Briefly noted: A recent study (A Mosca et al. J Pediatr 2019; 211: 72-7) examined 182 obese/overweight children with nonalcoholic fatty liver disease (NAFLD). 137 (75.3%) had liver fibrosis. 39 had fibrosis level ≥2 (21.4%)
Risk factors for liver fibrosis:
Not being breastfed OR 3.1
Parenteral obesity OR 2.9
PNPLA3 (palatin like phospholipase domain-containing 3) GG (1148M) variant OR 2.1
Fructose consumption (OR 1.6 per 1 g/day increase)
Vitamin D deficiency (25-OH <20 mg/dL) OR 1.24
A high socioeconomic status was inversely associated with fibrosis OR 0.3
New Test Expedites the Diagnosis of Biliary Atresia
A groundbreaking test developed at Cincinnati Children’s can expedite a diagnosis of biliary atresia (BA), helping physicians decide quickly whether to perform a liver biopsy followed by an operative cholangiogram, the definitive test for BA. The test quantifies the concentration of MMP-7 (matrix metalloproteinase-7), a serum protein that researchers at Cincinnati Children’s discovered in 2017 is a biomarker of BA.
Physicians can order the MMP-7 assay by submitting a requisition form. Test results are available within 48 hours, and a pediatric hepatologist is always available for consultation regarding the interpretation of test results.
NH Ebel et al. JPGN 2019; 68: 788-92. Hepatic venous pressure gradient (HVPG) did not correlate with the risk of complications from portal hypertension in this pediatric cohort (n=41); this is in contrast to studies in adults showing the utility of HVPG measurements.
AG Singal et al. Gastroenterol 2019; 156: 2149-57. AGA Practice Update on Direct-Acting Antivirals for Hepatitis C and Hepatocellular Carcinoma. There are 12 best practice advice –here are the first three:
BEST PRACTICE ADVICE 1: DAA treatment is associated with a reduction in the risk of incident HCC. The relative risk reduction is similar in patients with and without cirrhosis.
BEST PRACTICE ADVICE 2: Patients with advanced liver fibrosis (F3) or cirrhosis should receive surveillance imaging before initiating DAA treatment.
BEST PRACTICE ADVICE 3: Patients with advanced liver fibrosis (F3) or cirrhosis at the time of DAA treatment represent the highest-risk group for HCC after DAA-induced sustained virologic response. These patients should stay in HCC surveillance
N Hamdane et al. Gastroenterol 2019; 156: 2313-29. This study found that chronic HCV infection induced specific genome-wide-changes in H3K27ac which correlated with expression of mRNAs and proteins. These epigenetic changes persisted after an SVR to DAAs or interferon-based therapies. These changes could explain some of the reason why HCC remains a risk after successful treatment with DAAs.
“The algorithm begins with universal HCV screening and diagnosis by testing for HCV antibody with reflex to polymerase chain reaction to detect HCV RNA. The pretreatment evaluation uses platelet-based stratification to initially assess fibrosis, and the pan-genotypic regimens glecaprevir/pibrentasvir or sofosbuvir/velpatasvir are recommended for treatment. Unless clinically indicated, on-treatment monitoring is optional. Confirmation of cure (undetectable HCV RNA 12 weeks posttreatment) is followed by harm-reduction measures, as well as surveillance for hepatocellular carcinoma every 6 months in patients with advanced fibrosis/cirrhosis.” My take: This algorithm is much simpler than the expanded recommendations from HCVguidelines.org website, though these agents, to my knowledge, do not yet have a pediatric indication.
A large retrospective study (M Deneau, M Perito, A Ricciuto, N Gupta et al. J Pediatr 2019; 209: 92-6) examined the outcomes/response of ursodeoxycholic acid (UDCA) for pediatric primary sclerosing cholangitis (PSC).
“Within 10 years of diagnosis, 30% of children with PSC will require liver transplantation and 50% of children will develop complications, including biliary strictures and hypertension.”
Because UDCA has not been shown to improve survival (& may worsen outcomes), it is not recommended in adults by the AASLD.
In pediatrics, UDCA remains the most common treatment, used in more that 80% on long-term treatment
263 patients at 46 centers
Median age 12.1 years
UDCA median dose: 15 mg/kg/day
Normalization of GGT (<50 IU/L) occurred in 46% of patients in the first year after diagnosis
Patients with normalization was less likely among patients with Crohn’s disease and those with laboratory profiles indicative of more advanced hepatobiliary fibrosis (eg. lower platelet count, lower albumin, hyperbilirubinemia)
The 5-year survival with native liver was 99% in those who achieved normalization vs 77% in those who did not
Even in those without normalization, improvement in GGT was associated with better outcomes. “Those who had a reduction in GGT of >75% had nearly the same long-term survival as those with GGT<50 IU/L at 1 year.”
It has previously been shown that nearly “one-third of children who are UDCA-naive have spontaneous GGT normalization by 1 year.” Thus, the number to treat with UDCA to have one additional case of GGT normalization is four.
In a previous study, one-third of patients with GGT normalization on UDCA therapy for 1 year, maintained GGT <29 after withdrawal of UDCA for 12 weeks.
The authors note that “patients who do not achieve normalization could reasonably stop UDCA as they are likely not receiving clinical benefit.”
My take: This study shows that patients who have improvement/normalization of GGT with UDCA therapy have improved outcomes. The retrospective design of the study limits conclusions about whether UDCA therapy actually improves long-term outcomes, particularly since UDCA at higher doses has been associated with detrimental affects in adults with PSC.
Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist. 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.
E Cowell et al. JPGN 2019; 68: 695-99. This study reviewed 61 cases of pediatric hepatocellular carcinoma to determine predisposing conditions (in Houston TX). The majority did NOT have recognizable predisposing conditions. 25 of 61 (41%) had a predisposing condition including cryptogenic cirrhosis/steatosis (9), genetic (7), biliary pathology (4), viral hepatitis (1), and other (4). Those without a recognizable predisposing condition were diagnosed later and with more advanced disease/decreased survival.
VA McLin et al. JPGN 2019; 68: 615-22. Useful review on congenital portosystemic shunts.
DE Kaplan et al. Gastroenterol 2019; 156: 1693-1706. This large study form the VA with more than 70,000 patients examined the relationship between statin exposure and survival in patients with cirrhosis. “Each cumulative year of statin exposure was associated with an independent 8-8.7% decrease of mortality of patients with cirrhosis of Child-Turcotte-Pugh classes A and B.”
AG Singal et al. Gastroenterol 2019; 156: 1683-1692. Direct-acting antiviral therapy was not associated with recurrent hepatocellular carcinoma (HCC) in a multicenter cohort study with 793 patients with HCV-associated HCC. Thus, DAAs appear safe in patients who have achieved a complete response to HCC Rx
YH Yeo et al. Hepatology 2019; 69: 1385-97. The prevalence of high risk individuals in the U.S. who are susceptible (not immune) to hepatitis B has decreased from 83% to 69% from 2003 to 2014. That still leaves 64 million who would benefit from HBV vaccination.
M Sharma et al.Hepatology 2019; 69: 1657-75. This meta-analysis compared therapies for primary prevention of esophageal varices and concluded that nonselective beta-blocker (NSBB) monotherapy may decrease all-cause mortality and carried a lower risk of serious complications than variceal band ligation (VBL). However, the commentary (1382-84 by L Laine) reaches a different conclusion. “Current recommendations for primary prevention with VBL or NSBB or carvediolo still appear to be acceptable…using a shared decision-making approach” to weigh issue such as daily medication or periodic endoscopy.
J Nguyen et al. J Pediatr 2019; 207: 90-6. This study modeled the cost-effectiveness of early treatment with direct-acting antiviral therapy in adolescents with hepatitis C infection. With pangenotypic agenst, the cost would be $10000 to $21000 per QALY gained.
S Trinh et al. Clin Gastroenterol Hepatol 2019; 17: 948-56. This retrospective hepatitis B study examined the changes in renal function between 239 tenofovir disoproxil fumarte (TDF) treated patients and 171 entecavir treated patients. Key finding: TDF was not associated with higher risk of worsening renal function in this cohort with a mean followup of 43-46 months in patients with baseline normal renal function. In patients with renal impairment, deterioration of renal function was noted in TDF-treated patients. Thus, TDF should be avoided in patients with impaired renal function.
A recent study (B Fischler et al. JPGN 2019; 68: 700-05) compared the similarities and differences in allocation experience among 15 countries based on a survey completed by a representative hepatologist in each country.
The number of liver transplants was 4 to 9 million inhabitants younger than 18 years for 13 of the 15 respondents. USA had the 5th highest rate at ~7 per million inhabitants (Figure 2)
USA had the 3rd highest donation rate per million inhabitants, ~26 per million. Spain had highest rate at 35 per million. This is partly related to Spain allocating all nonugent pediatric cadaveric donors to pediatric candidates.
USA had the 3rd lowest rate of living-related liver transplantation percentage in children < 2 yrs, approximately 10%. Both Turkey and Poland had rates near 90%.
USA had one of the lowest rates of %split liver transplantations for children <2 yrs, less than 10%. Italy, Netherlands, and New Zealand had rates near 90%.
USA had the 4th highest waitlist mortality for children <2 yrs, approximately 11%
My take: This study indicates that the rate of split liver transplants and living related liver transplants are much lower in USA than in other countries. This is likely to reduce donor pool and contribute to increased waiting list mortality.