HBV in the Joseon Dynasty

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Investigators have found evidence of Hepatitis B virus (HBV) in the mummified remains of a Korean child from the 16th century (Hepatology 2012; 56: 1671-80).

There are at least 10 HBV genotypes (A-J) and several sub genotypes; each have a specific geographical distribution.  Genotypes are defined by an >8% sequence divergence whereas as sub genotypes have 4-8% sequence divergence.  The HBV in this study corresponds to C2 clade.

While the technical aspects are fascinating, the other important contribution of this article is to the understanding of the evolutionary history of HBV.   There are two theories with regard to the origin of HBV, which may have occurred 100,000 years ago.  One suggests a primate origin with subsequent cross-species transmission.  Another theory suggests a common ancestor of HBV for primates and humans.

In this study, the mummy-derived HBV has the same genotype C which is currently predominant in Korea (>95%); and C2 sub genotype is the most common sub genotype.

The studies conclusions regarding the identification of the subtype is supported by the process of testing the samples in three independent laboratories.  The genetic diversity noted in the sample is likely related to natural evolutionary processes.

Additional references:

Can I take this expired pill?

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While physicians may not be able to recommend the use of expired medicines, it is likely that most drugs remain effective long after the expiration date (Arch Intern Med. 2012;():1-2. doi:10.1001/archinternmed.2012.4501).

In this study, investigators identified eight long-expired medications with 15 active ingredients that were discovered unopened in original containers in a retail pharmacy.  All had expired 28-40 years prior to analysis.

12 of 14 tested drugs retained at least 90% of the labeled amounts.  The authors also note that testing of federal drug stockpiles has shown that 88% of 122 different drugs stored under ideal conditions had their expiration dates extended by more than 1 year (average was 66 months) (Biosecur Bioterror 2009; 7: 101-7).

Given the expense of medications, examining expiration dates would yield significant cost-savings.

Learning a lot from ChiLDREN (part 1)

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Several recent studies highlight the benefits of multisite collaboration to study infrequent pediatric liver problems.  In one of these, it is shown that pancreatic insufficiency (PI) is not a common problem for patients with Alagille syndrome (JPGN 2012; 55: 612-614).

In these studies, the Childhood Liver Disease Research and Education Network (ChiLDREN) collected prospective longitudinal observational date from multiple centers, 16 in this study.

150 subjects who met criteria for Alagille syndrome were enrolled between December 2007 to September 2010.  42 had fecal elastase results available.  Elastase results were characterized as normal if >200 μg/g, indeterminant if 100-200 μg/g, and pancreatic insufficient if <100 μg/g.

  • 40/42 (95%) had normal results
  • 2/40 (5%) were indeterminant

The collaborative study provides a few teaching points:

  1. Fecal elastase is a very reliable tool for detecting exocrine PI with a 99% negative predictive value for ruling out PI.
  2. Previous results suggesting that PI was common in Alagille syndrome were flawed due to the fallibility of previous secretin stimulation testing and due to the occurrence of steatorrhea induced by impaired bile salt secretion

Previous related posts:

Vaniprevir for HCV

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Vaniprevir (MK-7009) is a hepatitis C virus (HCV) NS 3/4A protease inhibitor.  A phase II study has shown that vaniprevir can be an effective agent in combination with pegylated interferon alpha-2a (PEG-IFN) and ribavirin (RBV) (Hepatology 2012; 56: 884-93).

This double-blind, placebo-controlled study examined 94 patients with treatment-naive genotype 1 HCV.  In combination with PEG-IFN/RBV, patients received either placebo, vaniprevir 300 mg BID, 600 mg BID, 600 mg QD or 800 mg QD for 28 days & then open-label PEG-IFN/RBV for 44 weeks.  There were 18-20 patients in each group.

With all of these vaniprevir doses, there was a rapid two-phase decline in viral load; the HCV RNA level was approximately 3log10 IU/mL lower in vaniprevir-treated patients than placebo.  Rapid viral response occurred in 68.8-83.3% of vaniprevir-treated patients compared to 5.6% of control patients.  Sustained virologic response was higher but did not reach statistical significance.

Resistance to vaneprevir with variants at R155 and D168 was detected in a small number of patients.  The authors note that treatment outcomes were not related to interleukin-28B genotype.

