement in symptoms) and histologic remission (improvement in appearance of esophagus with microscope).  Unfortunately, these two outcomes are not always synchronous; more proof of this comes from a recent study (Clin Gastroenterol Hepatol 2012; 10: 742-49, 750-52 [editorial]).

In this double-blind, randomized, placebo-controlled study of fluticasone in adult patients with a new diagnosis of EoE, 19 patients were treated with fluticasone (880 μg BID) and 15 patients were treated with placebo inhaler –for six weeks.  Initially, 21 patients were assigned to each group; 2 dropped out of treatment group and 6 dropped out of placebo group before completion of followup EGD.   The average age in the treatment group was 37 years versus 38 years in the placebo group.  A complete histologic response was defined as >90% reduction in mean eosinophil count; this occurred in 62% of fluticasone patients and in none of the placebo group, based on an intention-to-treat analysis.  Another measure of eosinophil activity, eosinophil-derived neurotoxin (EDN), was reduced by 81% on intracellular staining in the treatment group compared with 8% in the placebo group.  Figures 1 through 3 show this staining –it’s pretty cool!

Yet, the clinical response was not statistically different.  Dysphagia was reduced by 57% in the treated subjects compared to 33% in the placebo subjects in an intention-to-treat analysis.  Results were improved modestly in those who actually were treated: 63% (12 of 19) compared to 47% of placebo patients.  A complete response for dysphagia was noted in 42.9% of fluticasone group compared with 28.6% of control group based on an intention-to-treat analysis.  A fairly high rate of candidiasis was noted in treated patients 26%;  no placebo patients developed candida.

Another interesting finding was that among those who continued PPIs for heartburn symptoms the response to fluticasone was not improved.  40% of PPI users had a complete histologic response compared with 79% of non-PPI users.

So what are the reasons for the discrepancy between clinical and histologic response?

  • Established strictures and small-caliber esophagus may require dilation rather than medicines to relieve dysphagia
  • Esophageal fibrosis and subsequent esophageal compliance may not respond to topical therapy or take a lot longer to improve
  • Secondary candidiasis may reduce clinical response –though in this study, 5 of 6 patients with candida did in fact have symptom resolution
  • Compensatory behaviors may improve clinical symptoms –chewing food, cutting up food better, drinking more fluids, and avoiding some foods.  This may make it harder to detect important differences.

Patient information link: (Eosinophilic esophagitis – CCDHC Home)

Related posts:

Look of improvement on an EoE diet

Guidelines for Eosinophilic Esophagitis

Eosinophilic Esophagitis -Six Food Group Diet

The undiscovered country

MicroRNA signature for eosinophilic esophagitis

Pregnancy after Liver Transplantation

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As there are about 14,000 women of reproductive age in the U.S. who have undergone liver transplantation (LT), data about the outcomes of pregnancy are important for counseling.  A review and meta-analysis (Liver Transpl 2012; 18: 621-29) provides some information; going forward the National Transplantation Pregnancy Registry (NTPR) which was established in 1991 offers the promise of additional insight.

In the current review, Deshpande et al found 8 of 578 studies which met inclusion criteria; in total 450 pregnancies in 306 LT recipients were examined.  While healthy live births were the most common outcome, there were several pertinent risks identified.  The main concerns were development of preeclampsia, rejection/graft loss as well as the potential for birth defects.  While miscarriage rates were similar to the general population (15.6% compared with 17.1%), the following were much higher:

  • preeclampsia 21.9% vs. 3.8% in general population
  • cesarean section delivery 44.6% vs. 31.9% in general population
  • preterm birth 39.4% vs. 12.5% in general population

While rates of rejection and graft loss are not given for the entire cohort, specific study results were discussed.  In one study, rates of acute rejection ranged from 2% to 8% and loss of graft within two years of pregnancy occurred in 6-11%.

Similar to rejection data, the data for birth defects was not uniformly reported.  Specific study results were discussed and included several birth defects: 1 patient with total anomalous pulmonary venous return, 1 with pyloric stenosis, 2 with hypospadias, 1 with tracheoesophageal fistula, 1 with unilateral cystic kidney, and 2 with ventricular septal defects.

Take-home message:

Liver transplant recipients can have successful pregnancies but should be considered high risk.  Active reporting to established registries can give more accurate and up-to-date information.

Related post:

Alive and well? 10 years after liver transplantation

Advice on drug-induced liver injury (DILI)

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Practical information and advice on continuing or stopping drugs with associated hepatoxicity is available from a recent commentary (Gastroenterol Hepatol 2012; 8: 333-36).

Most drugs with a “bump” in aminotransferases do not need to be stopped.  Many drugs induce an “adaptive response” in which elevated LFTs will spontaneously resolve; this is most common in the first 12 weeks of drug usage.  This type of response must be distinguished from an immune reaction/hypersensitivity response which is much more likely to progress.  A hypersensitivity response could include rash, fever, and eosinophilia.

Recommended STOP RULES:

  • Drugs that cause symptomatic hepatitis: abdominal pain, jaundice, loss of appetite.
  • ALT values that exceed 8 times the ULN
  • ALT values >3 times the ULN and Bilirubin >2 times the ULN

Other caveats:

  • If the ALT value is >3 times the ULN but not associated with symptoms or rise in bilirubin, the drug can likely be continued with periodic monitoring.
  • ALT values >5 times the ULN require more intensive monitoring.
  • Hy’s law (named for Hyman Zimmerman): AST or ALT > 3 ULN AND   bili > 3 ULN indicate serious hepatotoxicity with >10% mortality rate.
  • Statins have similar rates of hepatotoxicity as the general population
  • Acetaminophen accounts for 40-50% of the 2000-2500 U.S. cases per year of acute liver failure (ALF).  Of the remaining cases of ALF, about 12% (250-300) are due to other cases of DILI.  Isoniazid is the 2nd most common cause of ALF due to DILI with about 50 cases.
  • Potential risk factors for DILI include alcohol usage, obesity, adult age group, and female gender.

Additional blog entries and references:

When death is on the line

Pediatric pharmaceutical poisoning

  • -J Pediatr 2011; 158: 802. Developing liver toxicity with valproic acid (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. (Ann Neurol 2004; 55: 706.)
  • -NEJM 2009; 360: 1575. propylthiouracil assoc c liver failure in ~1 in 2000
  • -JPGN 2008; 47: 395-405. Drug-related hepatotoxicity and acute liver failure.
  • -NEJM 2003; 349: 474. (review)
  • PDF] What Do We Mean by Looking?  FDA powerpoint with related information

Regurgitation harder to treat than heartburn, especially for NERDs

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While all pediatric gastroenterologists know that the title of this blog entry is right, it is helpful to have data.

A recent study (Clin Gastroenterol Hepatol 2012; 10: 612-19) used a reflux questionnaire to evaluate responsiveness of regurgitation from 2 randomized controlled trials.  The trials compared a newer acid blocker (AZD0865 dosed at 25-75 mg/day)) to esomeprazole (20-40 mg/day).  Patients had either non-erosive reflux disease (NERD , n=1460),  or reflux esophagitis, (RE, n=1314).  Inclusion criteria included the presence of substernal burning for ≥4 days/week.

Regurgitation-taste (RT), defined as an “acid taste in the mouth,” or regurgitation-movement (RM), defined as an “unpleasant movement of material upwards from the stomach” were analyzed.  Among NERD patients, either or both symptoms were present in 53% at baseline compared with 54% among the RE group.  In both NERD and RE patients, the presence of these regurgitation symptoms was associated with a poorer response to therapy.

  • Complete response of NERD patients with regurgitation symptoms:  RT 34%, RM 26%; in comparison to heartburn response of NERD patients which was 49%
  • Complete response of RE patients with regurgitation symptoms:  RT 44%, RM 33%; in comparison to heartburn response of NERD patients which was 55%

Additional references/blog entries:

Diet or drugs for cyclic vomiting syndrome

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Dietary modifications are frequently recommended for migraines.  Given the overlapping features between migraines and cyclic vomiting syndrome (CVS), dietary treatments for CVS have aimed at eliminating trigger foods.  Investigators from the UK describe a single center cohort of 21 children (2-16 years) were placed on a low-amine diet with instruction from a dietician (JPGN 2012; 54: 698-99).  16 (76%) of the children had a strong family history of migraines.  The diet was implemented for a ‘minimum of 6 to 8 weeks.’ 13 had a complete resolution of vomiting and 18 (86%) had at least a partial response.

Specific foods that were avoided included cheese, chocolate, citrus fruits, pork, peas, broad beans, shellfish, yeast extract, beef extract, gravies, caffeine, and alcohol.

This small study does not prove that a low-amine diet is effective.  In fact, most of the information on a low-amine diet is derived from alternative medicine sources (eg .  Low Amine Diet | www.integrative-medicine.com.au).  Nevertheless, it is likely that a subset of patients will benefit from avoidance of trigger foods.  How to identify potential culprits is unclear.

NASPGHAN Guidelines for CVS (JPGN 2008; 47: 379):

  • Diagnostic criteria: (90% will have idiopathic CVS)

1. at least 5 attacks or 3 over 6-month interval
2. episodic, last 1 hour to 10 days & at least a week apart
3. stereotypical pattern for individual patient
4. vomiting >4 times/hr for at least 1 hour
5. healthy in between & no other attributable problem

  • PROPHYLACTIC Measures:

Avoid triggers:
fasting, excessive excitement (eg. downplay big events), sleep deprivation
foods that trigger symptoms (?chocolate, cheese, caffeine, MSG)
excessive fatigue

Assure adequate carbohydrates
-provide sugar-containing drinks & extra snacks before exertion & bedtime

  • PROPHYLACTIC TREATMENT:

Less than 5 years:
1. cyproheptadine (0.25-0.5mg/kg/day divided bid)
2. propranolol 0.25-1/kg/day –often 10mg bid or tid
contraindications: asthma, diabetes, heart disease, depression
keep resting heart rate >60

5 years & older
1. amitriptyline (or nortriptyline -liquid formulation) start at 0.25mg/kg qhs and increase ’til 1mg/kg/dose
check EKG before and 10 days after peak dose
2. propranolol 0.25-1/kg/day –often 10 mg bid or tid
contraindications: asthma, diabetes, heart disease, depression
keep resting heart rate >60

Alternative prophylactic treatments:
1. phenobarbital 2mg/kg qhs
2. anticonvulsants: topiramate, valproid acid, gabapentin, levetiracetam -?consult neurology

Supplements:
L-carnitne 50-100mg/kg/day divided bid (max 1gm tid)
Co-enzyme Q10 10mg/kg/day divided bid (max 100mg tid)

  • SUPPORTIVE/ABORTIVE CARE

Fluids: D10NS w KCL @ 1.5 maintenance (or possibly D10 0.45NS -some children prone to hyponatremia); add TPN if no enteral intake for 3-5 days
Antiemetics:
1. ondansetron 0.3-0.4mg/kg/dose q4hours (max 20mg); alternative granisetron
Sedatives:
Benadryl 1mg/kg/dose q6hours
Ativan 0.05-0.1mg/kg/dose q6hours
Thorazine (chlorpromazine) 0.5-1mg/kg/dose q6hrs (with benadryl)
Analgesics:
Toradol 0.4-1mg/kg/dose q6hrs (max 30mg)
Narcotics (morphine)

May need to treat hyponatremia, hypertension, hematemesis (H2RAs & PPIs)

Also, can try Sumatriptan 20mg intranasally at onset of episode as potential abortive measure or other triptan

  • TYPICAL EVALUATION:

1. CMP, Amylase/lipase, UGI on all patients
2. If pain/hematemesis, check U/S of abd/pelvis, and EGD
3. If abnormal neuro features: (motor asymmetry, gait abnormality, severe altered mental status)
ammonia
lactate, serum amino acids, urine organic acids, plasma carnitine/acylcarnitine profiles, urine ketones
MRI brain
4. If precipitated by fasting/high protein meals, or intercurrent illness= neuro w/u w/o brain MRI.

  • ALARM symptoms:

1. pain & bilious emesis
2. attacks precipitated by intercurrent illness, fasting or high protein meals
3. progressive/worsening/chronic pattern
4. abnormalities on neuro exam

**Note to blog readers –I recommend that all drug dosing be reviewed for individual patients.  The recommended doses are based on my reading of the referenced material & transcription errors are possible.

Additional references:

  • -Clin Gastro & Hep 2007; 5: 44. Use of zonisamide or levetiracetam (used at Sz dosing in 20 adults); 75% response & 20% remission.
  • -J Pediatr 2002; 141: 724. Suggests initial treatment along with UGI as most cost-effective strategy. Extensive w/u in those with persistent sx.
  • -Am J Gastro 1999; 94: 2855. response to TCAs.
  • -J Pediatr 1999; 134: 567. 82% migraine-assoc or FHx. Better response to Rx
  • NASPGHAN 2003:  postgraduate course (B Li):80% response to elavil if fhx migraines.
    “There are no controlled randomized, double-blinded trials, only open label ones. In these studies, beta-blockade (Pfau Pediatrics 97:364,1996), cyproheptadine (Anderson Pediatrics 100:977, 1997), amitriptyline (Anderson), phenobarbital (Gokhale JPGN 25:64, 1997) and erythromycin (Vanderhoof JPGN 17:387, 1993) all have approximately 70% efficacy as prophylactic agents. In Dave Fleisher’s work, he has demonstrated a 70% effect of consultation alone without pharmacologic therapy. In other words, there appears to be a striking placebo effect in this disorder that should temper any interpretation of results. In addition, I believe CVS is a heterogeneous disorder that has multiple etiologies that could allow it to respond to multiple classes of agents.”

DDx:
Infection, IBD, addison’s, diabetes, renal dysfxn, metabolic errors/urea cycle d/o, FAO d/o, porphyria, CDG (glycosylation), pregnancy, ipecac/munchausen, PUDz, Giardia, pancreatitis, UPJ, malrotation/duplication, increased ICP/CNS Dz, Migraine-equivalent

Workup:

1. CBC, ESR, amylase, ammonia,UA, stool heme, chem 20, HCG
2. UGI
3. giardia ag, abd U/S & DPTA, EGD, urine organic acids, plasma amino acids, carnitine, lactate, pyruvate, sinus films, head CT/MRI, toxicology, delta-aminolevulic acid/ porphobilinogen (urine), beta-HCG, serum transferrin isoelectric focusing

Fish intake may reduce liver cancer

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In a large Japanese adult population (n=90,296), the consumption of n-3 fatty acids and fish was associated with reduced risk for hepatocellular cancer (HCC) (Gastroenterology 2012; 142: 1468-75 and editorial 1411-12).

HCC ranks fifth among cancer incidence and third for mortality worldwide.  Many factors contributing to HCC cannot be modified.  The main factors subject to modification include diet and avoidance of viral hepatitis.  Dietary studies are methodologically-challenging due to difficulties assessing diet and due to the complex nature of diets.  Without going into any significant detail, this study shows an inverse relationship between fish intake and incidence of HCC.  The hazard ratio for the highest quintiles compared to the lowest were 0.56-0.64 depending on the specific dietary agent.  The specific n-3 polyunsaturated fatty acids (PUFA) examined included eicosapentaenoic acid (EPA), docosapentaenoic adic (DPA), and docosahexaenoic acid (DHA).

HCC Established Risk Factors:

Age, males, family history of HCC, HCV/HBV infection, alcohol, cirrhosis, tobacco, aflatoxin exposure, Hereditary Hemochromatosis, α-1 antitrypsin deficiency, primary biliary cirrhosis

Likely Risk Factors:

Diabetes, obesity, NAFLD

Possible Risk Factors:

Red meat, saturated fat, fructose, oral contraceptives

Possible Protective Factors:

Coffee, micronutrients (vitamin D, vitamin E, selenium), white meat (fish, poultry), and n-3 fatty acids

Related blog posts:

Looking for trouble

Live longer -drink more coffee

Drink Up!

More about coffee

Pediatric NAFLD Position Paper

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A previous blog post (NAFLD Guidelines 2012) described comprehensive, up-to-date NAFLD guidelines from AASLD, AGA, and ACG.   Another group of experts from ESPGHAN (European Society for Pediatric Gastroenterology, Hepatology, and Nutrition) has also published a position paper on the diagnosis of NAFLD in children; coincidentally, these were published recently as well (JPGN 2012; 54: 700-13).

While there is some overlap in the information between the two guidelines, there are some notable differences.  The JPGN manuscript does include a nice differential diagnosis list  which can cause fatty liver disease (Table 2), including some rare entities like Dorfman-Chanarin syndrome, Cantu syndrome, Madelung lipomatosis, and numerous medications.  This review has more emphasis on etiology.

Table 3 lists a recommended workup in children with suspected NAFLD:

  • Standard liver function tests/blood counts/coagulation studies
  • Fasting glucose & insulin
  • Lipid profile
  • Glucose tolerance test & glycosylated hemoglobin
  • Calculation of HOMA-IR, markers of insulin resistance

AND Tests to exclude other liver diseases: 

  • Lactate, uric acid, iron, ferritin, pyruvate
  • Copper, ceruloplasmin, 24-hour urinary copper
  • Sweat test
  • Celiac serology (TTG IgA and serum IgA)
  • α-1-antitrypsin levels and phenotype when indicated
  • Amino and organic acids
  • Plasma free fatty acids and acyl carnitine profile
  • Urinary steroid metabolites
  • Other specific tests as suggested by evaluation (eg. viral hepatitis panel, serum immunoglobulins, liver autoantibodies)

When one looks at the recommended diagnostic algorithm (Figure 1) and tests outlined, these guidelines are not nearly as practical as the NAFLD guidelines from AASLD, AGA, and ACG and often contradictory between the tables/figures and the text.  How much would it cost for the recommended testing if/when extrapolated to the vast numbers of individuals with these disorders?  In addition, a much more limited diagnostic approach is suggested in the final section than outlined in Table 3 and Figure 1.

Imaging: these authors advocate LFTs and ultrasonography in all obese children (> 3 years) and adolescents.  If normal LFTS and sonography, the algorithm suggests the use of MRI if clinical signs of insulin resistance.  Later, the authors conclude “MRI is not cost-effective.”

Liver Biopsy: while the authors state that there is “no present consensus or evidence base to formulate guidelines” for liver biopsy, this is not well-reflected in their diagnostic algorithm in which arrows point to liver biopsy in almost everyone –either early liver biopsy or eventual biopsy in patients with persistent disease.  Accepted liver biopsy indications, according to the executive summary, include the following:

  • Exclude other treatable disease
  • Suspected advanced disease
  • Before pharmaceutical/surgical treatment
  • Research purposes

My conclusion about this position paper is it is less helpful than the AASLD/AGA/ACG guidelines.  In fact, when extensive diagnostic testing is recommended by experts, it is fortunate that other expert guidelines are available that support a more cost-effective approach.  In NAFLD cases that seem atypical and especially in the very young patient, this reference may still be helpful.

Geographic Inequity for Liver Transplantation

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Organ scarcity remains a big problem for liver transplantation.  Use of the Model for End-Stage Liver Disease (MELD) score was intended to address inequity in liver transplantation allocation.  However, it has not been successful.  One recent study which examines donation after cardiac death versus brain death (Liver Transpl 2012; 18: 630-40) also yields some insight into liver transplantation allocation across the U.S.

In Figure 3, the thirty-day probability of receiving a liver transplantation (brain death donation) for patients with MELD score >20 was compared across UNOS regions.  In regions 3 and 11 (Southeastern U.S. extending to Kentucky and Virginia), the rate was ≥40%.  In region 1 (Northeastern U.S) and region 5 (Southewestern U.S.) , the rates were 9.6% and 11.8% respectively.  Thus, some patients with the exact same MELD score have a 4-fold higher probability of receiving a liver transplant.

Related blogs:

Alive and well? 10 years after liver transplantation

Picking winners and losers with liver transplantation allocation

Big gift, how much risk

Sarcopenia, fatigue, and nutrition in chronic liver disease

Best gastrostomy tube

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A recent report touts the feasibility of a one-step percutaneous gastrojejunostomy (GJ) as the latest advance in enteral access (JPGN 2012; 54: 820-21).  This reference describes a new variation in technical placement: gastropexy using t-fasteners to secure gastrostomy tube site and then advancing neonatal scope via gastrostomy site to advance guidewire for  GJ placement.  This technique was used in three infants.

Most centers have developed their own protocols for enteral access and it is likely that the familiar approach to that center will be safest for their patient population.  Recently, the subject of gastrostomy tube placement was extensively reviewed in our institution (see below) due to variation in care at two children’s hospitals.  In one hospital, the surgical group primarily placed laparascopic button gastrostomies and argued that better visualization led to lower complications like colonic interposition.  Furthermore, this approach was considered similar in cost effectiveness as the group would place a primary Mic-Key® (http://www.mic-key.com/home.aspx) thereby eliminating the need for anesthesia for a button placement.

The alternative approach utilized a Corflo® gastrostomy tube (http://www.corpakmedsystems.com/product_main/enteral_main.html#FeedingTubes).  The advantages of this approach were 1) less anesthetic time/a smaller operation, and 2) lower likelihood of tube dislodgment.  This group approach argued that dislodgment was the greatest risk and that there was no urgency for a button tube.

Despite a joint meeting of these groups weighing the pros and cons, there was not a single best gastrostomy tube.

My experience is that tube dislodgment is quite common with button tubes.  In addition, primary button tubes can be difficult to size when the patient is under anesthesia.  As such, it is my practice to discourage primary gastrostomy button placement.  In addition, most patients who need gastrostomy tubes can wait until they are good surgical candidates both in terms of cardiorespiratory status and size.

Resources:

Gtube Products:
• AMT clamp –helps eliminate tubing pullouts
www.amtinnovation.com

• Gtube washable pads
www.oley.org  (specific web address: http://oley.org/lifeline/TubetalkJF11.html)

Additional references:

  • -J Pediatr 2011; 159: 602. Preemptive gtube assoc with improved survival post Norwood. High number needed fundoplication.
  • -JPGN 2011; 53: 293. 95% success with PEG in infants 2.1-5.6kg
  • -JPEN 2011; 35: 50-55. Predictive factors of mortality after PEG.
  • -JPGN 2009; 49: 237. Gtube improves height & weight in Rett syndrome.
  • -Clin Gastro & Hep 2007; 5: 1372. PEG placement does NOT prolong life in dementia patients.
  • -Arch Dis Child 2006; 91: 478-82. PEG reduced hospitalizations for respiratory dz in 57 severely impaired children
  • -J Pediatr 2006; 149: 837. inreased risk of PEG in SMA type 1 -42% w aspiration; 17% death (2/12)
  • -Pediatrics 2004; 114: 458-61. Moratlity rate of 0.4% -one death related to sepsis/peritonitis & 5% complication rate.
  • -Teitelbaum JE, Gorcey SA, Fox VL. Combined endoscopic cautery and clip closure of chronic gastrocutaneous fistulas. Gastrointest Endosc. 2005;62(3):432-435
  • -JPGN 2006; 43: 624. Satisfaction with PEGs: 94% of parents viewed PEG as positive influence on child’s situation & 98% would have chosen PEG insertion again (n=121).
  • -Sullivan PB, Dev Med Child Neurol 2005; 47: 77-83. 57 CP pts -almost all had improved health/nutrition p gtube
  • -Gastroenterology 2001; 121: 970-1001 & JPEN 2004; 28: S16. Provision of nutrition does not, for the most part, favorably alter clinical outcome.
  • -Lancet 2005; 365: 755-763. Pts c stroke/PEG did not do better than those c stroke/NGT.
  • -Sullivan PB, Dev Med Child Neurol 2004; 46: 796-800. gtube improves QOL.

Gastrostomy Tube Review with annotated references: Laparoscopic gtube versus conventional PEG placement

 Zamakhshary et al.  JPS 2005; 40: 859-62.   i.  Retrospective review, n=119 (only 26 with laparoscopy =21%). (2002-2003)  ii.  States same operative time of ~53 min by combining 2nd procedure w PEG (in 77% w PEG).  It takes these authors a long time to perform PEG and gtube change procedures.  Also, it is not noted how many of these 2nd procedures were coordinated with other needed anesthesias.  (Many times a PEG is replaced at the time of another procedure.)   iii.   3 PEG with transcolonic tube, 2 failed PEG –one with peritonitis, 4 with tract disruption when PEG pulled.  Similar rate of local problems (eg granulation tissue).  ARTICLE does not detail when PEG tubes are pulled –VERY high rate of tract disruptions.   iv. Article missing key details regarding size of PEGs & gtube buttons which may impact complications.  v. Cited advantages according to authors:

  1. “eliminates” risk of hollow viscus injury (JH: this is NOT  accurate)
  2. Useful for small infants (<2kg) (JH: usually gtube NOT needed in <2kg)
  3. Enables “ideal” location (JH: this is NOT  accurate)
  4. Primary button ‘advantage’ (JH: DOES NOT cite potential pitfalls like button too tight, possibility of balloon breakdown, possibly higher rate of dislodgment)

 Vervloessem et al. JPS 2009; 18: 93-97.     i. Retrospective review: 1992-2008.  N=467.  ONLY 19 Lap PEG –thus limited ability to provide comparison.  ii. Cites 59 “major complications” due to PEG –Table 2, including “13” new cases of GERD after PEG (or worsened GERD).  Of the major complications, important complications included 1 sepsis death, 7 peritonitis, 5 gastrocolic fistulas, 4 major granulation tissue, and 11 buried bumpers.  iii.  States that VPS is risk factor for infection but does not state whether any Lap gtubes were done in these patients.  iv. Complication rate decreased over the years—p=0.003; thus PEG procedure became safer with time and experience.   Could not demonstrate a decrease in complications with lap gtube versus PEG.  Authors recommend lap PEG in specific situations such as previous abdominal surgery or if not a good puncture site.

 Segal et al. JPGN 2001; 33: 495-500.    i. Retrospective study, n=110 (1990-97). N=110 –ALL PEG (no LAP). Thus, limited utility in comparing two methods. ii. “44%” developed late complications with PEG.  Most common: 24 extruded tubes/buried tubes (would NOT be better with lap button); other important: cologastric fistula n=2, peritonitis.  Table 1 indicates that 75% of dislodgment were due to buttons not PEG.  12 of the complications were granulation tissue and proliferative gastric mucosa.  Buried tubes occurred 14 & 19 months after placement with button tube!!   iii.  Thus this article adds little to the discussion of PEG vs lap gtube.

Akay et al. JPS 2010; 45: 1147-52  i.  Retrospective review (2004-2008) n=238 (134 PEG, 104 LAP)  ii. PEG with higher complications;  authors were changing PEG after 6-8 weeks. iii.  6 patients had early PEG dislodgment –this is higher than expected.  iv. 1 patient with gastrocolic-cutaneous fistula with both PEG & with LAP.  v. Table 4 lists complications: similar stomal issues, 2 patients with leak after PEG exchange (too early! –see page 1152) vi. Cited advantages: “eliminating” risk of hollow viscus injury, allows for sutures, small infants (<2kg) & possible primary buttons.**These authors did not place primary buttons –this makes it difficult to draw any conclusions about PEG vs primary LAP button.  Many feel PEG tube is a better tube and less prone to dislodgment than button and guarantees appropriate size.

Lantz et al. Int J Pediatr 2010; ID# 507616, 1-4.   i. Literature review, included 54 studies that qualified (1995-2009).  N=4331 (1027 LAP, 3304 PEG).  Very few details given in this review.  ii.Fistulas in 1.27% of PEG vs 0% for LAP.  iii.  Lists significant limitations: different studies, not blinded, nonpublication bias.  iv.  “This study highlights the need …for trials, comparing PEG to” LAP. v.  Does not include the limitation that LAP technique developed later and with more experience less complications.  Except for gastrocolic-cutaneous fistulas –no specific information is given about complications.

Avitsland et al.  JPGN 2006; 43: 624-28.  i. Restrospective review. N=121 –all PEGs  ii.     PEG “safe technique…major complications rare.”  “Most children experience minor stoma-related complications.”  iii. 29 died due to other factors.  Of 85 with f/u, 21 able to remove gastrostomy.  iv. No early mortality (<30 days).  1 of 85 had tube dislodgment.  3 had tube migration into esophagus (in cases where tube was not endoscopically removed).  v.     Frequent tube site problems ~75% -most easily treated. vi. Parents with high satisfaction: 83/85 (98%) would choose PEG again, 80/85 (94%) stated PEG improved child’s situation

Gauderer M. JPS 2001; 36: 217-19.   i.  Focused literature search and personal 20 year experience. ii. >216,000 PEGs performed annually in U.S. according to article (~5000 children).  PEG procedure developed 1st for children. iii.  Suggested approach to PEG with or w/o fundoplication: “Because PEG is such a simple procedure, a well-accepted approach is to place gastrostomy initially in children who can tolerate nasogastric tube feedings and add an antireflux procedure later, if needed.”

Srinivasan et al. JPGN 2009; 49: 584-88.   i.Prospectively collected data from observational study, n=601 (384 PEG insertions, 165 button conversions).  ALL pediatric. ii.  Complications:  PEG site erythema 15%, buried bumper migration (1 patient), 3 PEG dislodgments, one patient had laparotomy due to severe pain (no findings identified).   No procedure-related mortality.   iii.  49 of 384 removed –no longer needed.  iv. “The role of PEG is well established…our experience..PEG has been generally safe, with low procedure-related morbidity in children.”

Nutr Clin Pract 2005; 20 (6): 607-12.  Bankhead RR et al. i. Comparison of 91 patients.  23 PEG, 39 LAP, 29 open.  ii.   PEG had lowest complication rate

Surg Endosc 2006; 20: (8): 1248-51.  Ljungdahl M.                                         i.     Prospective, randomized study. N=70.  ii.  PEG with lower complication rate than surgical (open) gastrostomy –lower mortality & morbidity in adult patients.

UK Review Online: http://www.patient.co.uk/doctor/PEG-Feeding-Tubes-Indications-and-Management.htm   2009  i. Review of alternatives to PEG for gastrostomy insertion. There are alternative methods of gastrostomy tube insertion to PEG. They are: a) Laparoscopic insertion b) Open surgical technique c)Percutaneous radiologically guided gastrostomy (PRG) insertion. ii.  “There are reports over the years since introduction of PEG in the 1980s with often inconclusive results.21▪    A small study from Ireland and one from London favour PRG in patients with amyotrophic lateral sclerosis as it avoids the need for sedation or endoscopy.22,23▪  One meta-analysis suggested a higher success rate with PRG than with PEG, and less morbidity than either PEG or surgery.24 However a more recent comparison of a relatively small number of endoscopic, surgical and laparoscopic placement favoured PEG25 and another favoured PEG over PRG.26▪     A literature review suggested PEG as the procedure of choice for placement of gastrostomy tubes.27▪    A recent prospective randomized trial favoured PEG over surgical gastrostomy insertion.28▪     There is some evidence that polyurethane PEGs are less troublesome than silicone PEGs (less tube deterioration, less blockage).29▪    PEG is preferred in trauma patients.30▪                Antibiotic prophylaxis for PEG insertion appears to reduce the incidence of wound infection.19,20▪      Laparoscopic insertion was considered preferable to PEG by one study in children with PEG insertion having higher complication rate in children and often requiring repeat anaesthetics.31   An earlier study in children showed similar results for surgical, PRG and PEG insertion but did not look at the laparoscopic technique.32    A recent study from Norway found PEG insertion safe and very well tolerated by children and parents but made no comparison with other techniques.

Conclusions of review: PEG likely increases risk of gastrocolic fistulas (1-2%) but this has been reported with LAP as well.  The incidence is low.  No well-designed  studies have demonstrated superiority of LAP over PEG in terms of safety.  Potential drawbacks of LAP are likely underreported.  There have been cases of severe peritonitis at local hospitals following lap with primary gtube balloon misplacement.  Many feel PEG tube is a better tube and less prone to dislodgment than button (dislodgment is most frequent serious adverse event) and can be easily adjusted to  appropriate size.  To minimize complications, tube should not  be changed early.

Natural laws not patentable: the case with Prometheus

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While most individuals might think of greek mythology or the recent movie when hearing the word “Prometheus,” pediatric gastroenterologists might think of the company that performs a number of useful diagnostic tests.  Recently, Prometheus has had a legal setback (NEJM 2012; 365: 2338-40). 

Since the 1990s, Prometheus has tested for azathioprine (& 6-mercaptopurine) metabolites.  A therapeutic level of 6-thioguanine (6-TG), a metabolite for these drugs, is recognized as generally between 230-400 pmol per 8×10(to the 8th) red cells.  Levels outside this range often require drug adjustments.

When the Mayo clinic started to offer a slightly different assay, priced 25% below Prometheus’s test, Prometheus sued for patent infringement.  The court held that “if a law of nature is not patentable, then neither is a process reciting a law of nature;”  hence, Prometheus’s patent was rejected.

There are implications of this lawsuit on the use of a large number of biomarkers.  For example, patents for BRCA DNA sequences that increase the risk for cancer will probably be overturned.  Industry groups argue that denying patents will halt progress as companies will not be able to recoup investments in biomarker development.  Congress could consider passing laws allowing exclusive marketing of these innovations.  Alternatively, adequate funding through the NIH (National Institutes of Health) could allow development of biomarkers without the need for patents; in fact, 100 projects are in progress at this time.