Category Archives: Pediatric Gastroenterology Liver Disease

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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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)

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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Autoimmune Hepatitis Associated with Anti-TNF Therapy

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A recent study (A Ricciuto et al. J Pediatr 2018; 194: 128-35) identified an index case of autoimmune hepatitis (AIH) associated with anti-tumor necrosis factor (TNF) therapy and reviewed liver biochemistries in a cohort of 659 children.

Key findings:

  • In the index case, features of autoimmune hepatitis (AIH) on liver biopsy were noted 23 weeks after starting infliximab.   These findings resolved entirely within 4 months after withdrawal of infliximab
  • Overall, 7.7% of cohort had elevations of ALT while receiving anti-TNF therapy.  Most were mild and attributable to other causes than drug toxicity. No other cases of AIH were identified.

The authors recommend a careful investigation in those with elevations >2-3 times ULN which persists >3 months. Livertox (NIH) website notes the following for infliximab:

“The liver injury caused by infliximab is usually mild and rapidly reversed once therapy is stopped.  However, fatal instances of HBV reactivation and induction of autoimmune hepatitis due to infliximab have been reported, and regular monitoring of patients early during the course of infliximab is recommended.”

My take: Serious liver injury related to anti-TNF therapy is rare. A great place to understand the spectrum of liver problems potentially related to infliximab is the livertox website:

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AIH:

Views from inside Hoover Dam, including Mike O’Callaghan–Pat Tillman Memorial Bridge

Mechanisms in Fatty Liver Disease Improved After Bariatric Surgery

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A recent prospective study (V Nobili et al. J Pediatr 2018; 194: 100-8) consecutively enrolled 20 severely obese adolescents with biopsy-proven nonalcoholic fatty liver disease (NAFLD). The authors used liver histology, immunohistochemistry and cytokine analysis to assess the changes (after 12 months) induced by bariatric surgery with laparoscopic sleeve gastrectomy (LSG).

Key findings:

  • NAFLD Activity Score and fibrosis improved after LSG. Steatosis, hepatocyte ballooning, and NAS score showed a significant improvement (Z=-2.7; P=.007) at 12 months following surgery. Fibrosis improvement (Z=-2.449) was noted as well.
  • The histologic improvement “is associated with activation of local cellular compartments (hepatic progenitor cells, hepatic stellate cells, and macrophages), thus, strengthening the role of cellular interactions and hepatic adipocytokine production in the pathogenesis of NAFLD.”

This study has a large number of figures illustrating the changes in liver architecture and immunohistochemistry changes.

My take: This study shows specific improvements following LSG and shows correlation with cytokines and immunohistochemistry providing a mechanistic explanation for these improvements.

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Hepatic Tumor Pointers

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A grand rounds report (CK McLean et al. J Pediatr 2018; 193: 245-48) focuses on the presentation of a rare tumor in a neonate, angiosarcoma.  A few pointers from the discussion:

  • The most common benign hepatic vascular tumors are congenital hemangiomas and infantile intrahepatic hemangiomas (IHH)
  • The AAP dermatology section recommends assessing for hepatic lesions when there are 5 or more cutaneous hemangiomas.  The risk of a hepatic hemangioma may be 23%, according to one study, when there are >5 cutaneous hemangiomas or one large cutaneous hemangiomas.
  • “Consumptive hypothyroidism is a unique characteristic in some IHH.” This is due to tumor expression of a type 3 iodothyronine deiodinase enzyme which inactivates thyroid hormone.

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Predicting Hepatitis B Vaccination Failure in Infants

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A brief report (KW Cheung et al. Clin Gastroenterol Hepatol 2018; 16: 144-5) describes a prospective multicenter study (2014-16) in Hong Kong which examined immunoprophylaxis failure (IF) of infants (n=654) born to mothers infected with hepatitis B virus (HBV) infection.  All infants had received HBV vaccine and HBV immunoglobulin (within 12 hours of birth).  Maternal HBV DNA & serology was measured at 28-30 weeks.

Key finding:

  • There were 7 cases of IF (1.1%). All were born to women with positive HBeAg and HBV DNA >8 log10 copies/mL (>17 million IU/mL)
  • The authors note that “although a cutoff of 200,000 IU/mL (~6 log10 copies/mL) has been recommend, the optimal viral load cutoff to initiate HBV antiviral treatment remains debatable.”

My take: HBV prophylaxis with HBV vaccination and HBIG is very effective.  However, HBV DNA levels can be used to target HBV antiviral treatment to further minimize the chance of IF failure.

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Challenging Assumptions: Self-Management Adolescent Skills and Poor Outcomes

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If you think that teaching more self-management to adolescents will lead to better outcomes, you might be wrong.  A recent study (RA Annunziato et al. J Pediatr 2018; 193: 128-33) shows that adolescents who reported greater self-management, following liver transplantation, had worse outcomes.

In this study of 9-17 year olds and their parents (213 dyads), the key finding was based on a score derived from the REFILS survey.  REFILS is an acronym for “Responsibility and Familiarity with Illness Survey.”  This survey was curtailed from 22 items to the following 13 items:

  • Understands key aspects of liver disease
  • Discusses management plan with team
  • Self-manages liver regimen
  • Knows names/dose of medications
  • Keeps track of medications
  • Correctly takes medications
  • Calls pharmacy for refills
  • Knows different types of providers
  • Knows date of next appointment
  • Makes appointments
  • Know insurance details
  • Understands insurance plan
  • Keeps healthcare records

Key finding:

  • “Negative outcomes were more likely to occur if patients reported that they are ‘in charge.’ A higher [REFILS] score, which denotes a higher level of (self-reported) management, was significantly and consistently correlated with worse adherence and organ rejection.”

The implication is that the transition of responsibilities from the parent/caregiver to the adolescent “may in fact not always be indicated or advisable…education about self-care might actually be harming patients…It is probably prudent to discourage rather than encourage adolescents from assuming self-care in some cases.”

My take: While adolescents and young adults are capable in many aspects, there are hardly any that I would trust to care for our dog (see below) for any protracted period.  Thus, in my view, without close parental supervision, entrusting the life of a liver transplant recipient to an adolescent is risky.

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Screening for Bile Acid Synthesis Disorders

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A recent study (AA Al-Hussaini et al. JPGN 2017; 65: 613-20) showed that serum (total) bile acids is effective in screening for bile acid synthesis disorders. In this prospective study from Saudi Arabia, with 626 patients and 450 with infantile cholestasis, the authors identified bile acid synthetic disorder (BASD) in 2.7% of infantile cholestasis patients.  Among the 15 cases, 11 were due to 3β-hydroxyl-Δ5-C27 steroid oxidoreductase dehydrogenase deficiency (HSD3B7).  In these conditions, serum bile acids are low or normal (< 10  μmol/L) in the setting of cholestasis; most cholestatic conditions have elevated bile acids. In addition, all of their patients with bile acid synthetic disorders had a normal or low GGT.

Cholic acid is the “only effective therapy” for bile acid synthetic disorders.  It has a high cost of “$31,000 yer year in Europe” (50 mg per day).

My take: While the authors provide a diagnostic algorithm (figure 3) for diagnosis of bile acid synthetic disorders, this will likely change with the emergence of genetic screening panel.  At this time, in infants/children with cholestasis along with a normal/low GGT and normal/low serum bile acids, one should check urine for fast atom bombardment mass spectrometry.

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Second-Line Treatments for Autoimmune Hepatitis

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A recent retrospective study (C Efe et al. Clin Gastroenterol Hepatol 2017; 15: 1950-6) examined both mycophenolate mofetil (MMF, n=121) and tacrolimus (TAC, n=80) as second-line therapies for autoimmnue hepatitis with a median followup of 62 months. Patients were divided into two groups. The first group (n=108) had a complete response to steroids/azathioprine but had side effects.  The second group (n=93) were nonresponders to steroids/azathioprine. Overall, the cohort examined patients as young as 7 years and as old as 76 years.

Key findings:

  • No significant difference in complete response noted in 69.4% of MMF-treated compared with 72.4% in TAC-treated patients.
  • In group 1 patients (responders to azathioprine), MMF and TAC maintained biochemical remission in 91.9% and 94.1% respectively.
  • In group 2 (prior nonresponders), TAC-treated patients had a complete response rate of 56.5% compared with 34% for MMF-treated patients (P=.029).
  • Liver-related deaths and transplantation occurred with similar rates: MMF 13.2% compared with TAC 10.3%.  With each treatment, 10 patients withdrew from treatment due to side effects.

My take: In this study, both agents were effective in those who changed due to side effects.  However, tacrolimus-treated patients had a higher response among prior nonresponders.

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