The potential advantage of vaneprevir over currently available triple therapy agents (eg. telaprevir and boceprevir) would be easier administration, QD or BID, and possibly more favorable side effect profile.

Take home message: more treatment options, including vaneprevir, for HCV are on the horizon.

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Testing worm therapy for chronic diarrhea/IBD in Monkeys

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Today’s blog is an excerpt from BBC News (Thanks to Ben Gold for the tip).  The full link:

BBC News – Parasitic worms ‘treat diarrhoea‘

“Chronic diarrhoea could be treated using parasitic worms, a study of monkeys has suggested. Research published in PLOS Pathogens, suggests the treatment restores gut bacteria to a healthy state. Other work in mice has already suggested conditions such as ulcerative colitis could be treated in this way. A UK expert said parasitic worms were being investigated for a range of conditions, including multiple sclerosis and allergies.”

Captivity

“Inflammatory bowel diseases, like colitis, are often fuelled by a wrongly targeted response by the immune system to gut bacteria. Such diseases are more common in developed countries – and scientists suggest this is because people in developing countries have more exposure to parasitic worm (helminth) infections and therefore have a natural protection that has evolved as people and worms learnt to co-exist.


Recent studies have used parasitic worms to successfully treat inflammatory bowel disease in humans, but it is unclear exactly how they do this.

This latest study looked at monkeys because young macaques kept in captivity often develop chronic diarrhoea that can be hard to treat. Five macaques with diarrhoea were treated with parasitic worms called whipworms. Tissue samples were taken before and after treatment and it was found the balance of gut bacteria was restored to required levels. And four out of five animals had less diarrhoea and started to gain weight.

Dr P’ng Loke, of the New York University Langone Medical Center, who led the study, said: ‘The idea for treating colitis with worms is not new, but how this therapy might work remains unclear.  Our findings suggest that exposure to helminths may improve symptoms by restoring the balance to the microbial communities that are attached to the intestinal wall.’

The researchers now plan a study in humans to look at how pig helminth eggs might help alleviate the symptoms of colitis.

Compensating

Prof Graham Rook, of the centre for clinical microbiology at University College London, said a number of research teams were investigating the effects of parasitic worms in various conditions. ‘This is not part of the hygiene hypothesis [which says exposure to bacteria strengthened the immune system]. It’s the “old friends” hypothesis. We co-evolved with these things, so they had to be tolerated. We found ways of suppressing the immune systems, and in some way have come to depend on them.’ And he said the field of research as a whole would be “hugely significant”.  He added: ‘With helminths, if you get the dose right, you can probably live with worms and not have symptoms. But it may well be there is going to be a battery of molecules you could be dosed with to compensate for not meeting our “old friends”.’

THE WONDER OF WORMS

  • Parasitic worms are “old friends” and humans have lived with them for as long as we have existed.
  • And while people in developing countries still do so – and have low levels of inflammatory disease, the opposite is true in developed countries.
  • It appears our immune systems came to rely on parasitic worm infections as part of the way our body defended itself.
  • And when they are no longer there, it appears that may upset our immune systems.
  • Now researchers are looking at how the worms’ effects can be harnessed to treat conditions ranging from multiple sclerosis to allergies.
  • Hookworms and pig whipworms are amongst those being investigated.
  • Results are promising.
  • But those squeamish about dealing with worms or their eggs may not have to worry – it is more likely drugs will be developed that mimic their effects.”

Additional references:

  • -Gastroenterol 2012; 142: 55.  Helminth infection (with enterobiasis) did not reduce risk of IBD in large population-based study (924,000 Danish database).
  • -Gastroenterol 2005; 128: 825. Trichuris suis for UC. 43% improved vs 17% of placebo. Only mildy effective.
  • -Gut 2005; 54: 87-90. Trichuris suis for Crohn’s
  • -Gastroenterol 2005; 129: 768-69. (letter re safety)
  • -NEJM 2010; 363: 1476-78. Interactions between Helminths and immunogenicity.

Missing “C”

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Ascertainment rates for pediatric hepatitis C virus (HCV) are as bad as in adults with HCV (J Pediatr 2012; 161: 915-21).

