Category Archives: Pediatric Gastroenterology Liver Disease

Pediatric Fatty Liver Disease Study: New York City

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A recent autopsy study (DM Fernandes et al. J Pediatr 2018; 200: 174-80) examined nonalcoholic fatty liver disease (NAFLD) in a pediatric cohort of 582 (2-19).  Approximately 75% were in 14-19 years of age and 50% were black; black pediatric patients (n=290) were over-represented in this sample only 25% of the New York population is black or African American based on the 2010 census.

Key findings:

  • Causes of death: 49% homicides, 31% accidents, 10% acute illness, 9% suicide, 1% other
  • Overall, NAFLD was present in 4.5%; this low overall prevalence was due in part to the low rate of NAFLD in black children; only 3 of 290 (1%) had NAFLD and none had nonalcoholic steatohepatitis (NASH)
  • The rate of NAFLD was 7.9% in hispanics and 8.3% in white patients.
  • In this cohort, 36% were overweight or obese.  In this subgroup, 14.1% of hispanics and 14.8% of whites had NAFLD.
  • Overall, NASH was present in 1.7% of the entire cohort.  NASH and fibrosis have been shown in prior studies as the best predictors of disease progression

My take: If black children are not killed by homicide or accidents, it is unlikely that they will die from NAFLD due to its low prevalence.

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Sunshine Meadows, Banff

Effects of Surgical Shunts on Liver Atrophy in Patients with Noncirrhotic Portal Vein Thrombosis

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A recent study (AS Elnaggar et al. Liver Transplantation 2018; 24: 881-87; editorial 868-9) examine the effect of different types of surgical shunts in the setting of portal vein thrombosis (PVT).  The authors examined surgical shunts from 1998-2011 in their institution (senior author: Jean Emond).

  • 40 patients received “portal flow-preserving shunts”: 32 mesoportal and 8 selective splenorenal
  • 24 received portal flow-diverting shunts (16 nonselective splenorenal and 8 mesocaval)
  • Of these 64 patients, only 39 had preoperative and postoperative cross-sectional imaging.   In addition, only 11 patients who had mesoportal shunt (7 children and 4 adults) had preoperative and postoperative cross-sectional imaging allowing for volume comparison.

Key finding:

  • In patients receiving portal flow-preserving shunts (mainly mesoportal), this was associated with liver volume expansion (886 versus 1131 cm to the third), whereas diverting shunts were not.

The authors note that liver atrophy, especially in children, can have a “significant effect on cognitive function and somatic growth.”  Thus, restoring portal flow may improve adverse effects that PVT has caused.

Limitations:

  • Lack of validation of their formula to calculate liver volumes in the pediatric age group
  • Relatively short follow-up:5.7 months in the portal-preserving group and 11 months in the other group
  • Small numbers of patients..

Long-term followup of patients who have needed surgical shunts is needed.  For mesoportal shunts, strictures have been noted in the hepatic end in 15% of patients.

My take: This study shows that portal blood flow, which was interrupted by PVT and restored by mesoportal (Rex) shunt, is important in maintaining liver mass. So, while all shunts may stop upper GI bleeding, mesoportal shunt is likely to improve other adverse effects of PVT.

Virginia Museum of Fine Arts (Richmond) has acquired Chihuly’s Red Reeds

Elastography –Accuracy in Children

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Background: Transient elastography may help identify patients at greater risk for advanced fibrosis but there is a significant overlap between fibrosis stages and values with transient elastography. In some conditions, like fatty liver, elastography may be less helpful than in others (eg. chronic viral hepatitis).

A recent study (J Pediatr 2018; 198: 84-9) examined the results of transient elastography in 267 children (97 for calibration, 170 for validation) between 2006-2016.  The median age was 13 years.  Liver diseases included autoimmune (21%), viral (19%), fatty liver (11%), cholestatic (9%), primary sclerosing cholangitis (9%) and post-transplantation (12%).

Key findings:

  • Cut points to discriminate F3-F4 and F4 were >8.6 kPa and >11.5 with 81% and 84% accuracy, respectively in calibration cohort
  • To discriminate F3-F4 and F4 in validation cohort, these cut points, >8.6 kPa and >11.5, had accuracy of 67% and 75% respectively

Figure 2 provides much greater detail in the typical values for each Metavir stage. For example, in the calibration cohort, the median values and range were the following:

  • F0   6.0 (3.2-12.4)
  • F1   6.2 (3.2-75)
  • F2   5.8 (2.5-52.7)
  • F3  10.3 (4.9-32.6)
  • F4  20.5 (5.9-68.1)

In the validation cohort, values were similar:

  • F0   6.2 (3.0-75.0)
  • F1   7.1 (3.3-31.6)
  • F2   7.1 (2.5-52.7)
  • F3  9.6 (4.4-75.0)
  • F4  20.8 (6.8-75.0)

My take: Elastography in measuring liver stiffness is a lot like checking a CRP for inflammatory bowel disease.  That is, it can be helpful but cannot be relied on the same way as many radiographic tests (eg. CT scans for appendicitis).

Related blog post:

Moraine Lake, Banff

How Often Is Surgical Treatment for Biliary Atresia Delayed Beyond 60 Days?

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It is recognized that there is often a delay in the diagnosis of biliary atresia (BA).  A recent study (MR Townsend et al. J Pediatr 2018; 199: 237-42) indicates that hepatoportoenterostomy (HPE) or Kasai procedure is performed in only 37.7% of patients with BA prior to 60 days of age. The data was obtained from the Agency for Healthcare Research and Quality’s Healthcare Cost and Utilization Project (HCUP) Nationwide Inpatient Sample files from 2000-2011.

  • Risk factors for delayed HPE: This study of 1243 patients with BA found that those with delayed HPE were more often uninsured–all self-pay patients had HPE after 60 days, more often black (aOR 4.22), and less likely at a teaching hospital (aOR 0.27).
  • Delayed HPE was associated with increased adverse perioperative outcomes and increased cost.

My take: We have a long way to go if we are going to consistently identify and treat BA in a timely manner.

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Pediatric NAFLD: You Don’t Have to be Obese/Overweight to Have Fatty Liver Disease (but it helps)

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A recent study (P Kumar et al. JPGN 2018; 67: 75-9) examined suspected NAFLD in 12 to 18 year olds using data from NHANES. In the analysed cohort, there were 124 suspected NAFLD and 1385 without suspicion of NAFLD.  This subset was weight to represent a U.S. population of over 18 million.

Key definitions:

  • Suspected NAFLD was defined by abnormal ALT (>25.8 U/L for boys and >22.1 U/L for girls) who did not have another explanation (eg. viral hepatitis, medication)
  • Lean BMI was defined by BMI less than 85th% for age
  • Hypertriglyceridemia ≥ 150
  • Low HDL ≤ 40 mg/dL
  • HOMA-IR =fasting glucose x insulin (microU/mL) divided by 405. Insulin resistance was defined as HOMA-IR ≥ 3

Key findings:

  • Suspected NAFLD affects ~8% of lean adolescents in the U.S.
  • Hypertriglyceridemia was noted in 10 of 124 suspected NAFLD and was a risk factor (P=0.028) as was Low HDL which occurred in 15 (P=0.016) and IR which occurred in 43 (P=0.053)

My take: Elevated ALT, a marker for fatty liver disease, is common even in adolescents without obesity. Elevated triglycerides, low HDL, and insulin resistance are all risk factors for suspected NAFLD in non-overweight/non-obese teens.

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Cumberland Island 2018

Pilot Study: Treating Obstructive Sleep Apnea with Beneficial Effects on Fatty Liver Disease in Children

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Briefly noted: A small pilot study (n=9) (SS Sundaram et al. J Pediatr 2018; 198: 67-75) showed that treatment (with home CPAP) of obstructive sleep apnea (OSA) was associated with improved alanine aminotransferase levels, reduced metabolic syndrome markers and lower F(2)-isoprostanes (a marker of oxidative stress) in pediatric patients with nonalcoholic fatty liver disease (NAFLD). All nine of the participants were Hispanic males with a median age of 11.5 years; they had a median BMI of 29.5 and had biopsy-proven NAFLD. The improvement in NAFLD parameters occurred despite an increase in BMI. The authors note that studies in adults have shown contradictory findings with regard to whether treatment of OSA helps NAFLD.

My take: This study suggests potential beneficial liver effects of treating OSA.  Regardless, treatment of OSA could be considered a quality metric in the care of children with NAFLD as better sleep at night has additional clear benefits.

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Outside Mercedes-Benz Stadium (Atlanta)

More Acceptance (of livers), Better Outcomes

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An important metric of liver transplantation outcome is not readily available: acceptance of organ offers.  A recent study (E Mitchell et al. Liver Transplantation 2018; 24: 803-809) showed a great deal of variability among pediatric liver transplantation centers in this metric.

The authors examined data from 2007-2015 with 4088 unique patients and 27,094 match runs. The range in organ acceptance rates was 5.1% to 14.6% with a median of 8.9%.

Key finding:

  • “Center-level acceptance rates were associated with wait-list mortality, with a >10% increase in the risk of wait-list mortality for every 1% decrease in a centers adjusted liver offer acceptance rate (odds ratio, 1.10, CI 1.01-1.19)

As noted in a previous post, Pediatric Liver Transplantation -Past Time to Split, larger centers generally have higher acceptance rates.

My take: This study adds to the literature regarding the inequities that some patients unknowingly face when listed in some centers.

Related article: HPJ van der Doef et al. Liver Transplantation 2018; 24: 810-9.  This article describes the wait-list mortality of young patients with biliary atresia.  Those listed before age 6 months and with higher MELD scores (>20) were at increased risk. Recognition of these factors may help improve allocation.

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Hate it when this happens!

Time-to-diagnosis of Biliary Atresia

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A recent study (S Harpavat et al. JPGN 2018; 66: 850-6) identifies race/ethnicity as a factor affecting the timeliness of diagnosis.

Specifically, non-Hispanic white infants were diagnosed earlier than non-Hispanic black infants and Hispanic infants (P=.007); this was related to the timing of referral from the primary care physician.  The authors speculate that this could be related to three factors:

  • lighter colored skin could help identify jaundice more quickly
  • better access to health care
  • implicit bias leading to uneven treatment

The other finding in the study was that after referral, patients referred after 30 days of life had a more expedited diagnosis than those referred prior to 30 days of life.  The authors caution that the histology in these early cases is similar to those who present later, even if their aminotransferases are normal.  In addition, while physicians and parents want to avoid ‘over testing,’ prompt diagnosis, even prior to 30 days of life, may lead to improved outcomes.  Thus, the authors recommend proceeding with liver biopsy if there is clinical suspicion of biliary atresia.

My take: Obtaining objective evidence of cholestasis in infants that are jaundiced beyond 2 weeks of life is important.  This study highlights some of the reasons why the diagnosis is delayed in so many.

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How to Identify Dubin-Johnson Syndrome

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Typically, most pediatric gastroenterologists want to remember that the gross appearance of the liver in patients with Dubin-Johnson is black as this is rumored to be a frequently asked question for board testing.  Practically, though other features are important to recognize since the color of the liver is not readily evident except during surgery.  As such, a recent retrospective study (T Togawa et al. J Pediatr 2018; 196: 161-7) describes 10 neonatal patients from Japan.

Key findings:

  • Only 3 of the 8 patients who underwent liver biopsy had a grossly black liver
  • All liver specimens showed no expression of multidrug resistance-associated protein 2 and increased expression of the bile salt export pump protein
  • Homozygous or compound heterozygous pathogenic variants of ABCC2/MRP2 (ATP-binding cassette subfamily C member 2/multidrug resistance-associated protein 2) were identified in all patients

The clinical course was similar in the patients:

  • Cholestasis self-limited/benign: “severe cholestasis developed in the neonatal period…reaching a maximum at 19 to 60 days. Cholestasis then decreased and disappeared at 2 to 9 months of age.”  Acholic stools were common during the cholestatic phase.
  • Serum AST and ALT remained consistently normal
  • There was no hepatosplenomegaly and no failure to thrive

My take: Dubin-Johnson syndrome is much easier to identify with the availability of genetic panels.

Related blog post: Dubin-Johnson Syndrome

 

Hereditary Fructose Intolerance

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A recent case series (Li H, A Diaz-Kuan, M Vos et al. Mol Genet Metab. 2018 Apr;123(4):428-432) highlights the importance of dietary history in infants with liver failure (abstract below).  Congratulations to my colleague Miriam Vos one of the coauthors.

Commentary on this publication from Emory News (from Kipp Ellsworth’s twitter feed):

Babies with inherited intolerance of fructose face a risk of acute liver failure if they are fed certain widely available formulas containing fructose, pediatricians and geneticists are warning. Baby formula manufacturers should remove fructose or sucrose, or explicitly label their products to allow parents to avoid those sweeteners if necessary, the doctors say.

In a recent paper in Molecular Genetics and Metabolism, Emory geneticists Hong Li, MD, PhD and Michael Gambello, MD, PhD together with Children’s Healthcare of Atlanta pediatric hepatologist Miriam Vos, MD and colleagues report four cases of hereditary fructose intolerance (HFI), all diagnosed in early infants. All had acute liver failure that resolved when the infants switched to formula without fructose.

HFI is estimated to occur in 1 out of 20,000 live births. It comes from mutations in the aldolase B gene, resulting in an inability to metabolize fructose. Early symptoms include nausea, vomiting, abdominal pain and failure of an infant to gain weight. If unrecognized, HFI can result in liver and kidney damage, seizures or death.

HFI-related problems do not appear if an infant is being breastfed exclusively. It is normally recognized when fructose-containing solid foods, such as fruit, are introduced into the diet several months after birth. However, some baby formulas – often soy-based – contain sweeteners such as high-fructose corn syrup or sucrose (table sugar), which is made of fructose and glucose linked together. Sometimes, the label only says “sugar” instead of sucrose…

Since HFI is a treatable disease, Li urges pediatricians to consider HFI as a potential diagnosis if there is a feeding problem, elevated transaminase enzymes or jaundice (a sign of liver damage) and the infant has been fed formula containing fructose or sucrose.

Some information about a young patient’s condition can be obtained from urine carbohydrate tests, but the only way to confirm HFI is by genetic sequencing.

Abstract:

Hereditary fructose intolerance (HFI) is an autosomal recessive disorder caused by aldolase B (ALDOB) deficiency resulting in an inability to metabolize fructose. The toxic accumulation of intermediate fructose-1-phosphate causes multiple metabolic disturbances, including postprandial hypoglycemia, lactic acidosis, electrolyte disturbance, and liver/kidney dysfunction. The clinical presentation varies depending on the age of exposure and the load of fructose. Some common infant formulas contain fructose in various forms, such as sucrose, a disaccharide of fructose and glucose. Exposure to formula containing fructogenic compounds is an important, but often overlooked trigger for severe metabolic disturbances in HFI. Here we report four neonates with undiagnosed HFI, all caused by the common, homozygous mutation c.448G>C (p.A150P) in ALDOB, who developed life-threatening acute liver failure due to fructose-containing formulas. These cases underscore the importance of dietary history and consideration of HFI in cases of neonatal or infantile acute liver failure for prompt diagnosis and treatment of HFI.

Related blog post: Changing Approach to Neonatal Acute Liver Failure

Chattahoochee River Near Island Ford