Category Archives: Uncategorized

Immunoglobulin deficiencies with DiGeorge Syndrome

Posted on by

I participate in a Children’s Healthcare of Atlanta multidisciplinary clinic to help provide care for children with DiGeorge syndrome/22q deletion.  As such, I am interested in a range of issues in these patients.  A recent discovery has been that humoral immunity and not just T-lymphocyte immunodeficiency occurs in a significant number of patients with DiGeorge syndrome (J Pediatr 2012; 161: 950-3).

A cohort of 1023 patients were identified from a number of registries that spanned 21 countries and 40 different contributors. Among this group, 3% were receiving immunoglobulin therapy and 6% over the age of 3 years had hypogammaglobulinemia (IgG <500 mg/dL).

Additional references/resources:

  • –Growth charts for 22q: http://www.22q.org/index.php/growth-charts
  • -J Pediatr 2011; 159: 332. 22q guidelines.
  • -J Pediatr 2009; 155: 560. n=64. 22q11.2 deletion found in <60% of DiGeorge Anomaly pts. DiGeorge Anomaly =(at least 2): congenital heart dz, immune deficiency, hypocalcemia. Also, 86/121 with deletion do not fulfill requirement of anomaly (“syndrome”).
  • -Mol Syndromol. 2011 January; 1(4): 192–209. “Introduction: The 22q11.2 deletion syndrome is increasingly recognized in pediatric patients with an incidence of approximately 1 in 3,000. GI manifestations are common and can impact significantly on feeding and growth. To date, there have been few papers on feeding disorders and isolated case reports of various GI anomalies. Methods: A retrospective chart review was conducted on 766 patients with confirmed 22q11.2 deletions followed in the 22q and You Center at CHOP. Data abstracted included GI symptoms, evaluation and management. Results: Average age was 15 years (0.2–62 years). Male:female ratio was 1:1. Ethnic distribution was predominantly Caucasian (67%), Hispanic (33%) and African-American (10%). 32% of patients had no GI symptoms. In patients with GI symptoms, nasopharyngeal reflux, feeding problems, gastroesophageal reflux and constipation were common. Diagnoses included dysmotility (27), intestinal malrotation (7), esophageal diverticula (5), gastroparesis (5), rectal prolapse (2), esophageal atresia (2), gallstones (2), imperforate anus (1), tracheo-esophageal fistula (1), pyloric stenosis (1), choledochal cyst (1), Hirschsprung’s disease (1), and celiac disease (1). About 27% of patients underwent GI testing. Upper GI series and modified barium swallowing study were frequently performed. 5% of patients underwent fundoplication. Feeding tubes were common (27%). Conclusions: Significant GI manifestations are frequent in patients with the 22q11.2 deletion syndrome. Clinicians need to be aware of these conditions to avoid delays in diagnosis. Moreover, all patients with GI symptomatology will benefit from evaluation with a gastroenterologist.”
  • -Pediatrics 2003; 112: 101.n=43; 1 in 5950 births. phenotype in 43 pts
  • -JPGN 2002; 35: 423 (56 Abstract) DiGeorge syndrome GI manifestations; 6 of 46 c malrotation, dysmotility in 7
  • -J Pediatr 2001; 139: 715. DiGeorge immunologic features.

22q Deletions Resources for Families

SUPPORT GROUPS & WEB RESOURCES

  1. 22Q Foundation

  2. DiGeorge syndrome – Wikipedia, the free encyclopedia

  3. Welcome to the Velo-Cardio-Facial Syndrome (VCFS) Educationa

  4. DiGeorge Syndrome – American Heart Association

  5. Living with 22Q – Dempster Family Foundation

  6. Friends of Quinn | Blog | Quinn Bradlee

EDUCATIONAL RESOURCES:

Monitoring TNF antagonists in inflammatory bowel disease

Posted on by

Previously, this blog has discussed the use of drug monitoring in inflammatory bowel disease (Drug levels for inflammatory bowel disease | gutsandgrowth).  A good review of this topic has been published recently (Clin Gastroenterol Hepatol 2012; 10: 1079-87).

