Category Archives: Pediatric Gastroenterology Liver Disease

Liver Biopsy -Risks and Benefits

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Even in the ‘old USA,’ there is a mortality risk from liver biopsy in the pediatric population.  A recent study from Los Angeles confirms this (JPGN 2013; 57: 644-48).

This retrospective review of all children (n=213 children & 328 biopsies) who underwent a percutaneous liver biopsy between 2008-2011 were examined.  These biopsies were completed by radiology with ultrasound or CT.  Gel foam was injected in cases of multiple biopsies.

Results:

  • 9 (4.2%) dropped hemoglobin > 2 /dL.
  • 7 (3.3%) needed a transfusion.
  • 1 (0.5%) died.  This was a 2.6 kg infant seen for transplant evaluation.
  • 63 (19%) had insufficient samples for definitive histologic evaluation.
  • In 81% of initial biopsies, “a definitive pathologic diagnosis was obtained.”
  • Biopsies for unexplained elevation of liver function tests were nondiagnostic in 34.9%.

The authors take: “our data demonstrate that percutaneous liver biopsy is generally safe; yet, finite risk remains, with bleeding-related complications occurring 5.2% of children.”

Bottomline: make sure you need the information from the liver biopsy enough to justify the risk, particularly in small children and in those at increased risk for bleeding.

Related blog post (with annotated references):

Liver biopsy risk in children | gutsandgrowth

Progression of Hepatitis C in Children

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A retrospective study (Hepatology 2013; 58: 1580-86) of liver biopsies from treatment-naive children enrolled in the PEDS-C study confirm the perception that hepatitis C histologic progression is typically slow.

This study examined 35 pediatric patients (84% genotype 1) who had at least two liver biopsies more than a year a part at eight different centers.  For this study, all of the liver histology was scored by a single pathologist.  Mean age at first and final biopsy were 8.6 and 14.5 years.  Mode of transmission: 57% vertical and 39% transfusion.

Results:

  • Inflammation was minimal in about 50% at both timepoints.
  • Fibrosis was absent in 16% at both timepoints.  Fibrosis was limited to portal/periportal in 73% at first biopsy and 64% at second.
  • Proportion of patients who had bridging fibrosis/cirrhosis at second timepoint increased from 11% to 20%.  Overall, 29.5% (n=13) showed an increase in severity of fibrosis.
  • In aggregate, “this cohort did not show significant histologic progression of liver disease over 5 years.”

Implications for treatment per authors: “It may be argued that treatment of a slowly progressing disease in an asymptomatic child may be deferred given the side effects and limitations of the currently available therapy. On the other hand, some might favor early treatment…a liver biopsy …may influence decisions regarding therapy.”

Related blog posts:

Reclassifying Biliary Atresia -Three Subtypes

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Using a large prospective multicenter cohort (ChiLREN study group), a recent study examined 289 infants and identified three subtypes of biliary atresia (BA) enrolled in PROBE (Hepatology 2013; 58: 1724-31).

Previously, BA has been considered to have two presentations:

  • Acquired/nonsyndromic ~90%
  • Embryonic/syndromic ~10%

However, this study suggests the following:

  • Group 1 -nonsyndromic, isolated BA. n=242 (84%)
  • Group 2 -BA with major malformation but without laterality defect. n=17 (6%)
  • Group 3 -syndromic, with laterality defect. n=30 (10%)

Group 3 BA defects included splenic abnormalities (eg. asplenia, polysplenia, right-sided spleen), cardiovascular anomalies (eg. dextrocardia, TAPVR, interrupted IVC) and gastrointestinal anomalies (eg. “abdominal heterotaxy,” malrotation, annular pancreas).

In contrast, Group 2 BA had frequent genitourinary problems (cystic kidney and hydronephrosis) along with different cardiovascular anomalies and gastrointestinal anomalies which included esophageal/duodenal/jejunal atresia and imperforate anus.

Other points:

  • The frequency of cardiac problems is particularly important to recognize as this could make differentiation from Alagille syndrome more difficult.
  • One other interesting finding was the high incidence of autoimmunity in first-degree relatives of all BA groups (~44%).