As noted in previous blog entries, it has been recommended by the CDC that adults born between 1945-65 undergo a one time screening for HCV due to the high frequency of undetected cases along with improvements in therapy.  The same rationale may apply to children in the near future as some of these therapies are shown to be safe and effective in the pediatric population.

In the meanwhile, it is apparent that most pediatric HCV cases remain undetected.  In the aforementioned study, the investigators examined statewide data from Florida and data from health departments across the United States.  This was compared with data from NHANES III which reported HCV prevalence of 0.2% in children 6-12 years old and 0.4% of 13-18 year olds.  The absolute prevalence may be higher as NHANES did not capture some populations at high risk, like homeless or incarcerated youth.

Results:

  • From 2000-2009, only 2007 children were identified as HCV-antibody positive in Florida.  During this period, it is estimated that this represents about 12% of the expected number of cases (n=12155).
  • In Dade county which has 13 pediatric gastroenterologists, 100% responded to an online questionnaire.  They reported caring for 31 cases of HCV in 2009 and another 55 in the preceding 5 years.  This indicates that 1.6% of the expected number of HCV-antibody-positive children in this region received care in 2009 and 2.8% over previous 5 years.
  • Nationwide, only two states (VT, MA) identified more than 20% of expected cases.

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Mechanisms of irritable bowel syndrome

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An excellent succinct review of the various peripheral mechanisms of irritable bowel syndrome (IBS) has been published (NEJM 2012; 367: 1626-35).  Understanding these mechanisms is crucial in developing and targeting appropriate therapy.

Peripheral factors affecting IBS (Table 1 in review):

  1. Colonic motility –affects up to 45% of diarrhea-predominant IBS and 25% of constipation-predominant IBS.  Specific factors include enteroendocrine cell products (eg. 5-HT, granins), organic acids (eg. bile acids, short chain fatty acids [SCFAs]) impaired bile acid synthesis.
  2. Colonic motor and sensory response to food ingestion. Factors like fat content of meal can contribute to pain, urgency and diarrhea.
  3. Sensing responses in small bowel and colon.  Food stimulation of enteroendocrine cell products may trigger diarrhea, bloating and pain.
  4. Colonic mucosal permeability.  This may lead to malabsorption of carbohydrates or fats and subsequently increased levels of SCFAs.  Also, could trigger immune activation and altered feedback of bile acid synthesis.
  5. Mucosal immune activation.  Previous gastroenteritis along with mast cells, T lymphocytes, and circulating cytokines may be involved factors.
  6. Colonic microbiome.  There may be increased types of some bacteria (eg. firmicutes).  Antibiotics and probiotics could influence the microbiome. Fermentable oligosaccharides, disaccharides, and polyols (FODMAPs) are a group of foods that may trigger IBS symptoms, possibly due to a relationship with the colonic microbiome.

With regard to gluten intolerance, the author notes that the prevalence of celiac disease among IBS is similar to that among controls; however, a subgroup of individuals with diarrhea-predominant IBS respond to a gluten-free diet.

Some genetic factors have been identified which can contribute to IBS:

  • mutation in the guanylate cyclase C secretory pathway
  • mutations that increase the risk of postinfectious IBS
  • genetic variability in bile acid synthesis
  • variation in expression of neurotransmitters and cytokines

Towards the end of the review, the author notes that “IBS is no longer regarded as an idiopathic bowel dysfunction” due to stress.  The specific factors that have been identified will likely be further defined and likely lead to more specific individualized therapy.  Potential treatments:

  • diets -including gluten-free and FODMAPs
  • bile acid sequestrants and 5-HT3 antagonists
  • prokinetics or secretagogues in patients with constipation-predominant IBS
  • probiotics and non-absorbed antibiotics
  • antiinflammatory agents
  • tignt-junction modifiers
  • biofeedback

Previous related blog entries:

Additional references:
  • -J Pediatr 2009; 155: 416.  n=43 children & 56 control pts.  High incidence of abnormal lactulose (65%) breath test with IBS but not control pts (7%).  (lactulose 10g given in 20mL)
  • -Gastroenterol 2009; 137: 766.  Notes relatively weak data supporting use of antispasmotics, probiotics, and antidepressants for IBS.
  • -Am J Gastroenterol 2010; 105: 859-865.  n=466 & 451 controls.  IBS pts with lower incidence of adenomas (7.7.% vs 26%).  9% had diverticulosis (lower).  Microscopic colitis present in 1.5%.
  • -Gastroenterol 2002; 123: 2105-07. & 2108-2131. AGA guidelines for IBS
  • -Gastroenterol 2007; 133: 799.  Natural hx of functional disorders: 20% persist w same Sx, 40% develop other Sx, 40% get better.  Large study from Olmstead county (n=1365)
    • -Clin Gastro & Hep 2005; 3: 397.  managing pts c severe IBS; advocates low dose tricyclics..
  • -Am J Gastro 2003; 98: 412-9.  use of neomycin for SBBO in IBS (43% response). 84% IBS pts c abnl lactulose vs 20% placebo
  • -Gastroenterol 2003; 124: S1152.  only 4 of 33 IBS pts had abnl jejunal samples
  • -J Musculoskel Pain 2001; 9:107-113.  78% of fibromyalgia pts c abnl BHT.

Neonatal cholestasis and Down syndrome

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A retrospective Swedish study adds some useful information on the incidence of neonatal cholestasis with Down syndrome (J Pediatr 2012; 161: 899-902).

In this retrospective study of all neonates born between January 2005-September 2011 in Stockholm , a total of 206 newborns were identified as having Down syndrome.  This represents an incidence of 1 in 880 newborns.

  • 3.9% (n=8) had cholestasis
  • 47% (n=96) had congenital heart disease
  • 11.2% (n=23) had GI disorders: duodenal stenosis (n=7), duodenal atresia (n=4), omphalocele (n=3), Hirschsprung disease (n=2), esophageal atresia/duodenal atresia (n=1), jejunal atresia (n=1), and other conditions (n=5)
  • 3.4% (n=7) had bone marrow diseases including transient abnormal myelopoiesis

All eight children with cholestasis had congenital heart disease.  However, severe cholestasis was only seen in the 3 patients with concomitant bone marrow disease. Two of these patients died and one developed cirrhosis/chronic liver disease. All cholestatic patients had involvement of other organ systems.  As this was a retrospective study, some milder cases of neonatal cholestasis may not have been detected.

In children with concomitant bone marrow disease, neonatal cholestasis may forebode an increased risk for severe disease.  While all 3 of the newborns with severe disease also had congenital heart disease, most infants with combined congenital heart disease/cholestasis (n=5) did not have a severe case.

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Six year outcomes with bariatric surgery

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Recently I read that suicides were increased in a group of individuals who underwent bariatric surgery.  This piqued my interest in finding the reference (JAMA 2012; 308: 1122-31 -21 authors).

This Utah study was a prospective trial between 2000-2011 involving 1156 severely obese participants between 18-72 years of age.  There were 3 groups.  The treatment group of 418 underwent Roux-en-Y gastric bypass (RYGB).  The second group (control group 1 =CG1) sought bariatric surgery but did not have surgery, and the third group (control group 2 =CG2) were a randomly selected population-based sample.

All participants had BMI ≥35.  RYGB group had average BMI of 47.3, CG1 was 46.3 and CG2 43.8.  The respective average age was 42.5, 43, and 49.4 years.  In CG1, 84 had undergone bariatric surgery by six years; in CG2 17 had undergone bariatric surgery by six years.

Results at six years:

  • Weight loss: RYGB (92.6% retained at followup): 27.7% loss of initial body weight; CG1 (92.6% followup) 0.2% weight gain, and 0% in CG2 (98% followup)
  • Diabetes remission rate: RYGB 62%, CG1 8%  and CG2 6%.  In addition, there was a 5- to 9-fold reduction in the risk of new diabetes in surgical patients compared to nonsurgical controls.
  • Mortality: No improvement in mortality was evident at six years.  RYGB 12 deaths, CG1 14 deaths  and CG2 3 deaths. None of the RYGB deaths occurred within 30 days of surgery.
  • Suicide:  all 4 patients who took their own life were in the RYGB group and 2 of 3 poisonings (undetermined intention) were in the RYGB group as well.
  • Mental health: The authors note an absence of improvement in the SF-36 mental component score in the surgical group which is in contrast to the SF-36 physical component score.
  • Glucose/insulin, Lipids & Blood pressure: Marked improvements in all of these parameters were noted at six years (Table 2).

It appears that much longer followup will be needed to show mortality benefits from bariatric surgery* and that preoperative/postoperative psychological assessment is needed.

* Mortality benefit has been evident in some studies (see references below)

Related blog entries:

References:

  • -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.

Complications from surgery:
Early: bowel obstruction, DVT, GI bleed, leaks, pul 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)
Suggested Nutrient Monitoring–every 3 months x 3, then yearly: Vitamin A, B12, Folate, Ceruloplasmin, Vit D-25OH, Iron studies, Zinc, thiamine, Selenium, Intact PTH, Mg, PT/PTT
Suggested supplements per references: Calcium c vitamin D 1200mg, Iron, MVI with zinc/selenium
Also if duodenal switch, add Vitamin A and Vitamin D3 1200units daily or 50,000 units weeekly

Supplements:
Roux-en-Y: MVI 200%, Calcium 1500-2000mg, Fe at least 18-27mg/day, B complex (optional)
Gastric Band: MVI, Calcium, B complex (optional)
Biliopancreatic/duodenal switch: MVI, ADEK: A 10,000 IU, D 2000 IU, K 300 mcg, Calcium, Fe, B complex

  • –NASPGHAN 2011:

Bariatric surgery:
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

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

  • -NEJM 2009; 361: 445/520. perioperative safety.
  • -NEJM 2007; 357: 741, 753, 818. Bariatric surgery improves mortality rate.
  • -NEJM 2007; 356: 2176. Review
  • -Gastro 2006; 130: 1848, 1564, 1617. Bariatric surgery frequently improves steatosis/NAFLD. Less improvement if ongoing insulin resistance.
  • -J Pediatr 2005; 147: 10-19. Review of bariatric surgery. suggests gastric bypass/gastric banding for adolescents.
  • -Pediatrics 2004; 114: 217-23, & 252, 253, 255. Consensus panel recommendations and commentary.

Note: Medication dosages should be checked in standard references for individual patients.  The blog may have transcription errors with regard to dosages listed with references.

Azathioprine metabolite measurement for Autoimmune Hepatitis

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While obtaining azathioprine (AZA) metabolite levels in inflammatory bowel disease has proven clinical utility, there is less data with regard to autoimmune hepatitis (AIH).  Now a study of 70 adults with AIH reports that therapeutic levels of 6-thioguanine (TGN) (>220 pmol/8 x 10 to the 8th) are associated with remission (Hepatology 2012; 56: 1401-8).

Patients in this study had an average age of 61 years; the average participant had a diagnosis of AIH for 8 years at the start of the study. For induction of remission, patients had received a combination of prednisolone along with AZA.  AZA was started at 1 mg/kg/day and gradually increased to 2 mg/kg/day.  All patients had a complete response to steroids prior to AZA dose escalation.

Outcome from this study was characterized by ability to maintain remission with ALT <33 IU/L and/or relapse which was indicated by ALT >2 x ULN (upper limit of normal) or liver histology showing active disease.

Serial measurements of red blood cell TGN and methylmercaptopurine nucleotides (MeMPNs) were obtained over two years.

Results:

  • 53 patients maintained remission and 17 did not.
  • Those in remission tended to be receiving lower doses of AZA (1.7 vs 2 mg/kg/day) but had higher average TGN levels (237 vs 177 pmol/8 x 10 to the 8th)
  • TGN levels >220 pmol/8 x 10 to the 8th best predicted remission
  • There was no measurable difference in thiopurine methyltransferase (TPMT) activity between the two groups (remission vs relapse).
  • Two patients developed cholestasis and this was associated with high MeMPN levels.

The authors note that several previous studies did not demonstrate a relationship between TGN levels and efficacy.  This is likely related to patient selection (all in remission at start in current study), repeated TGN levels, and the definition of remission.

Conclusion: Obtaining metabolites in adherent patients may be beneficial in patients with active disease to assist with dose modification and in individuals with potential AZA toxicity.

Related blog entries: