Online Aspen Webinar (Part 2) -Abnormal Liver Enzymes in a Tween

What Do Abnormal Liver Enzymes Mean in a Tween William Balistreri

Below I’ve included a few slides and some notes; my notes may have errors of omission or transcription.

Key Points:

  • Provided updated normal reference data for ALT/AST along with patterns of abnormalities
  • Reviewed step-wise workup for teenagers with elevated ALT/AST, particularly fatty liver disease and drug-induced liver disease
  • Increasingly frequent cause of fatty liver disease: psychotropic medications
  • Discussed role/indications of liver biopsy. Liver biopsy is NOT practical option for all children with fatty liver disease and elevated liver enzymes
  • However, ALT values tend to underestimate severity of liver disease



ACG Review (Zobair Younassi, MD): NAFLD and NASH

For PDF copy of slides: NAFLD and NASH

Dr. Zobair Younassi gave a recent virtual grand rounds –here are some of the slides:


Natural History:

  • Progression of disease is not linear
  • Fatty liver disease is a multisystem disorder.  Cardiovascular disease is leading cause of death in patients with fatty liver disease
  • Fatigue (~50%) is common with fatty liver disease

Main treatment:

  • Weight loss -Mediterranean diet may be helpful
  • Exercise
  • No FDA-approved treatments, though pioglitizone supported by AASLD for biopsy-proven NASH
  • Public health interventions are needed

China Is Catching and Passing U.S. with NAFLD Plus Updates

F Zhou et al. Hepatology 2019; 70: 1119-33. The authors performed a systematic review (n=392 studies, more than 2 million subjects) and found that NAFLD in China increased from 25.4% in 2008-2010 to 32.3% in 2015-2018. The pooled prevalence across all studies was 29.2%. The associated editorial speculates that some of this increase is related to diet changes as well as PNPLA3 gene.  This allele “is more common among East Asians than Caucasians”  It is lower in African Americans in the U.S. which helps explain why this population is at reduced risk.

JB Schwimmer, JS Johnson et al Gastroenterol 2019; 157: 1109-22.  In this prospective study with 87 children (89% Hispanic), the authors associated fecal microbiomes with NAFLD and NASH.  Both NAFLD and NASH were associated with intestinal dysbiosis with lower diversity and high abundance of Prevotella copri. Full text link: Microbiome Signatures Associated With Steatohepatitis and Moderate to Severe Fibrosis in Children With Nonalcoholic Fatty Liver Disease

S Pelusi et al. Clin Gastroenterol Hepatol 2019; 17: 2310-9.  This study analyzed data from 1738 subjects (45% with severe obesity) who had undergone liver biopsy.  132 of 389 (33.9%) with significant fibrosis did NOT have nonalcoholic steatohepatitis (NASH) and 39 patients (10%) had no inflammation. NASH diagnosis required steatosis (≥5% of hepatocytes), hepatocellular ballooning, and lobular inflammation. Factors associated with significant fibrosis in the absence of NASH, included fasting hyperglycemia, severe steatosis, mild inflammation or ballooning, and PNPLA3 1148M variant.  My take: this study shows that the finding of NASH on liver biopsy is NOT required for the development of severe liver disease related to NAFLD.

D Linden et al. Molecular Metabolism 2019; 22: 49-61. This study, summarized in Gastroenterol 2019; 157: 1156-9) showed that PNPLA3 silencing with antisense oligonucleotides ameliorates NASH in PNPLA3 1148M knock-in mice.  The summary notes that the mutated 1148 M PNPLA3 protein variant accumulates on lipid droplets altering clearance and affecting triglycerides and phospholipid turnover.

How Successful is Liver Transplantation for Fatty Liver Disease?

A recent guideline update (ZM Younossi. Liver Transplantation 2018; 24: 166-70) provides some useful information about nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and liver transplantation (LT).

Key points:

  • “Despite metabolic comorbidities, posttransplant outcomes of NASH patients are generally good.  In fact, 1-, 3-, and 5-year patient and graft survival rates are …similar to other liver diseases.”
  • NASH/NAFLD can recur following LT…”NASH with significant fibrosis (stage ≥2) occurs in approximately 5% of recipients by 5 years after transplantation.”
  • Additional issues to manage after LT, include weight management, and metabolic conditions including diabetes, hypertension, dyslipidemia, and hypertension.  All of these conditions can be affected by specific immunosuppressants.  For example, calcineurin inhibitors and corticosteroids can exacerbate type 2 diabetes mellitus.

My take: This article indicates better LT outcomes than I expected in patients with NASH/NAFLD.

Related blog posts:

Bright Angel Trail

NAFLD Guidance from American Association for the Study of Liver Diseases

Link: AASLD Guidance for the Diagnosis and Management of Nonalcoholic Fatty Liver Disease

This guidance provides a 2018 review of NAFLD and current diagnostic/management recommendations in both adults and children.  Some points from this practice guidance:

  • “Liver-related mortality is the second or third cause of death among patients with NAFLD.” Cardiovascular disease remains the number one and cancer-related mortality is in the top three.
  • “Routine screening for NAFLD in high-risk groups attending primary care, diabetes, or obesity clinics is not advised at this time because of uncertainties surrounding diagnostic tests and treatment options.” Likewise, screening of family members is not recommended.
  • In children: “Because of a paucity of evidence, a formal recommendation cannot be made with regard to screening for NAFLD in children with overweight and obesity.”
  • In patients undergoing evaluation with suspected NAFLD, the authors specifically recommend checking ferritin, iron saturation, and autoantibodies that could indicate autoimmune liver disease.
  • In patients with suspected NAFLD, the authors recommend evaluation for comorbities including dyslipidemia, diabetes, hypothyroidism, polycystic ovary syndrome, and sleep apnea.
  • “Liver biopsy should be considered in patients with NAFLD who are at increased risk of having…advanced fibrosis” and in “whom competing etiologies…cannot be excluded without a liver biopsy.”
  • Pharmacologic therapies are not recommended in those without biospy-proven NASH and fibrosis.  Specifically, the authors suggest consideration of pioglitazone and vitamin E and recommend against metformin, GLP-1 agonists, omega-3 fatty acids, and ursodeoxycholic acid.
  • “Weight loss (7%-10%) is needed to improve the majority of histopathological features of NASH.”
  • In patients with cirrhosis due to NASH, screening for varices is recommended and consideration of screening for HCC.

My take: This practice guidance is quite reasonable.  At this time, more focus on systemic measures to counter overweight and obesity is crucial.  Pharmacologic therapies for NAFLD will need to be effective for the cardiovascular, metabolic, and liver-related problems.

Related blog posts:

Bright Angel Trail, Grand Canyon

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:

Hepatology Update -Summer 2014

Preventing Perinatal Transmission of Hepatitis B Virus (HBV): Hepatology 2014; 60: 468-76.  This nonrandomized study, conducted between 2009-2011 with approximately 700 patients, showed that the rate of perinatal transmission of can be brought down almost to zero by instituting therapy with either telbivudine or lamivudine in the third trimester of pregnancy.  The accompanying editorial (pgs 448-51) indicates that either telbivudine or tenofovir (both pregnancy class B agents with regard to teratogenicity) are preferred agents due to higher barrier to resistance. And, the article suggests starting as early as week 28 (especially if high viral HBV DNA load) and no later than 32 weeks gestation. Other recommendations from editorial include stopping antiviral after delivery in women who intend to breastfeed.

More on coffee: Hepatology 2014; 60: 661-69.  Coffee but not tea conferred protection from cirrhosis mortality.  “Compared to non-daily coffee drinkers, those who drank two or more cups per day had a 66% reduction in mortality risk.”  This study also had an accompanying editorial (pg 464-67) which reviews the biologic plausibility and potential mechanisms.

NASH pathology: Hepatology 2014; 60: 565-75.  The study describes a more precise way to categorize the diagnosis of nonalcoholic steatohepatitis (NASH) using the European Fatty Liver Inhibition of Progression (FLIP) pathology consortium proposal.  The diagnosis of NASH requires the presence of ballooning and lobular inflammation in addition to steatosis.  Using the FLIP approach, diagnosis concordance increased significantly.

Related blog posts:


Does NAFLD cause hepatocellular cancer?

Probably (Clin Gastroenterol Hepatol 2012; 10: 1342-59).

The authors of this study reviewed original reports between 1992-2011 and narrowed them to those with pertinent information regarding evidence of whether non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) contributed to a higher risk of hepatocellular carcinoma (HCC).

17 cohort studies, 18 case-control and cross-sectional studies, and 26 case series were identified.


  • Cohorts with NASH and cirrhosis had a consistently higher risk of HCC; cumulative risk ranged from 2.4% over seven years to 12.8% over 3 years.
  • Cohorts with few or no cases of cirrhosis had a minimal risk of HCC; cumulative risk of HCC mortality was 0-3% for study periods up to 20 years.

The results of patients with NASH and cirrhosis are in agreement with a recent presentation at AASLD meeting; however, there may be a small risk even in the absence of cirrhosis (Fatty Liver Disease Cited for Rise in Hepatocellular Carcinoma November 2012):

“Of 17,895 HCC cases in the linked Surveillance, Epidemiology and End Results (SEER)-Medicare database, 2,863 (16%) had only NAFLD without any other risk factors or etiologies for HCC. The linked database covers 30% of the U.S. Medicare population. SEER itself contains data from 18 cancer registries covering 28% of the U.S. population.” In addition, “Cirrhosis was not present in 36% of the NAFLD-related HCC cases.” In the SEER database, the odds ratio for developing HCC with cirrhotic NAFLD was 16.5 compared with those with noncirrhotic NAFLD.

Related blog entry:

NAFLD Guidelines 2012 | gutsandgrowth

Can NALFD be improved with bile acid sequestration?

Probably not (Hepatology 2012; 56: 922-32).

Because bile acid sequestrants like colesevelam (& cholestyramine) lower plasma low density lipoprotein (LDL) levels and can improve glycemic control, a recent study tested the hypothesis that this would result in improvement in patients with biopsy-proven nonalcoholic steatohepatitis (NASH).

Methods: 50 patients were randomly assigned to either colesevelam 3.75 g/d or placebo for 24 weeks.  All patients had a liver biopsy within 6 months as a baseline study.  The primary outcome was liver fat as measured by a MRI technique (proton-density fat-fraction or PDFF) and by MR spectroscopy. At the start and conclusion of the study patients had biochemical assays, MRI-PDFF & MR spectroscopy; also, patients had a liver biopsy at completion of study.

Results: The colesevelam group had increased fat at the conclusion of the study period by a mean difference of 5.6% with PDFF and 4.9% with MR spectroscopy, both compared with placebo group.  In addition, liver biopsy did not detect any effect of treatment.  Looking at the biochemical indices, there was also a trend of increased transaminases in the treatment group compared to the control group (Table 3 in study).

Conclusions: The authors indicate that the increased fat may be due to a compensatory increase in bile acid synthesis.  Also, as the changes in fat were only detected on MRI, future NASH studies may benefit from this technique as well.

Related blog entries:

NAFLD Guidelines 2012 | gutsandgrowth

Pediatric NAFLD Position Paper | gutsandgrowth

Pediatric NAFLD Position Paper

A previous blog post (NAFLD Guidelines 2012) described comprehensive, up-to-date NAFLD guidelines from AASLD, AGA, and ACG.   Another group of experts from ESPGHAN (European Society for Pediatric Gastroenterology, Hepatology, and Nutrition) has also published a position paper on the diagnosis of NAFLD in children; coincidentally, these were published recently as well (JPGN 2012; 54: 700-13).

While there is some overlap in the information between the two guidelines, there are some notable differences.  The JPGN manuscript does include a nice differential diagnosis list  which can cause fatty liver disease (Table 2), including some rare entities like Dorfman-Chanarin syndrome, Cantu syndrome, Madelung lipomatosis, and numerous medications.  This review has more emphasis on etiology.

Table 3 lists a recommended workup in children with suspected NAFLD:

  • Standard liver function tests/blood counts/coagulation studies
  • Fasting glucose & insulin
  • Lipid profile
  • Glucose tolerance test & glycosylated hemoglobin
  • Calculation of HOMA-IR, markers of insulin resistance

AND Tests to exclude other liver diseases: 

  • Lactate, uric acid, iron, ferritin, pyruvate
  • Copper, ceruloplasmin, 24-hour urinary copper
  • Sweat test
  • Celiac serology (TTG IgA and serum IgA)
  • α-1-antitrypsin levels and phenotype when indicated
  • Amino and organic acids
  • Plasma free fatty acids and acyl carnitine profile
  • Urinary steroid metabolites
  • Other specific tests as suggested by evaluation (eg. viral hepatitis panel, serum immunoglobulins, liver autoantibodies)

When one looks at the recommended diagnostic algorithm (Figure 1) and tests outlined, these guidelines are not nearly as practical as the NAFLD guidelines from AASLD, AGA, and ACG and often contradictory between the tables/figures and the text.  How much would it cost for the recommended testing if/when extrapolated to the vast numbers of individuals with these disorders?  In addition, a much more limited diagnostic approach is suggested in the final section than outlined in Table 3 and Figure 1.

Imaging: these authors advocate LFTs and ultrasonography in all obese children (> 3 years) and adolescents.  If normal LFTS and sonography, the algorithm suggests the use of MRI if clinical signs of insulin resistance.  Later, the authors conclude “MRI is not cost-effective.”

Liver Biopsy: while the authors state that there is “no present consensus or evidence base to formulate guidelines” for liver biopsy, this is not well-reflected in their diagnostic algorithm in which arrows point to liver biopsy in almost everyone –either early liver biopsy or eventual biopsy in patients with persistent disease.  Accepted liver biopsy indications, according to the executive summary, include the following:

  • Exclude other treatable disease
  • Suspected advanced disease
  • Before pharmaceutical/surgical treatment
  • Research purposes

My conclusion about this position paper is it is less helpful than the AASLD/AGA/ACG guidelines.  In fact, when extensive diagnostic testing is recommended by experts, it is fortunate that other expert guidelines are available that support a more cost-effective approach.  In NAFLD cases that seem atypical and especially in the very young patient, this reference may still be helpful.