Some of the useful pointers:

  • Factors that influence clearance of TNF antagonists are reviewed:
  1. Antidrug antibodies (ADA) increase clearance and worsen outcomes
  2. Use of concomitant immunosuppressives reduces the likelihood of ADA formation and increase drug concentration.   In the SONIC trial, use of azathioprine was associated with trough infliximab (IFX) levels of 3.5 μg/mL compared with 1.6 μg/mL with monotherapy.  Also, ADA was reduce: 0.9% compared with 14.6% in the monotherapy group. [Other studies though have found variable effects of cotherapy.]
  3. Low serum albumin and high CRP are associated with increased drug clearance
  4. Individuals with high body size and males are more likely to have increased drug clearance.
  • Better assays for measurement of IFX and adalimumab (ADL) are now available.
  • Currently a trial evaluating trough levels is underway: Trough Level Adapted Infliximab Treatment (TAXIT).  With this study, the accepted target range for trough levels is 3-7 μg/mL.  Levels >7 μg/mL are considered supratherapeutic and allows for a prolongation of dosing interval.  Preliminary data confirm that trough levels inversely correlate with CRP.
  • Proposed algorithm in individuals with loss of response & positive ADA.  If ADAs present at high titer, then switch to different TNF antagonist.  If low  titer, could either switch or attempt drug escalation.
  • With IFX, when antibodies to infliximab (ATIs) are present, the likelihood of responding to increased dose is less than 20% whereas changing to different TNF antagonist has about an 90% response (in patients who were previous responders).
  • Proposed algorithm in individuals with loss of response & negative ADA.  If subtherapeutic trough levels (IFX ❤ μg/mL, ADL <8 μg/mL, or certolizumab <27.5 μg/mL), then dose escalation is worthwhile.  If drug levels are therapeutic, then dose escalation will not be effective.
  • With IFX, more than 85% of patients will respond to drug escalation when the trough level is subtherapeutic. This is much more favorable than switching agents.
  • One other issue with ADAs is that they may be transient is some patients.  Perhaps one-fourth of ATIs may be transient which may explain why some individuals with ATIs may still respond to dose escalation.

These points give several reasons why drug monitoring is useful in individuals with loss of response and may help determine whether patients responding to therapy may be able to prolong dose intervals.  At the same time, when an individual is not responding to therapy, it is also important to determine if in fact active inflammation is present with objective markers and to consider alternative explanations for GI symptoms (eg. Clostridium difficile infection, irritable bowel, bacterial overgrowth, etc.).

Related blog entries:

Only one chance to make first impression | gutsandgrowth

When nothing else is working | gutsandgrowth

Infliximab for children with Ulcerative Colitis | gutsandgrowth

Adalimumab for children with Crohn’s disease | gutsandgrowth

CHOOSE TNF TRIAL | gutsandgrowth

Reliability of colonic manometry

Posted on by

As noted in a previous blog entry (Gastroesophageal Reflux: I know it when I see it | gutsandgrowth), it is often surprising how variable test result interpretation can be in the hands of experts.  The most recent example of this is with colonic manometry (JPGN 2012; 55: 548-51).

In the current study, 57 colonic motility studies were independently reviewed by 5 experts. The youngest and least experienced was 45 years old with 8 years of experience.  The oldest and most experienced was 63 years old with 28 years of experience.

Unanimous differentiation of normal and abnormal motility studies was present in 69%.  In 81% of the studies, 4 of 5 were in agreement about whether the study was normal.

Specific measurements noted the following:

  • Fairly high degree of agreement with fasting high-amplitude propagating contractions (HAPC): 66% with unanimous agreement,  and 82% with at least 4 of 5 observers in agreement.
  • The gastrocolonic response had the most inconsistency with only 19% in unanimous agreement and 45% with at least 4 of 5 in agreement.
  • The postprandial measurements were reported to be useful in only 3-24% of the studies.

Colonic manometry studies “require interpretation of a complex visual bowel motility pattern and are subject to interpretation bias.” One proposal by the authors of the study would be to limit colon motility studies to 60 minutes followed by bisacodyl stimulation.  Further studies will be necessary to determine whether this will improve the reliability of colonic manometry interpretation.

Related blog entries:

Learning a lot from ChiLDREN (part 2)

Posted on by

As noted in previous post (Learning a lot from ChiLDREN (part 1) | gutsandgrowth), several recent studies highlight the benefits of multisite collaboration to study infrequent pediatric liver problems.  In these studies, the Childhood Liver Disease Research and Education Network (ChiLDREN) has collected prospective longitudinal observational date from multiple centers; data from 10 centers provides useful information on the frequency of portal hypertension (PHT) in young adults with biliary atresia (BA) (JPGN 2012; 55: 57-73).

163 subjects were enrolled between May 2006 and December 2009.  Seven patients were excluded due to the presence of polysplenia which interferes with the assessment of PHT.

Demographics: subjects ranged in age from 1 to 25 years with a mean of 9.2 years.  56% were female, 75% were caucasian.

PHT was considered definite if there was either a history of a PHT complication (variceal bleeding, ascites) or if there were clinical findings c/w PHT (both splenomegaly and thrombocytopenia).  PHT was considered “possible” if either splenomegaly or thrombocytopenia was present and “absent” if no criteria were met.

  • PHT: definite in 80 (49%), possible in 27 (17%) and absent in 56 (34%)
  • 43 subjects had a history of PHT complications: 32 with esophageal variceal (EV) bleeding, 14 with ascites, and 8 with hepatopulmonary syndrome.
  • Of the patients with EV, only 3 had normal platelet count and normal spleen size.

Teaching points:

  1. One-third of subjects with EV bleeding survived with their native liver for at least 5 years.
  2. EV age of onset was highly variable; 7 had bleeding in the first two years of life.
  3. Growth parameters were fairly unremarkable in those with definite PHT.
  4. Long-term followup will be needed to identify factors which predict progression of PHT and the development of adverse outcomes.

Previous related blog posts:

Can I take this expired pill?

Posted on by

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)

Posted on by

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:

Testing worm therapy for chronic diarrhea/IBD in Monkeys

Posted on by

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.

Risk of pancreatitis with celiac disease

Posted on by

More data on the risk of pancreatitis in the setting of celiac disease has been published (Clinical Gastroenterol Hepatol 2012; 10: 1136-1142).

In this medical records review study, 28,908 patients in Sweden with biopsy-proven celiac disease (1969-2008) were compared with a control population of 143,746 to determine the risk of pancreatitis due to celiac disease. The median age at study entry was 30 years and included patients as young as 10 years.

Among these cohorts, 406 pancreatitis patients with celiac disease were identified.  The expected number would have been 143, yielding a hazard ratio of 2.85.  The risk for any type of pancreatitis within 5 years of diagnosis was 2.76.  All types of pancreatitis were increased including acute pancreatitis with gallstones, non-gallstone acute pancreatitis, and chronic pancreatitis.

What are potential reasons for this association between pancreatitis and celiac disease?

  1. Malnutrition may impair pancreas function
  2. Associated papillary inflammation could increase risk of acute pancreatitis
  3. The two diseases may share immunologic characteristics that increase the risk of both disorders
  4. Elevated levels of asymptomatic pancreatic enzymes could lead to some false-positive cases

Related blog entries:

How new therapies impact colectomy in UC patients

Posted on by

Has the need for colectomy changed with the increasing use of more potent medical therapies for ulcerative colitis (UC)?  One article gives some insight into this question (Inflamm Bowel Dis 2012; 18: 1641-46).

This French study followed 151 patients with newly diagnosed UC from 2000-2008; median followup was 58 months. During this time, 21 patients (14%) underwent colectomy.  1.3% required colectomy in the first year following diagnosis.

Looking closer at their study, 55% of patients had pancolitis.  Cyclosporin usage, typically given in refractory cases, was the only medication determined to be a predictive factor for surgery.

Medication usage during study period:

  • 68% oral mesalamine products
  • 72% systemic corticosteroids
  • 7% methotrexate
  • 49% azathioprine
  • 9% cyclosporin
  • 30% had received at least one anti-TNF agent

The authors concede several limitations, including the evolving nature of UC treatment.  Yet, they conclude that colectomy still is frequently needed and the use of IBD medications, including anti-TNF, “does not appear to reduce the long-term need for surgery in UC.”

I take issue with the last sentence.  Whether anti-TNF agents prove to be a disease-modifying treatment over the long-term is not known.  In this particular cohort, only 30% were even exposed to these agents.  My conclusion: we need a study designed to answer the question.  This would require larger numbers of patients followed prospectively for many years.

Related blog entries:

Itchy and Scratchy

Posted on by

On TV’s “The Simpsons,” “Itchy” is a sadistic blue mouse and “Scratchy” is a hapless black cat (The Itchy & Scratchy Show – Wikipedia, the free encyclopedia, The Simpsons – Itchy and Scratchy – YouTube).  In real life being real itchy is not a joke; it is a common problem with cholestatic liver disease.  Beneficial treatments for pruritus may be partly due to their effects on serum autotaxin (Hepatology 2012; 56: 1391-1400, editorial 1194).

In this study, blood was drawn from different treatment groups:

  • 17 patients receiving colsevelam (a bile acid sequestrant)
  • 10 patients receiving MARS (molecular absorbance recirculating system)
  • 6 patients receiving rifampicin
  • 5 patients receiving nasobiliary drainage
  • Also, autotaxin levels were drawn from healthy controls, atopic dermatitis, Hodgkin’s disease (with and without pruritus), uremic patients, and cholestatic patients without pruritus

The most common diagnosis in all of the cholestatic groups was primary biliary cirrhosis; though some patients had primary sclerosing cholangitis, progressive familial intrahepatic cholestasis, benign recurrent intrahepatic cholestasis or other liver disorders.

Key findings:

  • Serum autotaxin is increased in pruritic cholestatic liver patients but not in other forms of pruritus.  In addition, autotaxin is normal in cholestatic patients without pruritus.
  • The level of autotaxin correlates closely with the effectiveness of the treatment as gauged by itch intensity

The reasons for pruritus in cholestasis have not been clear.  Several theories have been advanced regarding pathogenesis.  Specifically, retained bile acids and increased opiate activity have been thought to play a role.  More recently, lysophosphatidic acid (LPA) levels have been noted to be elevated in the serum of patients with cholestatic itch.  Injection of LPA into mice results in scratching activity.  LPA activity is a consequence of autotaxin.

Other important points:

  1. Rifampicin has been shown to reduce autotaxin levels in vivo.
  2. MARS and nasobiliary drainage do not directly drain autotaxin; their effects on autotaxin must result by eliminating another factor which stimulates autotaxin production.
  3. Autotaxin is likely to be a useful objective biological marker for pruritus and to evaluate potential novel treatments.
  4. Autotaxin elevation can occur in other noncholestatic inflammatory disease in which pruritus is not a feature; thus, the reasons for pruritus are likely multifactorial and not due to a simple causal role for autotaxin.

Related blog entries:

Challenges with primary sclerosing cholangitis | gutsandgrowth

BRIC, PFIC, and nasobiliary drainage | gutsandgrowth

Additional references:

  • -J Hepatol 2009; 51: 237-67.  EASL practice guidelines on mgt of cholestatic liver disease
  • -JPGN 2010; 51: 787.  Use of naltrexone in severe pruritus due to cholestasis: 1-2/kg/day. n=4.
  • -JPGN 2008; 46: 241.  Excellent review.  BRIC caused by FIC1 mutations (same as PFIC1).  Nasobiliary drainage of bile may be helpful.
  • -Hepatology 2007; 45: 666.  Use of sertraline (75-100mg; start with 25mg –in adults)
  •  -Clin Gastro & Hep 2007; 5:776 Use of zoloft for pruritus in cholestasis.
  • -Hepatology 2005; 42: 222. summary of cholestasis workshop
  • -JPGN 1999; 29: 442.  Rifampin treatment for cholestasis. 90% response, 40% complete response.  Extrahepatic cases c much better response.  No toxicity observed.
  • -Clin Liver Dis 2006; 10: 27-53.

Gene:                       Disorder (protein)

  1. ABCB11                     PFIC 2, BRIC 2 (BSEP)
  2. ABCB4                       PFIC 3, ICP (MDR3)
  3. CFTR                         CF (CFTR)
  4. ATP8B1                      PFIC1 -Byler’s (FIC1), BRIC, GFC -Greenland Familial
  5. CLDN1                       NISCH (Claudin 1) -neonatal sclerosing cholangitis/icthyosis VPS33B                     ARC syndrome (Vascular protein sorting 33) -arthrogryposis-   renal dysfn-cholestasis, low GGT
  6. AKR1D1                    BAS: Bile acid synthetic defect: neonatal cholestasis with giant cell hepatitis   (5Beta-reductase)
  7. HSD3B7                    BAS (C27-3Beta-HSD)
  8. CYP7BI                     BAS (CYP7BI)
  9. TJP2 (ZO-2)              FHC: Familial hypercholanemia (tight junction protein)
  10. BAAT                        FHC (BAAT)
  11. EPHX1                     FHC (epoxide hydrolase)
  12. JAG1                        Alagille (JAG1) JAG1 is transmembrance cell-surface protein important in   regulating cell fate during embryogenesis
  13. PKHD1                     ARPKD (fibrocystin -important in ciliary function and tubulogenesis)
  14. PRKCSH                  ADPLD (hepatocystin)
  15. ABCC2                     Dubin-Johnson syndrome (MRP2)
  16. CIRH1A                    NAIC -N Amer Indian childhood cirrhosis (Cirhin)