Pediatric Liver Enzyme Reference Values

A recent study (S Bussler et al. Hepatology 2018; 1319-1330)  provides reference age-related reference values for ALT, AST, and GGT for children from 11 months of age through 16 years.  This study from Leipzig used the LIFE Child prospective longitudinal population-based cohort with 3,131 cases (normal weight).

  • Figure 2 provides age- and sex-related percentiles for ALT.  At all ages and in both genders, the 90% cutoff was ~30 IU (or less).
  • Figure 3 provides age- and sex-related percentiles for AST.  There was a negative sloping curve with both genders, such that the 90% cutoff was ~60 IU at ~1 yr and ~40 IU at ~13 yr. Females tended to have modestly higher values.
  • Figure 4 provides age- and sex-related percentiles for GGT.  At all ages and in both genders, the 90% cutoff was ~25 IU. Males tended to have modestly higher values.

These values overall are similar to previous studies. From NASPGHAN NAFLD Guidelines: For ALT: “In the United States, sex-specific biologically based cutoffs have been determined from nationally representative data and have been validated in a fairly diverse cohort. These cutoffs are 22 mg/dL for girls and 26 mg/dL for boys. A Canadian study found the upper limit of normal for ALT to be 30 mg/dL in children 1 to 12 years of age, and 24 mg/dL in those between 13 and 19 years”

Related blog post: Pediatric NAFLD Guidelines 2017

Near Banff

 

In NASH, is ALT Wrongly Used as a Marker of Liver Injury?

According to a recent report (Hepatology 2015; 61: 153-60), elevation of alanine aminotransferase (ALT) which is frequently used as an indicator to select patients for further investigations (eg. liver biopsy) is NOT a good indicator of liver parenchymal injury in patients with nonalcoholic fatty liver disease (NAFLD).

The researchers enrolled 440 patients and divided them into three groups: no NAFLD (n=60), NALFLD with normal ALT (n=165), and NAFLD with elevated ALT (n=215). The patients were overweight/obese patients prospectively recruited from newspaper ads, general medicine clinics and hepatology clinics at several VA hospitals. Those with history of alcohol abuse were excluded.

Numerous investigations were performed including liver fat by proton magnetic resonance spectroscopy (H-MRS), liver biopsy (n=293), and insulin resistance measurements.

Key findings:

  • NAFLD & NASH patients with elevated ALT had higher liver triglyceride content (P<0.0001), worse adipose tissue insulin resistance (ATIR) (P<0.0001), and lower plasma adiponectin (P<0.05).
  • Steatosis was worse on liver biopsy in those with NASH and elevated ALT (P<0.0001).
  • There were no differences in liver inflammation (P=0.62), ballooning (P=0.13), or fibrosis (P=0.12). Thus, patients with normal versus elevated ALT had similar severity of NASH liver histology.

Take-home message:  In adults, ALT values are “poor surrogate markers of disease activity” in NAFLD.  ALT values, in these patients, are indicative of metabolic disease.  Given the staggering numbers of individuals, adults and children, with fatty liver disease, the lack of simple screen tool is quite problematic.  Equally problematic is a lack of a simple treatment approach.

Related blog posts:

NAFLD –Analogous to a Dog Chasing A Bus?

I am not sure of the origin of the expression “what is a dog going to do if it catches a bus?”  However, I am reminded of this expression after reading a recent article about nonalcoholic fatty liver disease (J Pediatr 2014; 164: 707-13).

This retrospective study, “Histologic Abnormalities in Children with Nonalcoholic Fatty Liver Disease with Normal or Mildly Elevated Alanine Aminotransferase Levels,” analyzed 91 children (5-18 years) with suspected NAFLD who had normal or mildly elevated ALT values from 12 U.S. medical centers.  They obtained liver biopsy specimens within 180 days of the ALT measurement and compared them from 392 children with elevated ALT.

When reading this title, one has to wonder, how did they select these children for this study?  First of all the authors used two NASH CRN databases with 483 children.  The reasons for NAFLD evaluation at entry in the current study included symptoms of liver disease in 22%, identification during evaluation of another illness in 38%, routine physical exam (41%), and other causes in 6%. At one point, elevated ALT was evident in 74% and radiographic evidence of steatosis in 55%.

The authors conclude that “liver biopsy specimens from children with NAFLD with normal or mildly elevated ALT levels show significant histological abnormalities, including advanced fibrosis…measurement of ALT may underestimate liver injury in NAFLD.” Yet, while it is true that ALT values may not have adequate sensitivity for liver injury, the authors deploy some circular logic; when one understands the selection of these patients, it comes as no surprise that some had advanced liver findings on biopsy.  If one identifies an abnormal liver on ultrasound and confirms this on liver biopsy, this is targeting a population whose findings are not generalizable.

Outside of a research study, how does one decide which patients will benefit from a liver biopsy? This study does not offer any clarity.

And, if one identifies more cases of NAFLD, what is one to do?  Besides weight loss (which should be recommended already in the majority), there are no other proven treatments.  The associated editorial (pgs 684-86) reminds the reader to use appropriate normative values for ALT (<25.8 U/L for boys and <22.1 U/L for girls).  In the study’s discussion, the lack of consensus among expert recommendations is acknowledged.  Furthermore, in those who have recommended frequent screening with ALT values in obese children, the authors note that “evidence of the utility and cost-effectiveness of this approach is still lacking.”

Another study in the same issue (J Pediatr 2014; 164: 699-706) suggests a possible link between obstructive sleep apnea (OSA) and more advanced liver histology in NAFLD.  This was a cross-sectional study with only 25 patients (88% Hispanic, mean age 12.8 years).  The authors speculate that nighttime hypoxemia triggers oxidative stress and may induce further liver injury.  53% of those with OSA had stage 2 or higher fibrosis compared with only 10% of those without OSA.

Bottomline: NAFLD occurs in a lot of children and a normal or mildly elevated ALT does not exclude more severe disease.  OSA may be either an epiphenomenon or a causative factor for more severe NAFLD findings.

Related blog posts: