Liver Disease in Joubert Syndrome

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A recent NIH study (A Strongin et al. JPGN 2018; 66: 428-35) provides prospectively-collected data from 100 individuals (mean age 9.1 years) with Joubert syndrome (JS). ( of the patients were >20 years old.

Background: JS is classified as a ciliopathy as mutations in JS genes result in nonmotile cilia.  Clinical features in this autosomal recessive condition include the following:

  • MRI finding of a “molar tooth sign” caused by cerebellar vermis hypoplasia, horizontally-oriented cerbellar peducles, and a deep interpeduncular fossa
  • Ocular features: retinal dystrophy, colobomas
  • Renal: nephronophthisis, polycystic kidneys
  • Skeletal abnormalities including polydactaly
  • Hepatic: congenital hepatic fibrosis (CHF).  CHF typically causes noncirrhotic portal hypertension and generally maintain synthetic function and do not progress to cirrhosis

Study Key Findings:

  • 43 (43%) had liver involvement indicated by elevated liver enzymes, and/or liver hyperechogenicity and/or splenomegaly
  • 13 (13%) developed probable portal hypertension; this group had more significant elevations in alkaline phosphatase (269 vs 169), ALT (92 vs 42), AST (77 vs 40) and GGT (226 vs 51)
  • The portal hypertension group were much more likely to have TMEM67 gene mutation
  • Probable portal hypertension was associated with renal involvement (P=0.001)
  • None of the patients with JS had macrocystic liver disease (which likely indicates a low risk of cholangitis)

The authors note that previous estimates of liver disease with JS of 10-15% are likely an underestimate and that “hepatic disease becomes more noticeable later in life.” In their discussion, they describe the limitations of their study which includes ascertainment bias as their cohort may differ significantly from those who have not bee brought to the attention of the NIH.

My take: JS patients are at increased risk for hepatic disease/portal hypertension, particularly at older ages.  The optimal surveillance strategy remains undefined.

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Do Acid Blockers Given to Infants Increase the Risk of Allergic Disease?

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A recent retrospective study (Mitre E, et al. JAMA Pediatr. 2018;doi:10.1001/jamapediatrics.2018.0315) suggests that acid blockers, both histamine receptor antagonists and proton pump inhibitors increase the risk of developing allergic disease.  Since this is a retrospective study, this association with allergic diseases has NOT been proven to have a causal relationship; thus, an alternative explanation would be that infants who are likely to develop allergic diseases could be prescribed these agents more frequently due to symptoms attributed to reflux.

Here is an excerpt from a summary of this study (from Healio):  Acid-suppressor, antibiotic use in infancy tied to later allergic disease

Of the 792,130 children included in the study (49.9% female), 7.6% were prescribed a histamine-2 receptor antagonist (H2RA) and 1.7% were prescribed a proton pump inhibitor (PPI) within the first 6 months of life. Antibiotics also were prescribed for 16.6% of infants included in the study during this time. Mitre and colleagues noted that data continued to be collected on these infants for a median of 4.6 years…

When children were prescribed an H2RA, the researchers noted adjusted HRs of 2.18 (95% CI, 2.04-2.33) for food allergy, 1.70 (95% CI, 1.60-1.80) for medication allergy, 1.51 (95% CI, 1.38-1.66) for anaphylaxis, 1.50 (95% CI, 1.46-1.54) for allergic rhinitis and 1.25 (95% CI, 1.21-1.29) for asthma.

Infants who were prescribed PPIs had comparable aHRs, which the researchers observed at 2.59 (95% CI, 2.25-3.00) for food allergy, 1.84 (95% CI, 1.56-2.17) for medication allergy, 1.45 (95% CI, 1.22-1.73) for anaphylaxis and 1.44 (95% CI, 1.36-1.52) for asthma.

Mitre and colleagues also calculated the aHRs related to later allergic disease in children who were prescribed antibiotics within the first 6 months of life. They observed these rates at 2.09 (95% CI, 2.05-2.13) for asthma, 1.75 (95% CI, 1.72-1.78) for allergic rhinitis, 1.51 (95% CI, 1.38-1.66) for anaphylaxis and 1.42 (95% CI, 1.34-1.50) for allergic conjunctivitis.

My take: This study is another reminder that these agents may be more detrimental than beneficial in the vast majority of infants.

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Physician Burnout -“Hidden Health Care Crisis”

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A really good review on the topic of physician burnout: BE Lacy, JL Chan. Clin Gastroenterol Hepatol 2018; 16: 311-17.

This topic has been discussed on this blog and multiple other sites.  This reference covers a lot of ground and provides a lot of useful information.  Also, some esoteric piece of information: “The term burnout first was used in the psychology literature in 1974 by Herbert Freudenberg during his work with drug addicts. He observed that many of his patients would stare blankly at their cigarettes until they burned out.”

Three key components to burnout: emotional exhaustion, depersonalization, and decrease sense of personal accomplishment

Physicians at greatest risk: perfectionists, personal qualities of idealism, and “intense sense of responsibility”

Root causes -work stress (in all its forms)

Prevention of burnout: take care of yourself, exercise, good sleep habits, “learn to say no,” use your vacation time/disconnect

Keys to treating physician burnout:

  • “learn to balance personal and professional goals”
  • “shape your career and identify stressors”
  • “nuture wellness strategies”
  • Try to become engaged in your job
  • Work on resilence

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Liver Articles -Spring 2018

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C Sikavi et al. Hepatology 2018; 67: 847-57.  This systematic review highlights that the combination of hepatitis C virus (HCV) infection and HIV infection is no longer a difficult-to-treat population with the implementation of direct-acting antivirals (DAAs). There are similar sustained virologic responses (SVRs) among those with and those without HIV.  In clinical trials, patients with combined HCV-HIV had SVRs of 93.5-98% with DAA treatment; “real-world cohorts” had SVRs of 90.9%-98%.

MS Middleton et al. Hepatology 2018; 67: 858-72.  Using data from the prospective CyNCh trial (cysteamine for NAFLD), the authors examined MRIs for diagnostic accuracy among 169 enrolled children.  In this group, 110 (65%) and 83 (49%) had MRI and liver biopsy at baseline. MRI-PDFF (proton density fat fraction) was able to classify grade 1 steatosis from grade 2-3 steatosis with area under receiving operator characteristic curve of 0.87.  Thus, this study shows MRI-estimated PDFF has high diagnostic accuracy.

G Mieli-Vergani et al. JPGN 2018; 66: 345-60.  Position paper for Pediatric Autoimmune Liver Disease (AIH, ASC, de novo AIH after liver transplantation). This is a very useful review.  A couple of pointers from the authors:

  • “Present experience with budesonide as the first-line treatment is limited and does not appear to offer clear clinical advantage over the standard treatment”[prednisone]
  • Fecal calprotectin should be obtained to evaluate for IBD in patients with autoimmune liver disease, “even in asymptomatic children.”

JM Cotter et al. JPGN 2018; 66: 227-33. This retrospective study with 39 patients with primary sclerosing cholangitis (PSC) showed a lack of correlation between liver tests and fibrosis at presentation.  Average age of PSC diagnosis was 11.2 years, 74% had inflammatory bowel disease and 51% had autoimmune hepatitis. Related blog post: Big Pediatric PSC Study (with 781 children)

Interchangeability, Immunogenecity and Infliximab Biosimilars

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A recent study (G Fiorino et al. IBD 2018; 24: 601-6, editorial by KH Katsanos et al 465-6) provides more data on “full interchangeability” in regards to infliximab (IFX) and biosimilars CT-P13 and SB2. Full abstract below.

Key finding in study:

  • Antibodies to infliximab (ATI) cross-reacted with any type of IFX or IFX-biosimilar

Points from the editorial:

  • “The landmark NOR-SWITCH randomized controlled trial showed that 1-time switching from RMC [Remicade] to CT-P13 is not inferior to continued treatment with the infliximab originator…there are no data regarding multiple switches…Consequently, cross-switching (switching between 2 biosimilars), reverse switching (switching from biosimilar to its originator) or multiple/repeated switching is not currently recommended.”
  • This study, however, shows that “if you have already developed antibodies to 1 infliximab product, there is no point in switching to another infliximab product.”

Abstract:

Background: Infliximab (IFX) biosimilars CT-P13 and SB2 have comparable efficacy, safety, and immunogenicity to the originator Remicade (RMC). However, concerns about cross-switching patients between the 3 brands were raised in the absence of cross reactivity data between them. We aimed to determine whether antibodies to infliximab (ATI) in inflammatory bowel disease (IBD) patients cross-react with RMC, CT-P13, and SB2.

Methods: Based on previous ATI status, samples from 34 patients participating in the BIOSIM01 study (13 RMC, 9 CT-P13, and 12 switchers) were selected. Patients were treated with either RMC only, or CT-P13 only, or with RMC switched to CT-P13. Additionally, 28 IFX-naïve patients were assayed as controls. In total, 180 samples were analyzed. ATI trough levels were measured in parallel with 3 different bridging Enzyme Linked Immunosorbent Assays constructed using the 3 drugs. Spearman’s coefficient and percentages of agreement were used to study the correlation between each assay.

Results: In total, 76 samples out of 152 IFX-treated patient samples were ATI-positive (30 RMC, 14 CT-P13, and 32 switchers). All resulted ATI-positive when either CT-P13 or SB2 bridging assays were used. The overall percentage of agreement was 100% when compared either with CT-P13 or SB2 assays. No significant differences were found among ATI levels and coefficients (Spearman’s 0.98 to 1.0, P < 0.0001).

Conclusions: ATI of RMC-treated, CT-P13-treated or RMC to CT-P13 switched patients show full cross-reactivity with CT-P13 and SB2. Findings suggest that immunodominant epitopes in the reference and CT-P13 drugs are equally present in SB2. Data support full interchangeability between biosimilars in regard to immunogenicity.

My take: In patients doing well with IFX, switching to a biosimilar is not currently recommended.  In patients naive to IFX, use of IFX or biosimilar is expected to have similar efficacy.

Related study: B Kang et al. IBD 2018; 24: 607-16.  This prospective study of 36 pediatric patients did not identify any significant differences in efficacy…or immunogenicity after switching from IFX to CT-P13.

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Breathing (Diaphragmatic) Helps Belching and Reflux Symptoms

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A recent prospective study (A M-L Ong et al. Clin Gastroenterol Hepatol 2018; 16: 407-16) of 36 patients (median age 45) showed that diaphragmatic breathing was helpful for PPI-refractory GERD symptoms/belching.  Patients enrolled all had “troublesome belching” for 6 months and GERD. Patients underwent high resolution manometry and pH-impedance study.

Key findings:

  • 9 of 15 (60%) in the diaphragmatic treatment group reduced their belching visual analog score by ≥50%, whereas none of the control group achieved the primary outcome
  • Treatment also resulted in lower GERD symptoms based on reflux disease questionnaire score -decrease of 12.2 vs 3.1 in the control group (P=.01)
  • Treatment improved QOL scores, based on Reflux-Qual Short form (15.7 increase for treatment group compared to 2.4 decrease in control group)
  • Treatment effects were sustained at 4 months after treatment

My take: Diaphragmatic breathing can be a useful adjunct in GERD, particularly in patients with belching.

Related blog post: Treatment for rumination and belching

 

Foggy Morning in Sandy Springs

Does C-section Increase Risk of Celiac Disease? Probably Not

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Using data from the prospective TEDDY (The Environmental Determinants for Diabetes in the Young) from 2004-2010, a recent study (S Koletzko et al. JPGN 2018; 66: 417-24) has shown that cesarean section is not associated with an increased risk of celiac disease (CD) or celiac disease autoimmunity (CDA). TEDDY participants are at increased risk for CD and type 1 diabetes (T1D) based on HLA-risk genotypes.

Key findings:

  • Of the 6087 singletons, 1600 (26%) were born via C-section
  • C-section was associated with a lower risk for CDA (HR 0.85) and a lower risk of CD (HR 0.75)

My take: While environmental factors are likely to be responsible for increasing incidence of CD, C-section compared to vaginal delivery does not appear to be a risk factor.

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Baclofen for Rumination

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A recent randomized, placebo-controlled cross-over study by A Pauweis et al (Am J Gastroenterol 2018; 113: 97-104) indicated that baclofen improved rumination syndrome in adults (mean age 42 years). Thanks to Ben Gold for this reference.

Baclofen (dosed at 10 mg TID) had the following effects:

  • reduced rumination episodes from 13 (8-22) to 8 (3-11) (P=0.004)
  • increased lower esophageal sphincter (LES) pressure (17.8 vs. 13.1, P=0.0002) and lowered number of transient LES relaxations (4 vs 7, P=0.17)
  • overall treatment evaluation was superior after baclofen compared to placebo (P=0.03)

My take: In this study, baclofen improved symptoms of rumination and regurgitation, but not supragastric belching.

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Eluxadoline and Pancreatitis

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It looks like eluxadoline, recently FDA-approved for IBS-D, is associated with a significant rate of pancreatitis.  The most recent report: AJ Gawron, K Bielefeldt. Clin Gastroenterol Hepatol 2018; 16: 378-84.

The authors extracted reports of eluxadoline adverse events using the Federal Adverse Event Reporting System.

  • Of the 597 reports, 98 (16.4%) were due to pancreatitis; 53 cases required hospitalization.  (The FDA separately reported 120 cases of pancreatitis –https://www.fda.gov/Drugs/DrugSafety/ucm546154.htm)
  • The FDA report, which noted the risk primarily in those with prior cholecystectomy, “listed 1 fatality caused by pancreatitis..which manifested within the first day of therapy.”

My take: This study showing a significant risk of pancreatitis changes the risk-benefit ratio of eluxadoline.  Since pancreatitis can result in hospitalization and even death, alternative therapies for IBS will be favored.

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Tenofovir to Prevent Perinatal Transmission of Hepatitis B

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Mother-to-child transmission of hepatitis B virus (HBV) accounts for the majority of cases of chronic HBV infection.  HBV infection affects more than 250 million people worldwide and in many cases results in cirrhosis or hepatocellular carcinoma.  As such, there has been interest in preventing perinatal transmission.

The most recent study (C Jourdain et al. NEJM 2018; 378: 911-23) again showed that tenofovir administration to pregnant women with HBV can prevent transmission.  This study enrolled 331 women.  Key findings:

  • 0% (0/147) infants in the tenofovir group developed HBV infection compared to 2% (3/147) in the control group. This did not reach statistical significance
  • The placebo group received HBV vaccination and hepatitis B immune globulin 1.2 hours and 1.3 hours after birth (median time).  This rapid provision of treatment along with completion of four doses of HBV vaccine likely helped keep the placebo group HBV infection rate low

In the related editorial (G Dusheiko. pg 952-3), it is noted that “current levels of evidence supporting antiviral therapy with TDF [tenofovir] (or possbily lamivudine or telbivudine) to reduce levels of maternal HBV DNA during pregnancy have been accepted by the” AASLD.

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