Liver Shorts: Biliary Atresia Organoids, AIH Pregnancy Outcomes, ALT Levels in Primary Care, Polyreactive IgG for AIH

SP Amarachintha et al. Hepatology 2022; 75: 89-103. Open Access: Biliary organoids uncover delayed epithelial development and barrier function in biliary atresia

This is a super cool article documenting a new human model for studying biliary atresia. The authors “generated biliary organoids from liver biopsies of infants with biliary atresia and normal and diseased controls…Organoids from biliary atresia are viable and have evidence of halted epithelial development. The induction of developmental markers, improved cell-cell junction, and decreased epithelial permeability by EGF and FGF2 identifies potential strategies to promote epithelial maturation and function.”

The authors note that delayed development of cholangiocytes impair barrier function and leave the liver susceptible to various insults which can trigger an inflammatory response with potential progression to obliteration of the bile ducts.

CW Wang et al. Hepatology 2022; 75: 5-12. Open Access: Outcomes of pregnancy in autoimmune hepatitis: A population-based study

Among 18,595,345 pregnancies, 935 (<0.001%) had AIH (60 with cirrhosis) and 120,100 (0.006%) had other CLD (845 with cirrhosis). Key findings:

  • AIH was not associated with postpartum hemorrhage, maternal, or perinatal death
  • AIH was associated with preterm births when compared with women without CLD (OR: 2.0)
  • The odds of gestational diabetes (GDM) and hypertensive complications (pre-eclampsia, eclampsia, or hemolysis, elevated liver enzymes, low platelets) were significantly higher in AIH compared to other CLD (GDM: OR 2.2 and hypertensive complications: OR: 1.8) and also compared to no CLD in pregnancy (GDM: OR: 2.4 and  hypertensive complications: OR: 2.4)

SJ Wu et al. J Pediatr 2022; 240: 280-283. The Prevalence of Elevated Alanine Aminotransferase Levels Meeting Clinical Action Thresholds in Children with Obesity in Primary Care Practice

In this brief report, the authors identified 7.8% of children from a cross-sectional California cohort (n=12,945) with ALT >44 U/L and BMI in the 95% or higher (2012-2014). Males were twice as likely to have elevated ALT. Ethnicity rates were higher in hispanics, asians than white and black children (in males: 12%, 10.4%, 7.3% and 3.1%, respectively)

R Taubert et al. Hepatology 2022; 75: 13-27. Quantification of polyreactive immunoglobulin G facilitates the diagnosis of autoimmune hepatitis

Key findings: Polyreactive IgGs (pIgGs) are a common finding in untreated AIH and have “the highest overall accuracy for the distinction between AIH and non-AIH LD compared to the most common conventional autoantibodies.” In addition, in this study with 1568 adutls, pIgGs were present in “up to 88% of patients with seronegative AIH and in up to 71% of AIH patients with normal IgG levels. Under therapy, pIgG returns to background levels of non-AIH-LD.”

IBD Shorts: High TNF levels, Biologics in Pregnancy, & Ileocolic Resection Outcomes in Pediatrics

M Zvuloni et al. JPGN 2021; 73: 717-721. Open Access PDF: High anti-TNFa Concentrations Are Not Associated With More Adverse Events in Pediatric Inflammatory
Bowel Disease

Key findings (retrospective study):

  • Higher trough concentrations (TCs) (>10 mcg/mL) of anti-TNFa were not associated with higher rate of anti-TNFa-related adverse events in 135 patients & >1500 TC measurements
  • Out of the 30 patients who presented with elevated transaminases, 27 (90%) patients had normalized transaminases values by the end of the follow-up
  • Adverse events were noted in 68 of 135 patients (see below)

OH Nielsen et al. Clin Gastroenterol Hepatol 2022; 20: 74-87. Open Access: Biologics for Inflammatory Bowel Disease and Their Safety in Pregnancy: A Systematic Review and Meta-analysis

Forty-eight studies were included in the meta-analysis comprising 6963 patients. Key findings:

  • Biologic therapy in IBD pregnancies was associated with a pooled prevalence of 8% for early pregnancy loss, 9% for preterm birth, 0% for stillbirth, 8% for low birth weight, and 1% for congenital malformations.
  • These rates are comparable with those published in the general population.
  • Importantly, studies with newer biologics (eg. vedolizumab, ustekinumab) had small sample sizes. In addition, ongoing prospective multicenter registries are ongoing.

EA Spencer et al. JPGN 2021; 73: 710-716. Open Access PDF: Outcomes of Primary Ileocolic Resection for Pediatric Crohn Disease in the Biologic Era

Key findings (n=78, retrospective study, 2/3rds received biologic postoperative prophylactic therapy):

  • Endoscopic recurrence was 46% at 2 years (median time to recurrence: 10 months).
  • Histologic recurrence was present in 44% in endoscopic remission
  • At diagnosis and surgery, over a quarter met the criteria for growth failure.. Following surgery, height, weight and BMI z scores improved significantly both at 1 year and last followup

Vedolizumab Exposure in Newborns

M Juulsgard et al. AP&T 2021: https://doi.org/10.1111/apt.16593. Vedolizumab clearance in neonates, susceptibility to infections and developmental milestones: a prospective multicentre population-based cohort study

Key findings:

  • In 50 vedolizumab-exposed pregnancies, we observed 43 (86%) live births, seven (14%) miscarriages, no congenital malformations and low risk of adverse pregnancy outcomes
  • The mean time to vedolizumab clearance in infants was 3.8 months (95% CI, 3.1-4.4)
  • No infant had detectable levels of vedolizumab at 6 months of age
  • Developmental milestones at 12 months were normal or above average
  • Neither vedolizumab exposure in the third trimester (RR 0.54, 95% CI, 0.28-1.03) nor combination therapy with thiopurines (RR 1.29, 95% CI, 0.60-2.77) seemed to increase the risk of infections in the offspring

My take: Given the good safety profile of vedolizumab, this small study provides additional reassurance regarding use of vedolizumab during pregnancy.

Related blog posts:

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Time to Adjust the Knowledge Doubling Curve in Hepatology

In his book, Critical path, Buckminster Fuller (Fuller 1981), American architect, systems theorist, author, designer, inventor, and futurist, created the ‘knowledge doubling curve’. He noticed that until 1900 human knowledge doubled approximately every century and by the end of World War II knowledge was doubling every 25 years (Knowledge is not everything, Paul Chamberlain). Now the doubling of knowledge, in the age of the internet and social media, has become even shorter, perhaps less than a year.

I was thinking about this knowledge doubling curve after reading two practice guidances in a recent issue of Hepatology:

The first guidance is mainly for reference as pediatric gastroenterologists do not focus on reproductive health. The authors do provide guidance on contraceptive options which is an important topic for adolescents. The main guidance is disease-specific information for pregnancy in the setting of underlying liver conditions including liver transplantation, cirrhosis, viral hepatitis, autoimmune hepatitis, PSC, PBC, Wilson’s disease, hepatitis C, nonalcoholic fatty liver disease, HELLP, acute fatty liver disease of pregnancy, Budd-Chiari, FNH, hepatocellular adenoma, and others. The guidance also provides recommendations for how to evaluate abnormal liver tests in pregnancy and reviews liver medications during pregnancy (Table 4).

The second guidance reviews the following:

  • An overview of the current understanding of bleeding and thrombosis in cirrhosis.
  • An evidence‐based justification for bleeding risk assessment in patients with cirrhosis before invasive procedures, including current concepts in preprocedural testing and laboratory analysis and their role in predicting bleeding complications.
  • An outline of established and recently identified risk factors for venous thrombosis in the portal and hepatic venous systems in both patients with and without cirrhosis along with thrombophilia testing recommendations.
  • A review of the strengths and weaknesses of the various classification systems for portal vein thrombosis and a proposal for standard nomenclature regarding characterization of portal vein thrombosis location, time course, and progression.

Useful points:

  • In patients with cirrhosis, there are “complex hemostatic changes that are not adequately captured by traditional laboratory measures of hemostasis, such as PT, aPTT, and platelet count.”
  • “Because of conflicting data in the literature, there is no data-driven specific INR or platelet cut-off in which procedural bleeding risk is reliable increased.” In some studies, the authors conclude that “that the low platelet count may have been merely a reflection of advanced portal hypertension and not a causative risk factor for bleeding.”
  • For Platelets in the setting of cirrhosis: “Given the low risk of bleeding of many common procedures, potential risks of platelet transfusion, lack of evidence that elevating the platelet count reduces bleeding risk, and ability to use effective interventions, including transfusion and hemostasis if bleeding occurs, it is reasonable to perform both low‐ and high‐risk procedures without prophylactically correcting the platelet count...An individualized approach to patients with severe thrombocytopenia before procedures is recommended because of the lack of definitive evidence for safety and efficacy of interventions intended to increase platelet counts in patients with cirrhosis.” The authors note in Table 4, that the AASLD does not have a specific threshold for platelets, whereas other societies have used values of >30 or >50.
  • For INR in setting of cirrhosis: “The INR should not be used to gauge procedural bleeding risk in patients with cirrhosis who are not taking vitamin K antagonists (VKAs)…Measures aimed at reducing the INR are not recommended before procedures in patients with cirrhosis who are not taking VKAs…FFP transfusion before procedures is associated with risks and no proven benefits.”
  • The guidance lists a step‐by‐step treatment and surveillance algorithm for portal vein thrombosis in patients with cirrhosis (and without cirrhosis).
  • The guidance provides updated diagnostic, treatment, and management recommendations for sinusoidal obstruction syndrome (formerly known as hepatic-veno-occlusive disease), hereditary hemorrhagic telangiectasia, and hepatic vein thrombosis (aka Budd-Chiari).
  • Classification and management recommendations for idiopathic noncirrhotic portal hypertension and the portosinusoidal vascular disorders.
  • Surveillance and evaluation recommendations for hepatic and splenic artery aneurysms.
  • A review of the management issues in vascular liver disorders specific to children and guidance on early intervention in extrahepatic portal vein obstruction in children.

My take: In essence, these two articles are condensed textbooks. The first on Liver Disease, Pregnancy and Reproductive Health. And the second on Bleeding in the Setting of Chronic Liver Disease and Vascular Liver Diseases.

IBD Updates: Outcomes of VEO-IBD, PIANO Study Update, and Insurance-Disparity Relationship

Outcomes of VEO-IBD. B Kerur et al. Inflamm Bowel Dis 2021; 27: 295-302. Bowel Disease in North America: A Retrospective Cohort Study The study population included 269 children (105 [39%] Crohn’s disease, 106 [39%] ulcerative colitis, and 58 [22%] IBD unclassified). Key findings:

  • By the end of follow-up, stricturing/penetrating occurred in 7 (6.6%) children.
  • Median age at diagnosis was 4.2 years. 71 (26%) were ❤ yrs.
  • Only 5 (1.7%) had a coexisting immunological disorder.
  • Over 5 years, cumulative use of an immunomodulator and biologic was 61% and 41% respectively. Exclusive enteral nutrition was used in 10 children (4%).
  • 11.5% (n=19) had a change in diagnosis from UC/IBD-U to Crohn’s disease
  • The risk of any bowel surgery in Crohn’s disease was 3% by 1 year, 12% by 3 years, and 15% by 5 years and did not differ by age at diagnosis.
  • The risk of colectomy in ulcerative colitis/IBD unclassified was 0% by 1 year, 3% by 3 years, and 14% by 5 years and did not differ by age of diagnosis.

Related blog posts:

IBD Therapies and Newborn Outcomes (also covered in a prior blog post: Disease Activity, Not Medications, Linked to Neonatal Outcomes in Women with IBD). U Mahadevan et al. Gastroenterol 2021; 160: 1131-1139. Pregnancy and Neonatal Outcomes After Fetal Exposure to Biologics and Thiopurines Among Women With Inflammatory Bowel Disease

In this PIANO study (2007-2019), pregnant women with IBD were enrolled in a prospective, observational, multicenter study across the United States. PIANO is an acronym for Pregnancy in Inflammatory Bowel Disease and Neonatal Outcomes.

Exposure was to thiopurines (n = 242), biologics (n = 642), or both (n = 227) vs unexposed (n = 379). 

Disparity Not Apparent Among Insured Population. EL Barnes et al. Inflamm Bowel Dis 2021; 27: 364-370. Black and White Patients With Inflammatory Bowel Disease Show Similar Biologic Use Patterns With Medicaid Insurance

In this study, which analyzed Medicaid Analytic eXtract data from 4 states (California, Georgia, North Carolina, and Texas) between 2006 and 2011, the authors identified 14,735 patients with IBD (4672 black [32%]). Key finding: “In patients with Medicaid insurance, where access to IBD-specific therapy should be similar for all individuals, there was no significant disparity by race in the utilization of IBD-specific therapies.”

Disease Activity, Not Medications, Linked to Neonatal Outcomes Among Women with IBD

U Mahadevan at el. Gastroenterology; 2020: (in press) DOI:https://doi.org/10.1053/j.gastro.2020.11.038. Pregnancy and Neonatal Outcomes after Fetal Exposure To Biologics and Thiopurines among Women with Inflammatory Bowel Disease

Methods: Between 2007 and 2019, pregnant women with IBD were enrolled in a prospective, observational, multicenter study across the United States (PIANO registry). 

Key findings:

  • Exposure was to thiopurines (242), biologics (642) or both (227) versus unexposed (379)
  • Medication exposure did not increase the rate of congenital malformations, spontaneous abortions, preterm birth, LBW, and infections over the first year of life
  • Higher disease activity was associated with risk of spontaneous abortion (HR 3.41, 95% CI 1.51-7.69) and preterm birth with increased infant infection (OR 1.73, 95% CI 1.19-2.51)

My take: This study provides some reassurance that treatments for IBD are unlikely to affect neonatal outcomes; however, increased IBD activity does affect outcomes

Related blog post: IBD and Pregnancy

IBD Briefs: May 2019 (Part 1)

H Khalili et al. Clin Gastroenterol Hepatol 2019; 17: 123-29.  Using data from two prospective Swedish cohort sutdies with 83,042 participants (age 44-83 yrs), the authors determined that there was “no evidence for association between consumption of sweetened beverages and later risk of” Crohn’s disease or Ulcerative Colitis.

WJ Sandborn et al. Gastroenterol 2019; 156: 946-57.  This study published data from 354 patients who received subcutaneous abrilumab, an anti-alpha4beta7 antibody as a treatment for moderate-to-severe colitis. This 8 week treatment increased the odds of remission compared with placebo.

B Wynne et al. Gastroenterol 2019; 156: 935-45. This study showed that a psychological intervention termed “acceptance and commitment therapy (ACT)” was effective in a randomized controlled trial in reducing stress and depression in patients with quiescent or mildly-active IBD (n=122). With ACT, the “primary aim is to encourage subjects to adopt positive life values and to accept adverse experiences, including thoughts, feelings and sensations that are an inevitable consequence of life.”  All program materials are available in article supplement: Full text and supplement: https://doi.org/10.1053/j.gastro.2018.11.030

D Duricova et al. Inflamm Bowel Dis 2019; 25:789-96. This study included 72 consecutive children born to mothers with IBD treated with anti-TNF therapy during pregnancy (2007-16) along with 69 unexposed controls.  Key findings: Anti-TNF therapy exposure in utero was NOT associated with a negative impact on postnatal complications, including infections, allergy, growth, or psychomotor development. Findings are limited by the small number of participants.

AW Gridnal et al. Inflamm Bowel Dis 2019; 25:642-45.  The authors examined the frequency of financial conflicts of interest (FCOI) among authors of 11 relevant clinical practice guidelines for IBD in the US,  the UK, Canada, and Europe. Key finding: FCOI were frequently present with 19% prevalence among US authors, 56% in UK, 84% in Canada, and 94% in Europe.

KN Weaver et al. Inflamm Bowel Dis 2019; 25:767-74. This retrospective study examined the efficacy of ustekinumab for Crohn’s disease of the pouch in 56 patients; 73% had previously been treated with anti-TNF therapy, vedolizumab or both. Key finding: 83% demonstrated a clinical response 6 months and 60% with endoscopic improvement after induction with ustekinumab. Clinical response was defined as “any improvement in symptoms …including a decrease in bowel movements, pain, or fistula drainage.”

Retiro Park, Madrid
Thanks to Jennifer

 

Biologic Exposure Prenatally and Perinatally

The widespread use of anti-TNF therapy for inflammatory bowel disease has improved clinical outcomes including fewer surgeries, hospitalizations, and complications.  One consequence of this usage has been the exposure of infants to biologics due to their usage by their mothers during pregnancy.  A recent study (M Julsgaard et al. Gastroenterol 2016; 151: 110-19) explores this topic further.

In this study, the authors prospectively followed 80 pregnant women: 36 received adalimumab & 44 infliximab. In addition, 39 received concomitant thiopurine therapy.

Key findings:

  • The time from last exposure to anti-TNF agent correlated inversely with the concentration of these drugs in the umbilical cord and in mothers at the time of birth.
  • Median ratio for infant: mother drug concentration at birth was 1.21 for adalimumab and 1.97 for infliximab.
  • Mean time for drug clearance: 4.0 months for adalimumab and 7.3 months for infliximab. Drugs were not detected after 9 months of life for adalimumab and after 12 months of life for infliximab.
  • No increased risk of adverse pregnancy outcomes were identified; preterm birth was low (n=3 or 3.8%). 48% of women experienced a disease relapse during pregnancy.
  • In this small study, the relative risk for infection was 2.7 in infants exposed to combination therapy.  Benign courses of viral infections were noted in 16 (20%) of the entire cohort and of bacterial infections in 4 (5%).

The authors recommend avoidance of live virus vaccines in biologically-exposed infants for up to 1 year unless drug clearance has been documented. Currently, this would affect only rotavirus vaccination.

My take (borrowed from editorial pgs 25-26): “For now, the sum of evidence seems to support continued use of anti-TNF therapy in pregnancy when clinically indicated and, despite measureable levels in offspring, there does not seem to be a significant clinical consequence.”

Related study: “Adverse Pregnancy Outcomes among women with inflammatory bowel disease: a population-basd study from England” Inflamm Bowel Dis 2016; 22: 1621-30. The authors identified 1969 pregnancies from a total of 364,363 singleton pregnancies.  Women with Crohn’s had increased preterm births with an Odd ratio of 1.42, babies with low birth weight (OR 1.39); women with ulcerative colitis had only a small increase risk in preterm birth (absolute risk <2.7%).

Related blog posts:

Art at Big Creek Greenway, Alpharetta

Art at Big Creek Greenway, Alpharetta

CCFA Conference Notes 2016 (part 4) –Pregnancy and IBD

Pregnancy and IBD –Dr. Doug Wolf

Dr. Wolf reviewed infertility, pregnancy issues, and PIANO registry. This topic has been covered elsewhere in this blog (IBD and Pregnancy | gutsandgrowth). Vedolizumab is a FDA category B; thus far, it is considered fairly safe. Thiopurines are category D but overall thought to be low risk.

This blog entry has abbreviated/summarized this terrific presentation. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.

Screen Shot 2016-04-16 at 2.30.04 PM

Screen Shot 2016-04-16 at 2.28.45 PM

Screen Shot 2016-04-16 at 2.29.35 PM

 

IBD and Pregnancy

While managing inflammatory bowel disease during pregnancy is not within the scope of my practice as a pediatric gastroenterologist, it is helpful to have some familiarity with the issues.

Here’s a full-text link to AGA Guidelines: The Toronto Consensus Statements for the Management of Inflammatory Bowel Disease in Pregnancy

From the abstract, an excerpt:

Consensus was reached on 29 of the 30 recommendations considered. Preconception counseling and access to specialist care are paramount in optimizing disease management. In general, women on 5-ASA, thiopurine, or anti–tumor necrosis factor (TNF) monotherapy for maintenance should continue therapy throughout pregnancy. Discontinuation of anti-TNF therapy or switching from combination therapy to monotherapy may be considered in very select low-risk patients. Women who have a mild to moderate disease flare while on optimized 5-ASA or thiopurine therapy should be managed with systemic corticosteroid or anti-TNF therapy, and those with a corticosteroid-resistant flare should start anti-TNF therapy. Endoscopy or urgent surgery should not be delayed during pregnancy if indicated. Decisions regarding cesarean delivery should be based on obstetric considerations and not the diagnosis of IBD alone, with the exception of women with active perianal Crohn’s disease. With the exception of methotrexate, the use of medications for IBD should not influence the decision to breast-feed and vice versa. Live vaccinations are not recommended within the first 6 months of life in the offspring of women who were on anti-TNF therapy during pregnancy.

Gastro March2016