Bottomline: there are at least 3 subtypes of BA.

Related posts:

Adult versus Pediatric Data: Autoimmune Hepatitis

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Recent data in adults indicate that budesonide may be more effective than prednisone for treating autoimmune hepatitis (AIH) (Gastroenterol 2010; 139: 1198-206).  Is this true in pediatrics? A small study and an associated editorial indicate that budesonide may be inferior (J Pediatr 2013; 163: 1347-53 & editorial 1246).

The study consisted of 46 pediatric patients with AIH (35 females) who were enrolled in a prospective double-blind, randomized, active-controlled trial with budesonide at a dose of 3 mg TID or prednisone (starting at 40 mg and tapered to 10 mg); all patients received concomitant treatment with azathioprine (1-2 mg/kg/day).  After the initial 6 months, a further 6-month open-label treatment with budesonide (n=42) followed.  Approximately 70% of the patients had type 1 AIH.

Results:

  • Normalization of aminotransferases occurred in only 16% of budesonide group and 15% of prednisone group after 6 months.
  • At 12 months, 46% of those on budesonide had biochemical remission

The editorial explains why these results are unlikely to affect current management and provides succinct summary of AIH management.

Key points:

  • “The juvenile form of AIH is particularly aggressive…between 40% and 80% of children are reported to have cirrhosis at diagnosis”
  • Standard treatment for juvenile AIH: Prednisone 2 mg/kg/day (max 60 mg) which is tapered over 4-8 weeks with the decline of aminotransferase levels to a maintenance dose of 2.5-5 mg/day.  80% of the improvement (in ALT values) occurs within the first two months.  Typically, azathioprine is added after some improvement in aminotransferases.  In the absence of toxicity, the dose is increased to 2-2.5 mg/kg/day.
  • Remission is defined as complete normalization of aminotransferases along with normalization of serum immunoglobulin G levles, negative or very low autoantibody titer, and histologic resolution of inflammation.
  • Histologic remission lags biochemical response, “though 95% of patients have a marked histologic improvement after a mean duration of 4 years of effective therapy.”
  • Budesonide is not used in the presence of cirrhosis
  • Problems with current study are detailed in the editorial.  The design likely contributed to remission rates which were significantly lower than reported with standard prednisone/azathioprine.

Related posts:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) and specific medical management interventions should be confirmed by prescribing physician.  Application of the information in a particular situation remains the professional responsibility of the practitioner.

Update on Hepatitis B & C -Postgraduate Course

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Update on Hepatitis B –Jean Pappas Molleston

Hepatitis B: Who to Treat:

  • Immune active Hepatitis B with active disease: HBeAg+ (> 6 months), HBV DNA > 20,000 IU/ml, ALT > 1.5 x normal or > 60 IU/L, &  moderate/severe inflammation/fibrosis
  • Reactivated Hepatitis B with active disease: HBeAg‐ (> 12 months), HBV DNA > 2000 IU/ml, ALT > 1.5 x normal or > 60 IU/L

Hepatitis B: Who to Not Treat:

  • Immunotolerant Hepatitis B: HBeAg+, HBV DNA > 20,000 IU/ml, Normal ALT
  • Inactive carrier: HBe Ag, HBV DNA < 2000

What to Use to Treat Children with Hepatitis B and When:

  • Only children with active disease should be treated
  • Many would suggest IFN as a first line drug, especially for younger children
  • Nucleoside analogues can now be considered in older children: Tenofovir is licensed for over age 12,  Entecavir is licensed for over age 16

What’s Exciting?

  • NCT01519960 Peg‐IFN monotherapy for children with chronic active hepatitis B
  • NCT01368497 Peg‐IFN and Entecavir for treatment of Hepatitis B in immunotolerant children
  • New drugs
  • New ways to predict who will have worse disease and who will respond
  • Direct Acting Antivirals

Treating HCV: 2013 and Beyond… Regino P. González-Peralta, M.D.

Standard of Care HCV Therapy: Children

  1. IFN/PEG-IFN-α-2a (PEG-2a):  ‘‘Branched’’ 40-kDa PEG moiety, Dose: 104 μg/m2 SQ once weekly, Available: prefilled syringes or as vials
  2. PEG-IFN-α-2b (PEG-2b): ‘‘Linear’’ 12-kDa PEG, Dose: 60 μg/m2 SQ once weekly, Available: Measured vials/ready-use pens

Other pointers:

  • Discussed IL-28 B Polymorphism –No pediatric data yet
  • Close monitoring for those who are treated
  • PEG-RBV is standard of care for children though with suboptimal efficacy and significant toxicity
  • Warp-speed evolution of HCV therapies
  • All ORAL’ regimen on horizon
  • Yearly evaluation: CBC, liver tests, HCV RNA and PT/INR (cirrhosis)

HCV Rx in Children: to treat or not:

IN FAVOR…

  • Avoid disease progression
  • Remove social stigma
  • Decrease HCV burden
  • Children ‘better’ candidates

…AGAINST

  • Benign disease
  • Efficacy
  • Toxicity
  • Direct Acting Antivirals (in the pipeline)

Full slides available on postgraduate Course Syllabus (posted with permission): PG Syllabus

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) and specific medical interventions should be confirmed by prescribing physician.  Application of the information in a particular situation remains the professional responsibility of the practitioner.

PSC 2013 Review

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A recent review of PSC was published (Gastroenterology 2013; 145: 521-36).  This review is a little more detailed than a previous review noted in this blog less than 6 months ago (Staying current with PSC | gutsandgrowth).

A couple of useful comments from the review:

  • “An increased serum level of alkaline phosphatase is the most common biochemical abnormality detected in patients with PSC.  In some cases, it is the only biochemical alteration observed, such as in patients with intrahepatic involvement.”
  • “Typically, a liver biopsy is not required to diagnose PSC unless small duct PSC is suspected or if there are concerns that a patient also has AIH.”  Cholangiography is the best way to identify PSC.
  • “Patients diagnosed with PSC should undergo colonoscopy… to determine if they have IBD, even when there are no symptoms.”
  • Autoimmune hepatitis-PSC overlap is thought to occur in ≤6% of cases.  AIH-PSC should be suspected if there are biochemical features of AIH (positive serology, increased transaminases), histology suggestive of AIH, or in AIH patients that become refractory to treatment.
  • No controlled trials have identified effective medical treatments.  Studied medications have included corticosteroids, etanercept, tacrolimus, cyclosporine, azathioprine, methotrexate, infliximab, and ursodeoxycholic acid.  The latter may increase disease progression, particularly at higher doses.

Also noted:

Hepatology 2013; 58: 1392-1400. “Primary Sclerosing Cholangitis, Autoimmune Hepatitis, and Overlap in Utah Children: Epidemiology and Natural History”

In this study the authors identified 607 cases of IBD, 29 cases of PSC, 12 cases of ASC (overlap), and 44 cases of AIH.  “Cholangiocarcinoma developed in 2 of the 29 PSC patients (6.9%).  PSC occurred in 9.9% of patients with ulcerative colitis (UC) and 0.6% of patients with Crohn’s disease.”

Related blog posts:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) and specific medical management interventions should be confirmed by prescribing physician.  Application of the information in a particular situation remains the professional responsibility of the practitioner.

Postgraduate Course Notes – Hepatitis Module

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Notes from NASPGHAN’s postgraduate course:

Refractory Autoimmune Hepatitis (AIH):  — Vicky Ng

Dr. Ng’s talk started with an overview of AIH and referred to AASLD guidelines: Diagnosis and Management of Autoimmune Hepatitis – AASLD

Recommendations included the following:

  • Cholangiography for all new cases of AIH
  • Starting azathioprine after seeing some improvement in transaminases with steroids
  • Monitoring for HCC
  • Monitor bone density/bone protection strategies discussed
  • Long term Rx needed in majority, though small number may be able to come off therapy if doing well for 2 years and normal liver biopsy

Refractory mgt:

  • This is applicable in 15-20% of patients
  • Reasons for refractory disease: non response, drug intolerance, non-compliance, overlap syndrome, comorbidities
  • If treatment failure, options could include increasing steroids and azathioprine.  If concerns for decompensation, refer for liver transplant evaluation.
  • NO standard Rx for refractory, but consider MMF (mycophenolate mofetil), cyclosporin (CYA), or tacrolimus (FK)
  • MMF most promising agent for refractory disease.  Small studies of MMF in adults/pediatrics indicates response in about 2/3rds of patients; best for those intolerant to azathioprine & helpful in dropping steroid dosing.  In pediatrics, a starting dose of 20 mg/kg/day is typical and increasing up to 40 mg/kg/day.  Pediatric study: 18/26 (69%) with response and 14/18 with normal AST w/in 2 months.
  • Tacrolimus –small study showed about ~90% response.  Dose was 0.1 mg/kg/day & target trough was 3 ng/mL
  • Briefly discussed budesonide.  More data in pediatrics needed.

Postgraduate Course Syllabus (posted with permission): PG Syllabus

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) and specific medical management interventions should be confirmed by prescribing physician.  Application of the information in a particular situation remains the professional responsibility of the practitioner.

Screening for NAFLD

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As noted in previous blogs (see below), there is not a consensus with regard to screening for NAFLD in overweight and obese patients.  While some have argued for aggressive screening leading to an expensive tiered evaluation, other experts have been reluctant to endorse this approach, in part due to the magnitude of the problem and due to the perceived lack of therapeutic options.  Weighing in on this controversy is a new study (Aliment Pharm Ther 2013; DOI: 10.1111/apt.12518, link -from Jeff Schwimmer’s twitter feed: http://t.co/q1CUKBJtVo).

In the study’s introduction, the prevalence of NAFLD, estimated to be 9.6% of all children aged 2-19 years, along with society guidelines are reviewed.

The authors examined information from the clinical evaluation of 347 children (>10 years) [overweight (7%)/obese (93%)] who were referred by their primary care physician due to either an elevated ALT or suspected NAFLD.  Referral was at the discretion of the primary care attending and not based on a specific ALT value.  Median age was 13.5 years and 64% were boys.

1st tier: Subsequently, all patients underwent hepatic panel, GGT, CBC/diff, and coagulation studies.  2nd tier: If abnormal, the next set of labs may have included any or all of the following: studies for hepatitis infection (HAV, HBV, HCV), HIV, alpha-1-antitrypsin, ANA, anti-smooth muscle antibody, anti-liver kidney microsomal antibody, quantitative IgG, ceruloplasmin,  24-h urinary copper, tissue transglutaminase antibody, serum IgA, serum amino acids, urine organic acids, serum acylcarnitine, creatine kinase, ESR, CRP, and thyroid studies. (The authors did not evaluate iron status.) 3rd tier: Then, if evidence of chronic liver disease, patients were offered a liver biopsy under general anesthesia.

Results:

  • 21% did not have significant liver disease (after 1st tier).  Also, 3 liver biopsies were normal.
  • 94% of 273 with evidence of chronic liver disease underwent liver biopsy; no significant complications were noted, though a small percentage had some discomfort.
  • Ultimately, 55% were determined to have NAFLD (75% of those who underwent liver biopsy.
  • The authors report that 61 patients who had a liver biopsy had another liver disease, including autoimmune hepatitis in 11, celiac disease in 4, sclerosing cholangitis in 1, and drug-induced in 6.
  • Advanced fibrosis was noted overall in 11% (38 of 347) and in 17% of those with NAFLD.  Those with advanced fibrosis were more likely to have higher aminotransferases (eg. ALT 120 U/L compared with 82 U/L), higher GGT, and higher ceruloplasmin; however, there was significant overlap.
  • Approximately half of NAFLD patients had steatohepatitis.

Take-home message: while this article does not resolve the issue of whether screening overweight/obese children is the best strategy, it does provide useful information in those with elevated liver tests.  Careful investigation for treatable causes (and possibly nontreatable) of liver disease is worthwhile in those with sustained abnormalities in transaminases.  At a minimum, tests for autoimmune hepatitis, celiac disease, viral hepatitis, and Wilson’s disease should be at the top of the list.

Related blog entries:

Breakthrough for Fatty Liver Disease?

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Could bile acids play a role in reducing metabolic syndrome and in particular fatty liver disease?  This question is now being studied (Gastroenterology 2013; 145: 574-82).

This recent study examined whether obeticholic acid (OCA) which is a semisynthetic derivative of the human bile acid chenodeoxycholic acid could aid with insulin resistance and ultimately nonalcoholic fatty liver disease (NAFLD).  OCA is an agonist of the farnesoid X receptor which is a nuclear hormone receptor that regulates glucose and lipid metabolism.

The authors performed a phase 2, double-blind, placebo-controlled study to assess the effects of OCA on insulin sensitivity in patients with NAFLD and type 2 diabetes mellitus.  Patients received either placebo (n=23), 25 mg OCA (n=20), or 50 mg OCA (n=21) once daily for 6 weeks.  Using an insulin clamp, insulin sensitivity was measured before and after the study period.  Numerous blood tests were obtained as well.

Results:

  • Insulin sensitivity improved 28% in the 25mg OCA group and 20.1% in the 50 mg OCA group whereas it decreased 5.5% in the placebo group.
  • The OCA groups also had significant reductions in gamma-glutamyltransferase, alanine aminotransferase, and dose-related weight loss.
  • Markers of liver fibrosis decreased in the 25 mg OCA group.
  • Side effects of OCA were minimal.  Constipation was reported in the 50 mg OCA group.

Take-home message: OCA may help patients with NAFLD and a bigger, longer study is in the works (FLINT study: 25 mg OCA for 72 weeks compared with placebo, http://www.clinicaltrials.gov; NCT01265498)

Related blog posts:

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What is the role for preventing variceal bleeding in Biliary Atresia?

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During medical school, I read a book called “The House of God”  (The House of God – Wikipedia, the free encyclopedia.  One of this cynical book’s premises is that doing more diagnostic tests and treatments to help patients actually harms them.

A recent study of children with biliary atresia reminded me of this premise (Gastroenterol 2013; 145: 801-7, eidtorial 719-22).   In this retrospective study, there were 66 children with endoscopic evidence of portal hypertension who underwent endoscopic therapy for either primary (n=36, mean age 22 months) or secondary (n=30, mean age 24 months) treatment of esophageal varices biliary atresia (2001-2011).  These children were at high risk for bleeding; they had a mean bilirubin of >10 mg/dL and 20% had ascites.

Results:

Primary prophylaxis group: mean of 4.2 sessions were needed to eradicate varices.  Varices reappeared in 37%; there was no breakthrough bleeding.  97% survived for 3 years.  All of these patients had varices grade 2 or higher and 94% had red wale markings.

Secondary prophylaxis group (after previous bleeding): mean of 4.6 sessions to eradicate varices.  Varices reappeared in 45% and 10% had breakthrough bleeding.  84% survived for 3 years.

Treatment:

  • For bleeding group, sclerotherapy was used in 73%, banding in 17%, and both in 10%.
  •  For prophylaxis group, sclerotherapy was used in 44%, banding in 41%, and both in 14%.
  • By the end of the study, sclerotherapy was mainly used in patients weighing less than 8 kg.
  • Each endoscopy session had the same endoscopist, used octreotide (2 mcg/kg/hr) an 1 hour before and then for 2-3 days afterwards.
  • With bleeding patients, these sessions occurred after the patient was stabilized, with a mean of 10 days afterwards.
  • Patients had an average of four 3-day hospitalizations.
  • Within an average of 14 months, more than half of the primary prophylaxis group had undergone transplantation

The authors interpret their data as follows:  “primary or secondary prophylaxis of bleeding is well tolerated and greatly reduces the risks of variceal bleeding in children with biliary atresia and high-risk gastroesophageal varices.  The results support the active detection of these signs by endoscopic procedures.”

In contrast, the editorial is much less supportive of primary prophylaxis.  “We need to weigh the risks and benefits of multiple procedures in a nonbleeding child who may not bleed for years, when varices have a high chance of recurring and transplant is sometimes imminent. Because mortality from gastrointestinal bleeding in children is quite low (zero in this small study), we may need to consider a ‘wait and see’ approach.”

Bottomline: A failed Kasai is an indication for transplantation which is a much more definitive treatment for portal hypertension.

Previous related blog posts: