Category Archives: Pediatric Gastroenterology Liver Disease

Pediatric NAFLD Guidelines 2017

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The concise recommendations (M Vos et al. JPGN 2017; 64: 319-34) from the Expert Committee on NAFLD (ECON)/NASPGHAN provide helpful advice on this increasingly common disorder. Link to full text: NASPGHAN Clinical Practice Guideline for NAFLD

The recommendations are graded on strength of recommendation and quality of the evidence.

Some key points:

  • Use ALT as a screening tool (despite its imperfections). Persistently elevations (>2xULN) should be evaluated for liver disease, including NAFLD.  (Norms: 22 U/L for girls, 26 U/L for boys). Values above 80 U/L “warrants increased clinical concern.”
  • Screening should be considered between ages 9 and 11 years for all obese children and for overweight children with additional risk factors.
  • Ultrasound and CT scans are NOT recommended.
  • Liver biopsy should be considered for the assessment of NAFLD in children who have increased risk of NASH and/or advanced fibrosis.  This could include those with splenomegaly, AST/ALT>1, higher ALT (>80 U/L), panhypopituitarism, and type 2 diabetes.
  • Treatment: Lifestyle modifications recommended.  No currently avaiable medications or supplements are recommended.
  • Look for & avoid comorbidities: dyslipidemias, hypertension, and diabetes. Assure vaccinations against Hep A/Hep B and counsel against binge drinking and against smoking.

Related blog posts:

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“When the Cause of Liver Disease Is the Heart”

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A recent review (S Ofei, C Gariepy. JPGN 2017; 64: 3-7) provides a good review of “congestive hepatopathy.”

Key points:

  • Overall, the liver receives 25% of cardiac output; though, 70% of blood flow to the liver is partially deoxygenated blood.  Cardiac disease can lead to liver disease due to hypoxic injury.
  • “Congestive hepatopathy (CH) results from chronic right heart dysfunction with decreased hepatic blood flow, arterial saturation, and increased central venous pressure.”  Ultimately, CH can lead to hepatic cirrhosis, termed ‘cardiac cirrhosis’ by the authors.
  • “Symptoms of CH are vague.” These symptoms could include abdominal pain nausea, and early satiety.
  • Treatment is uncertain.  “Guidelines and expert consensus..favor use of loop diuretics in patients with jaundice, hepatic congestion, and ascites.”
  • With regard to patients with Fontan-associated liver disease (FALD), “there is no consensus.” Patients should be treated for complications like varices, coagulopathy, and nutritional deficiencies.”  Some patients will need liver transplantation, though liver disease may be reversible with cardiac transplantation.  The article provides many references that provide more in-depth review of this topic.

My take: Overall, this article provides a succinct review of congestive hepatopathy.  There are many other cardiac conditions associated with liver dysfunction including heart disease associated with NAFLD, Alagille syndrome, and Kawasaki’s.

Cozumel

Cozumel

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Bariatric Surgery and Reversal of NASH

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A small prospective study (M Manco et al. J Pediatr 2017; 180: 31-7) provides evidence that bariatric surgery/sleeve gastrectomy is effective at reversing nonalcoholic steatohepatitis (NASH) and hepatic fibrosis in adolescents (n=20).

All patients in this study had BMI >35 and weere 13-17 yrs of age.

Key findings at one year following intervention:

  • Among the 20 patients who underwent sleeve gastrectomy, there was a 21.5% loss in baseline weight, which compared with weight loss of 3.4% among 20 patients who received intragastric balloon device and weight increase of 1.7% among 53 patients who received lifestyle intervention counseling.
  • Sleeve gastrectomy group had resolution of NASH in all 20 and disappearance of hepatic fibrosis in 18 (90%).  In the intragastric balloon group, NASH reverted in 24% and fibrosis in 37% whereas there was no improvement in the lifestyle intervention group.

Full text link: Sleeve Gastrectomy for NASH

Limitations are discussed in the editorial by Inge and Xanthakos (pgs 6-7) and included small sample size, absence of patients with type 2 diabetes, and short followup period.  Nevertheless, this is “the largest and most informative series…in select adolescents with severe obesity.”

My take: Given the lack of effective pharmaceutical therapy and the typically impotent effects of lifestyle intervention, this data supports bariatric surgery to facilitate weight loss/NASH reversal in select adolescents.

Related article: JCF Leung et al. Hepatology 2017; 65: 54-64.  This study showed that the histologic severity and clinical outcomes are modestly better in nonobese patients (n=72) with NAFLD compared with obese patients (n=307). High triglycerides and higher creatinine were associated with more advanced liver disease in nonobese patients.

Briefly noted: D Houghton et al. Clin Gastroenterol Hepatol 2017; 15: 96-102.  This study with 24 subjects with nonalcoholic steatohepatitis showed that exercise reduced hepatic triglyceride content, visceral fat, and plasma triglycerides. However, circulating markers of inflammation and fibrosis was not reduced.  The implication is that exercise should be part of NASH treatment but that weight management/diet are needed as well.

Glacier Natl Park

Glacier Natl Park

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New HCV Treatment Effective in Adolescents –Important Study Now Published Online

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A soon-to-be-published study (available online Hepatology) from WF Balistreri et al shows that the combination of Ledipasvir-Sofosbuvir is highly effective in pediatric patients aged 12-17 years.

Here is the abstract:

ABSTRACT

No all-oral, direct-acting antiviral regimens have been approved for children with chronic hepatitis C virus (HCV) infection. We conducted a Phase 2, multi-center, open-label study to evaluate the efficacy and safety of ledipasvir–sofosbuvir in adolescents with chronic HCV genotype 1 infection. One hundred patients ages 12 to 17 years received a combination tablet of 90 mg ledipasvir and 400 mg sofosbuvir once daily for 12 weeks. On the 10th day following initiation of dosing, 10 patients underwent an intensive pharmacokinetic evaluation of the concentrations of sofosbuvir, ledipasvir, and the sofosbuvir metabolite GS-331007. The primary efficacy endpoint was the percentage of patients with a sustained virologic response 12 weeks posttreatment (SVR12). Median age of patients was 15 years (range, 12-17 years). A majority (80%) were HCV treatment naïve, and 84% were infected through perinatal transmission. One patient had cirrhosis and 42 did not; in 57 patients the degree of fibrosis was unknown. Overall, 98% (98/100; 95% CI, 93% to 100%) of patients reached SVR12. No patient had virologic failure. The 2 patients who did not achieve SVR12 were lost to follow-up either during or after treatment. The 3 most commonly reported adverse events were headache (27% of patients), diarrhea (14%), and fatigue (13%). No serious adverse events were reported. AUCtau and Cmax values for sofosbuvir, ledipasvir, and GS-331007 were within the predefined pharmacokinetic equivalence boundaries of 50% to 200% when compared with adults from Phase 2 and 3 studies of ledipasvir and sofosbuvir. Conclusion: Ledipasvir−sofosbuvir was highly effective in treating adolescents with chronic HCV genotype 1 infection. The dose of ledipasvir−sofosbuvir currently used in adults was well tolerated in adolescents and had an appropriate pharmacokinetic profile.

My take: This is great news for pediatric patients.  This study indicates that this breakthrough therapy (and likely others) for adults will become more widely available for pediatric patients soon.

TV sports analysts have tremendous insight!

TV sports analysts have tremendous insight!  Virginia needs to score enough points to win.

Primary Sclerosing Cholangitis (PSC) –Natural History Study

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Last week, I posted an blog referencing new guidelines for peanut introduction.  A more detailed explanation of these guidelines: New Guidelines: Early Introduction of Peanut to Prevent Peanut Allergy from David Stukus (Thanks to Kipp Ellsworth for sharing this information)

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A recent study (PL Valentino et al. JPGN 2016; 63: 603-09) follows “the largest reported pediatric PSC cohort” to determine the natural history.

Study characteristics:

This retrospective study followed 120 children (1-21 yrs) with a median age of 14 years.  27% had autoimmune sclerosing cholangitis (ASC), 63% had PSC; 24% (n=29) of entire cohort had exclusive small duct PSC. Median followup was 3.7 years.

Key findings:

  • 81% of PSC patients had inflammatory bowel disease; most (72/97) had ulcerative/indeterminant coliits. 40/72 had pancolitis.
  • PSC-IBD was more common than ASC-IBD (85% vs 68%).
  • 10-year transplant-free survival in this cohort was 89%; there were 6 liver transplants.
  • The rate of cirrhosis was lower in the group who had IBD preceding PSC (15% vs 31%,P=0.05).
  • PSC is clinically silent in the majority of patients; 64% presented with abnormal chemistries and no other symptoms.
  • ERCP therapeutic intervention was low, 3% for stenting and 7% for balloon dilatation.

The authors speculate that one reason for milder PSC-IBD disease could relate to the fact that IBD patients undergo frequent chemistries.  In those without IBD, subacute PSC could be present for a much longer period before detection.  The authors note that PSC in children presents as a milder disease with only 10% having cirrhossi compared with 30% in studies with adult patients.

My take: We have a lot to learn about PSC including which patients are likely to develop clinically significant liver disease and whether most patients benefit from treatment.

Related blog post: Should we care about subclinical PSC? (This post has links to others related to PSC)

Thunder Hole, Acadia Nat'l Park

Thunder Hole, Acadia Nat’l Park

Top Posts 2016

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The following posts are the ones that I think are most useful from 2016.

Gastroenterology:

Liver:

General:

Doctoring:

IBD:

Nutrition:

truth-johnpohl

Characterizing Severe Liver Disease with Cystic Fibrosis

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A recent retrospective study (JR Stonebraker et al. Clin Gastroenterol Hepatol 2016; 14: 1207-15) examined data from 561 patients (76 international centers) with cystic fibrosis (CF), liver disease and portal hypertension.  The study period spanned 1999-2013. Key findings:

  • Male patients were diagnosed earlier: 10 vs 11 year, p =.01.  63% of patients were males.
  • Splenomegaly was noted in 99% and varices in 71%
  • Levels of liver enzymes were near normal in most patients. 63% had transaminases that were less than 2 x ULN.
  • 91 (16%) received liver transplants at a median age of 13.9 years.  Hallmarks of those receiving liver transplants included lower platelet counts (78 vs 113, P<.0001), higher INR (1.4 vs 1.2, P<.0001), and lower albumin (3.3 vs 3.7, P =.0002).
  • 99% of patients in this cohort were pancreatic insufficient

My take: In patients with CF, those with severe liver disease often present by age ~10 years.  Features of portal hypertension, like splenomegaly and low platelet counts, appear to be more important than liver enzymes.

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gardenpic

 

Weak Link in Liver Transplantation Survival

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A recent article and editorial (DH Leung et al. Liver Transpl 2016; 22: 1584-92 & editorial by JC Bucuvalas, S Feng 1466-68) provides a better picture of long-term survival for pediatric patients facing the prospect of liver transplantation.

Among patients less than 2 years in the UNOS data sharing registry, there were 994 with biliary atresia (BA) and 221 with other chronic liver disease.

The key data:

  • The overall postlisting mortality was 19.6% with most of this due to wait-list mortality (12.4%).  Posttransplant mortality was 8%.
  • The non-BA patients had a higher wait-list mortality compared with BA patients: 23.9% vs 9.8%
  • Risk factors for mortality included lack of exception points (HR 5.8), and initial creatinine >0.5.  In addition, BA patients without prior abdominal surgery (eg Kasai) was higher (risk was 1.6 times greater) than in those with BA with presumed Kasai.

Reviewing the article, it is not clear to me if patients removed the waitlist (eg due to sepsis and other causes) are included in this analysis.  Thus, the true postlisting mortality may be higher than 20% if all needy individuals are considered.

From the editorial -other aspects:

  • Only one-third of pediatric recipients have optimal outcomes which would include normal LFTs, maintained on monotherapy immunosuppression, normal growth, and free of comorbidity.  In addition, even among those with ‘optimal’ outcomes, many would still have histologic injury.
  • The “incidence of nonstandard exception requests has increased 5-fold and is now used on behalf of 44% of wait-listed children.”  Importantly, children with public insurance were less likely to have petitions for exception PELD points.

My take (with help from editorial): To improve outcomes, this means starting with candidate selection and working on each step: traversing wait-list management and optimizing posttransplant care.

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Mural in Rockland, ME

Mural in Rockland, ME

The Dark Cloud Inside the Silver Lining -What’s Really Going on with Hepatitis C Infection

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Despite the flood of articles touting the success and costs of the new hepatitis C virus (HCV) treatments, direct-acting antivirals (DAA), currently hepatitis C remains more dangerous than HIV and it is likely to continue to exert a huge mortality and morbidity for at least three more decades in the United States.

One study and an associated editorial look into this subject further:

  • J Chhatwal et al. Hepatitis C Disease Burden in the United States in the Era of Oral Direct-Acting Antivirals.  Hepatology 2016; 64: 1442-1450.
  • JM Pawlotsky. The End of the Hepatitis C Burden: Really?

In the study, the authors used a validated HCV burden simulation model (HEP-SIM) and noted the following:

“Even in the oral DAA era, 320,000 patients will die, 157,000 will develop hepatocellular carcinoma, and 203,000 will develop decompensated cirrhosis in the next 35 years.”

Part of the problems will be a large number of individuals who remain unaware of their diagnosis (560,000 by year 2020) but other barriers include medication costs.

From the editorial -some pushback on the cost-savings argument:

  • “Although current drug regimens were reported to be cost-effective, nothing justifies the current prices, except financial considerations on the drug makers’ side. On the one hand, one could consider that the money saved on liver disease-related expenses is not truly saved. Being cured from HCV and not dying from its complications will not prevent the same individual from dying from another cause at a very high cost.”

My take: To bend the HCV curve faster, there will need to be increased HCV screening, increased treatment capacity, and reasonable costs.

Related blog posts:

Acadia Natl Park

Acadia Natl Park