Increased ferritin predicts poor response in Hepatitis C

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Serum ferritin levels were independently shown to be a risk factor for poor response to treatment in hepatitis C virus (HCV) infection (Hepatology 2012; 55: 1038-47).  This article adds additional information to previous work which has shown that increased iron can be a comorbid factor in chronic viral hepatitis and other liver diseases.

This study used the Swiss Hepatitis C Cohort Study (SCCS) (n=3648).  In this group, the success of treatment with pegylated interferon alpha and ribavirin were correlated with clinical and histological features.

Ferritin levels ≥ the sex-specific median values was one of the strongest pretreatment predictors of treatment failure (OR 0.45). It had a similar predictive effect as the IL28B genotype.  In addition, higher ferritin levels were associated with severe liver fibrosis (OR 2.67) and steatosis (OR 2.29).  For women the sex-specific median for ferritin level was 85 μg/L and for men it was 203 μg/L.  The authors note that these cutoffs are quite close to the upper limits of normal of the general population (150 and 300 respectively).

Mechanistically, HCV interferes with the host’s iron metabolism leading to iron accumulation in the liver.  Part of this is explained by down-regulation of hepcidin (Help with hepcidin).  Part is due to ferritin acting as an acute phase reactant to inflammation.  Ultimately, excess iron promotes liver inflammation, oxidative stress and mitochondrial dysfunction.

How important ferritin will be with newer therapies is not clear.  It is likely that patients that are less responsive to dual therapy (pegylated interferon/ribavirin) will have poorer response as well to triple or quadruple therapies.

Additional references/previous related posts:

Recurrent pancreatitis and genetic underpinnings

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While the absolute number of patients with genetic causes of pancreatitis is small, due to frequent hospitalizations, this remains a significant problem.  This month additional information on genetic predisposition for pancreatitis is available (JPGN 2012; 54: 645-50).

Sultan et al (Milwaukee, WI) reviewed the charts of children <18 years with recurrent acute pancreatitis (RAP) and patients with chronic pancreatitis (CP) from 2000-2009.   RAP was considered if patient had a minimum of two distinct episodes of acute pancreatitis.  Acute pancreatitis was considered the diagnosis if patient had typical symptoms associated with 3-fold elevation of amylase or lipase or imaging changes consistent with acute pancreatitis. CP was defined as a minimum of 2 episodes of acute pancreatitis associated with pancreatic duct abnormalities or pancreatic insufficiency.

Among this cohort of 29 children, 23 (79%) had mutations which have been associated with genetic pancreatitis (GP).  Family history was positive in only five patients.

  • CFTR mutation in 14 (48%): two had homozygous mutations, six heterozygous, and four had 5 T variants.  The importance of a single CFTR mutation in contributing towards pancreatitis is unclear.  However, the Wisconsin population has a carrier frequency of 1:32; the striking difference in frequency  indicates that even a single mutation may be important in the pathogenesis of RAP.
  • SPINK1 (serine protease inhibitor Kazal type 1) in 8 (27%).  SPINK1 mutations occur in 1-3% of the general population.  It is often a modifying factor rather than an isolated causal factor in the development of RAP.  Four of the patients with SPINK1 mutations also had a CFTR mutation.
  • PRSS1 (cationic trypsinogen gene) in 7 (24%).  Individuals with these mutations are considered to have hereditary pancreatitis, an autosomal disease with incomplete penetrance.
  • Only one patient was tested for chymotrypsin C gene (CTRC) –tested negative.

Seven patients with RAP did not undergo genetic testing & were excluded from the study.  These patients had other known causes of RAP: 3 had gallstones, 2 had pancreas divisum, 1 had a metabolic disorder, and 1 had a medication-induced pancreatitis.  The authors note, however, that patients with pancreas divisum have had genetic mutations identified in other studies.

Additional References:

  • www.uni-leipzig.de/pancreasmutation. This link will take you to the hereditary pancreatitis database where you can search for the specific mutation you identified and find articles dealing with a variety of aspects of that particular mutation.
  • 2011 Naspghan Postgraduate Course:
    Pancreatitis Workup
    -1st bout, check U/S, trig
    -if 2nd bout, suggested to check MRI, genetics (SPINK1, PRSS1, CFTR), sweat test, fecal elastase, possibly IgG4/ANA
  • OMIM#167800/276000
  • -Gastroenterology 2006; 131: 1844.  Mouse model w R122H Trypsiongen expression.
  • -Whitcomb DC. Gut 2004; 53: 1710-17. test for PRSS1 (cationic trypsinogen), SPINK1 (Serine protease inhibitor, Kazal Type 1), and CFTR gene.
  • -JPGN 2002; 34: 1A pg 444. n=108 with hereditary or idiopathic pancreatitis. (28% had + fhx)  12 c PRSS1 mutation, 24 c SPINK1 (21 s fhx); 22 had + CFTR mutation.
    -Pancreatology 2001; 1: 405-415.  Consensus guidelines for testing for H. Pancreatitis. PRSS1 gene -cationic trypsinogen
    http://www.pancreas.org/assets/pdfs/Pancreatology/HPgeneTestConsensus.pdf
  •  David Whitcomb’s laboratory at the University of Pittsburgh. The test is commercially available there. Their web site for the forms is:
    http://www.pitt.edu/~whitcomb/HPINFO/MolGenTest.html
  • -JPGN 2011; 52: 262. Review.
  • -J Pediatrics 2011; 158: 612.  Acute pancreatitis can result in diabetes.
  • -Clin Gastro & Hep 2010; 8: 410-416, 417. REVIEW of acute pancreatitis.  Rec NJ generally over TPN.
  • -Clin Gastro Hep 2010; 8: xxii.  Anomalous pancreatobiliary jxn as a cause.
  • -JPGN 2009; 49: 137.  Pancreatitis assoc w celiac
  • -Clin Gastro & Hep 2009; 7: 702.  Harmless Acute pancreatitis score.  Nonsevere when NL hgb, NL creatitine, and no rebound tenderness/guarding
  • -Alim Pharm Ther 2008; 28: 777-781.  Use of a low fat diet helped shorten hospital stay among adult pts with acute pancreatitis.
  • -Clin Gastro & Hep 2008; 6: 1070, 1077.   Fluids and imaging in acute pancreatitis.  With imaging, CT probably best.
  • – J Pediatrics 2008; 152: 106.  Acute pancreatitis in young children

Related blog entry:

Indomethacin to prevent post-ERCP pancreatitis

How much radiation from your CT scanner?

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Our children’s hospital, along with many others, has made a concerted effort to reduce radiation exposure by adjusting CT scan settings.  Even a single abdominal CT scan may confer a small but real risk of developing cancer.  The trade-off with low-dose CT techniques has been a concern about poor image quality.  New research indicates that low-dose CT scan is not inferior to standard-dose CT with respect to detecting appendicitis (NEJM 2012; 366: 1596-605).

This single-center study examined 441 patients assigned in a single-blind fashion to low-dose CT (median dose: 116 mGy-cm) in comparison to 447 patients receiving a standard-dose CT (median dose: 521 mGy-cm).  All patients had CT for suspected appendicitis.  The negative appendectomy rate was 3.5% in the low-dose group and 3.2% in the standard-dose group.  There was no significant difference in appendiceal perforation rate or proportion of patients needing more imaging.

How much radiation do your patients receive with a CT scan?

Related newspaper article:

FDA issues guidelines to lower radiation exposure in children:

http://www.ajc.com/health/child-sizing-radiation-doses-1434081.html

Related posts:

Magnetic resonance enterography for Crohn’s disease

More imaging needed?

Additional references:

  • -NEJM 2010; 363: 1, 4. Safety of CT.  Can have overdose of radiation and even standard doses could cause complications.  Also, a big issue is downstream unnecessary testing due to incidental findings.
  • -JPGN 2011; 52: 280. Documents high exposure to radiation in large IBD pediatric cohort.
  • -J Clin Gastroenterol 2011; 45: 34-39. High levels of ionizing radiation thru CT scan in pts with IBD.
  • -Pediatr Radiology 2002; 32: 217-313. Minimizing radiation exposure, risk/benefit of CT. Proceedings from conference.
  • -Pediatr Radiology 2002; 32: 700-706. Risk of CT for young child: ~ 1 in 1000 risk of fatal cancer later in life.

Good care 24/7

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In hospital settings, there have been concerns about clinical care at night or weekends (see references below).  At least with liver transplantation, 24/7 care appears to be the rule rather than the exception (Liver Transpl 2012; 18: 558-65). 

Using the UNOS database, this study analyzed 94,768 transplants from 1987-2010.  Survival rates at 30, 90, and 365 days for nighttime operations: 96%, 93%, and 86% respectively.  For weekends, the respective rates were 95%, 92%, and 86%.  These rates did not differ from weekday rates.  Graft failure rates were modestly increased for weekend transplants at 365 days (HR 1.05, 95% confidence interval 1.01-1.11) but not for 30 days or 90 days.  In addition, there was no difference in graft failure between nighttime and weekday transplantations.

Additional reference:

  • -Clin Gastroenterol & Hepatol 2009; 7: 296., 303.  n>400,000 discharges.  OR 1.2 for mortality of UGI bleed if on weekend. 
  • NEJM 2001; 345: 663-668.   3,789,917 admissions (in Canada).  Weekend admissions were also associated with significantly higher mortality rates for 23 of the 100 leading causes of death and were not associated with significantly lower mortality rates for any of these conditions.

Proton pump inhibitors–infection risk with cirrhosis

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In a previous post (The Medical Pendulum and Gastroesophageal Reflux), I note that enthusiasm for proton pump inhibitors has started to wane.  In addition, a significant number of reported of potential side effects were referenced.  Another potential adverse effect is increasing the rate of spontaneous bacterial peritonitis (SBP) in patients with cirrhosis (Clin Gastroenterol Hepatol 2012; 10: 422-27).

This retrospective study examined 65 hospitalized cirrhotic patients with paracentesis-proven SBP between 2006-2009 and compared them to 65 contemporaneous hospitalized cirrhotic patients without SBP.   Patients with SBP had a higher incidence of use of PPI within previous 7 days: 71% versus 42%.  Of patients with SBP receiving PPI, the authors state that 68% did not have a documented indication for PPI use.

Additional references/previous posts:

  • –Treating reflux does not help asthma
  • -Risk of Hypomagnesemmia -2011. http://www.fda.gov/drugs/drugsafety/ucm245011.htm
  • –Gastroenterology 2010; 139: 1115.  Review of safety of PPIs.
  • –Gastroenterology 2010; 139: 93. n=167,000. PPIs associated with hip fracture risk, OR 1.3, in patients with other risk factors.
  • –Gastroenterology 2010; 138: 896-904. 5 yrs of PPI -no increase risk in hip/spine fx.
  • –Arch Intern Med 2010; 170: 765-71, 747 (ed). PPI not related to hip fx (n=161,806) women 50-79. INCREASE risk of spine fx, hazard risk 1.47
  • –Arch Intern Med 2010; 170: 772-8. PPIs increase risk of Clostridium difficile infection (hazard ratio 1.42 –42% increase in risk), n=1166.
  • –Arch Intern Med 2010; 170: 784-90. n=101,796. OR 1.74 for daily PPI, OR 2.36 if BID Rx; thus ~70% increase risk of nosocomial infection.
  • –Clin Gastro & Hep 2010; 8: 504. Increased bacterial overgrowth with PPI use.
  • -JAMA 2009; 301: 2120-2128. Use of PPIs associated with INCREASED hospital acquired pneumonia by ~30%. Could result in 180,000 HAP cases/yr with ~33,000 deaths. n+ 63,878 admissions, 52% on PPIs or H2RAs (83% PPIs, 17% H2RAs). H2RAs NOT associated with HAP cases.

Does it make sense to look for parasites in RAP?

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Probably not, in the absence of other symptoms.  A small study from Switzerland shows that treatment of Blastocystis hominis does not help recurrent abdominal pain (RAP) more than placebo (JPGN 2012; 54: 677-79).

This study result is not surprising.  A previous study of 157 RAP pediatric patients (JPGN 2007; 44: 524-26) showed that testing for ova and parasites was unnecessary as the incidence of parasitic infections in this population was not increased in RAP patients compared with controls. In this 2007 study, stool samples were positive for parasitic infection in 15 children, with no difference in prevalence between children with chronic abdominal pain (6/87; 7%) and healthy control children (9/70; 13%).

The current study had 37 patients complete the study.  The pain index (PI) for all patients improved in the study; however, there was no difference between patients who received antibiotics (trimethoprim-sulfa was used as first-line agent) compared to those who received placebo.

Regarding the methodology, the PI was either a visual analog scale with numbers from 0 to 10 or a standardized face scale; the specific scale was determined by the patient age.  Also, among the 20 patients who received antibiotics, 13 continued with B hominis in their stool tests after an initial round of therapy.  Yet the change in pain was virtually identical.  In antibiotic-treated patients, initial PI was 7.1.  After treatment, those with persistent B hominis detected in the stool had a PI of 4.2 whereas those with negative stool specimens had a PI of 4.1.  The placebo patients started with a PI of 7.4; after placebo treatment, a similar proportion cleared the B hominis from their stool –in this group, at the conclusion of the placebo treatment the PI was 2.4; the placebo group with persistent detection of B hominis had a PI of 3.2 at the conclusion of the study.

Although the potential pathogenicity of B hominis in humans remains unclear, it is not unusual in clinical practice for patients with this finding to receive treatment.   Besides trimethoprim-sulfa, metronidazole is frequently administered. Based on this study, placebo would be as helpful as an antibiotic in improving clinical symptoms.

Related blog entries:

What to make of FODMAPs

Pain changes brain

Treating diabetes with surgery

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Two articles in the New England Journal of Medicine point to the role of bariatric surgery in  treating type 2 diabetes in obese patients (NEJM 2012; 366: 1567-76 & 1577-85).  Type 2 diabetes looms as one of “the most challenging contemporary threats to public health.”

The first study was a randomized nonblinded single-center trial with 150 patients; mean BMI 36 with 34% having a BMI less than 35.  Intensive medical therapy was compared to Roux-en-Y gastric bypass or sleeve gastrectomy.  Mean patient age was 49 years. 42% of the gastric bypass group, 37% of the sleeve-gastrectomy group, and 12% of the medical treatment group achieved the primary end-point of a glycated hemoglobin level of ≤6% by the 12 month followup; the average starting glycated (HgbA1C) hemoglobin was 9.2%.  At the conclusion of the study, the average HgbA1C was 6.4, 6.6, and 7.5 respectively in the three groups.

The second study used a similar trial with 60 obese patients; all had BMI >35  At 2 years, diabetes remission occurred in 75% of their gastric bypass group, 95% of their biliopancreatic-diversion group and in no patients receiving intensive medical therapy patients. HgbA1C had similar rates of improvement as the 1st study: 6.3 in gastric-bypass, 4.9 in biliopancreatic-diversion group, and 7.7 in medical-therapy group.

While surgery has risks (see related material below), its benefits are likely to alter future treatment strategies with surgery being contemplated prior to exhausting all medical treatments.

Additional References:

  • -JAMA 2012; 307: 56-65.  Bariatric surgery and long-term cardiovascular events.
  • -JAMA 2011 [doi: 10.1001/jama.2011.817]). Large study failed to show that roux-en-Y gastric bypass prolonged life. n=850 VA pts to 41,244 controls. Same group showed no cost savings during initial 3 yrs: Med Care 2010; 48: 989-98.
  • -NEJM 2011; 365: 1365. Increased frequency of bariatric surgery in adolescents.
  • -NEJM 2009; 361: 445/520. perioperative safety.
  • -NEJM 2007; 357: 741, 753, 818. Bariatric surgery improves mortality rate.
  • NEJM 2007; 356: 2176. Review

Complications from surgery:

  • Early: bowel obstruction, DVT, GI bleed, leaks, pulmonary embolism, wound infection
  • After 30 days: anastomotic stricture, bowel obstruction, gallstones, dehiscence, fistula, Bleeding, Incisional hernia, nutrient deficiencies (iron, B12; calcium, Vit D (w RYGB), folate, B6/riboflavin).
  • Complications from gastric band: food impaction, erosion (now banned in Finland!), band slippage, gastric volvulus, band too tight, port infection
  • Roux-y gastric bypass:
    anastomotic leak 1.2%, anastomotic ulcers/stricture
  • Nutrient Monitoring–every 3months x 3, then yearly: Vitamin A, B12, Folate, Ceruloplasmin, Vit D-25OH, Iron studies, Zinc, thiamine, Selenium, Intact PTH, Mg, PT/PTT
  • Suggested supplements: Calcium c vitamin D 1200-2000mg, Iron at least 18-27mg/day, MVI with zinc/selenium
  • Also if duodenal switch, add Vitamin A 10,000 IU, and Vitamin D3 1200units daily or 50,000 units weeekly, Vitamin K 300 mcg,

Potential nutritional deficiencies:

  • B12, B6 (pyridoxine), Riboflavin (B2), B1 (Thiamine), Folate (B9)
  • Vitamins A,D,E, K
  • Calcium, Copper, Iron, Selenium, Zinc

Recommendations from NASPGHAN Post-Graduate Course 2011:

  • If post-op pain: epigastric –>do EGD & if neg do ‘RUQ w/u’, RUQ –> check U/S, LFTs possibly CT
  • If post-op vomiting –>do EGD
  • If post-op nausea –>Rx PPI and EGD if not improving
  • Anastomotic stricture in stomach –>dilate to 10-12mm in 1 session

Related blog posts (includes additional references)

Cardiovascular disease for the entire family

Staggering cost of obesity

A liver disease tsunami

Lower leptin with physical activity

Disease modifying treatment in IBD

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As noted in this blog (Only one chance to make first impression) and other sites as well, many have argued for early “top down” treatment to try to modify the natural history of Crohn’s disease (CD).  Early in the course of CD when an inflammatory process predominates, theoretically, treatment at this time point can prevent the development of intestinal fibrosis/strictured IBD phenotype.

Support for this approach can now be extrapolated from a mouse model as well (Inflamm Bowel Dis 2012; 18: 460-71).  In this study, the authors eliminated an inflammatory stimulus, Salmonella typhimurium, with levofloxacin treatment.  Treatment was initiated at sequential time points during infection.  Subsequently, the effects of the inflammation on the development of fibrosis was determined by examining histopathology; in addition, the effects on mRNA expression and protein expression were determined.  The time course of a number of cytokines is followed including TNFα, TGFβ, IL12p40, IL-17, IL-1β, and IL-6. While intestinal fibrosis developed even in those with early treatment, early treatment lessened, but did not eliminate, the development of fibrosis.

Since no effective antifibrotics exist and fibrosis may autopropagate even in the absence of inflammation, the authors postulate that early effective treatment has the best opportunity to alter the natural history.

Indomethacin to prevent post-ERCP pancreatitis

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“Take two and call me in the morning” may now apply to the use of indomethacin in preventing post-ERCP pancreatitis.  A multicenter, randomized, placebo-controlled, double-blind clinical trial has shown that rectal indomethacin (two 50 mg suppositories) can reduce the rate of post-ERCP pancreatitis (NEJM 2012; 366: 1414-22).

A total of 602 adult patients were enrolled.  Patient selection favored those at increased risk for post-ERCP pancreatitis (eg. suspicion of sphincter of Oddi dysfunction) and excluded those at low risk for this complication (eg. routine biliary stent exchange, chronic calcific pancreatitis, or a pancreatic head mass).  Other exclusion criteria included active pancreatitis, elevated creatinine (>1.4 mg/dL), active peptic ulcer disease, and those already receiving a NSAID.

The suppositories (or placebo) were administered immediately after ERCP while the patient remained in the procedure room.

Post-ERCP pancreatitis developed in 27 of 295 patients (9.2%) in indomethacin group and in 52 of 307 patients (16.9%) in placebo group.  In addition, moderate-to-severe pancreatitis was reduced as well 4.4% compared with 8.8% respectively.  In addition, there were no increased adverse events in the treatment arm; there was no increased risk of bleeding in particular.

While the mechanism of improvement is unclear, NSAIDs are potent inhibitors of phospholipase A2, cyclooxygenase, and neutrophil-endothelial interactions, all of which are known to play a role in the pathogenesis of acute pancreatitis.

Additional references:

  • -Am J Gastroenterol 2007; 102: 978-83.  Use of indomethacin to reduce pancreatitis after ERCP
  • -Gut 2008; 57: 1262-7.  Meta-analysis of rectal NSAIDs to prevent post-ERCP pancreatitis

Diseases peculiar to children

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In celebration of NEJM’s 200th anniversary, a special series of articles is being published.  A recent one, titled “What we don’t see” makes some useful observations about the history and trajectory of the field of pediatrics (NEJM 2012; 366: 1328-34).

According to the author, most physicians did not consider children as a distinct medical population in the early part of the 19th century.

  • In 1789 Benjamin Rush at the Univ of Pennsylvania gave lectures called “diseases peculiar to children.”
  • William Osler introduced the term “pediatrics” in 1880.
  • While advances in genetics, surgery, neonatology, oncology, and many other disciplines have been very important, infectious diseases have remained the predominant cause of childhood death both in the past and currently.
  • In 2008, causes of childhood death worldwide:  pneumonia 19%, diarrhea 15%, malaria 8%, other infections 26%.  Diarrhea and pneumonia each killed more than 1 million children.
  • Neonatal deaths comprised 41% of all deaths in the first 5 years of life.