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.

#NASPGHAN19 Postgraduate Course (Part 4)

Here are some selected slides and notes from this year’s NASPGHAN’s postrgraduate course. With my notes, there could be errors of omission and transcription on my part.

Link to the full NASPGHAN PG Syllabus 2019 (Borrowed with permission)

Liver/Pancreas Session

150 Miriam Vos, MD, MSPH, Emory University New news in NAFLD

Dr. Vos gave a terrific lecture. Key points:

  • NAFLD screening: recommended around age 10 years (in children with obesity) based on increasing prevalence with age
  • PNPLA3 encodes adiponutrin –> important for clearing stored triglycerides. Common polymorphism PNPLA3 rs738409‐is associated with NAFLD
  • Who to screen –all obese children >10 years. Overweight children  with risk factors: Type II diabetes,  Hispanic,  Family history,  Pituitary  disorders (GH),  Right sided  abdominal pain
  • ALT and ultrasound are imperfect screens
  • Alcohol worsens NAFLD.  Sugar/juice boxes are also culprits
  • #1 Recommendation: Sugar reduction in diet

Related blog post: “The Paramount Health Challenger for Humans in the 21st Century”

161 Saul J. Karpen, MD, PhD, Emory University School of Medicine/Children’s Healthcare of Atlanta New therapies for chronic cholestatic diseases

  • Limited therapies currently available.  A number of treatments appear promising:  Obeticholic acid, Norursodeoxycholic acid
  • For ABCB4, some drugs used for cystic fibrosis may help as well
  • ASBT inhibitor appears promising for Alagille (see ITCH study)

171 Sohail Husain, MD, Stanford Children’s Hospital Diagnosing drug-induced pancreatitis

  • In patients with IBD, thiopurines and mesalamine/ sulfasalazine (mesalamine have greater risk than sulfasalazine) are associated with pancreatitis
  • ~1/3rd of patients with drug-induced pancreatitis have other risk factors

179 Jaimie D. Nathan, MD, FACS, Cincinnati Children’s Hospital Medical Center Pediatric pancreatic masses: Steroids, surgery or surveillance?

Disclaimer: NASPGHAN/gutsandgrowth assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. The discussion, views, and recommendations as to medical procedures, choice of drugs and drug dosages herein are the sole responsibility of the authors. Because of rapid advances in the medical sciences, the Society cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure. Some of the slides reproduced in this syllabus contain animation in the power point version. This cannot be seen in the printed version.

 

Pediatric Fatty Liver Disease Study: New York City

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.

Related blog posts:

Sunshine Meadows, Banff

Silymarin for Nonalcoholic Steatohepatitis

A recent study (CW Kheong et al. Clin Gastroenterol Hepatol 2017; 15: 1940-9) examined the use of silymarin (milk thistle) in a randomized, placebo-controlled, double-blind trial for nonalcoholic steatohepatitis (NASH). Patients (n=49) who were assigned to silymarin received 700 mg three times a day for 48 weeks; there were 50 patients assigned to placebo..

Key findings: 

  • Silymarin did not significantly improve the primary outcome of achieving a lower NAS score by 30% or more; this occurred in 32.7% of the silymarin group vs. 26.0% in the placebo group.
  • Reduction in fibrosis was noted in the silymarin group (histology drop by 1 point or more): 22.4% compared to 6.0% in the placebo group.

Silymarin has many potential beneficial properties: anti-oxidant, anti-inflammatory, anti-fibrotic, anti-viral, and metabolic functions.

My take: Given the safety of silymarin, if these findings can be confirmed in a larger trial, it would be an exciting advance in the field of fatty liver disease which has no proven pharmacologic therapies.

Related blog post:

 

Grand Canyon Basin

Nonalcoholic Steatohepatitis Review

A concise and useful review of nonalcoholic steatohepatitis (NASH): AM Diehl, C Day. NEJM 2017; 377: 2063-72

A couple points:

  • About 25% of adults have fatty livers in the absence of excessive alcohol consumption
  • NASH is strongly associated with obesity/overweight which occur in  >80% of patients
  • NASH comorbidities in adults: 72% with dyslipidemia, 44% with type 2 diabetes mellitus
  • In a typical patient with NASH, liver fibrosis progresses “at a rate of approximately one stage per decade, suggesting that F2 fibrosis will progress to cirrhosis within 20 years.” However, there is considerable variability.
  • It is expected that NASH will be the leading reason for liver transplantation by 2020.
  • Cirrhosis related to NASH increases the risk of hepatocellular carcinoma with this occuring in 1-2% per year of patients with cirrhosis.
  • NASH is estimated to cost >$100 billion currently in annual direct medical costs
  • Staging of NASH and differentiation from isoloated steatosis identifies those at high risk for sequelae.
  • In Table 2, the authors list more than 10 pharmacologic agents in phase 2/3 studies

Current lifestyle treatment recommendations (for adults):

  • Lose 7% of body weight if overweight or obese
  • Limit consumption of fructose-enriched beverages
  • Limit consumption of alcohol (no more than 1 drink/day for women and 2 drinks/day for men)
  • Drink two or more cups of caffeinated coffee daily

Related blog entries:

 

Panels A & B show typical histologic findings: ballooned hepatocytes (arrows), inflammatory infiltrates (arrowheads), and fibrosis Panel C shows the relative distribution of NASH, cirrhosis, and hepatocellular carcinoma in U.S. Adults.

Research for Fatty Liver Disease

Recently the AASLD Postgraduate Course discussed emerging treatments for nonalcoholic fatty liver disease/nonalchoholic steatohepatitis. From AASLD News: Emerging Treatments for NASH 

Key point:

  • Quentin Anstee: “It is important to remember that our patients with fatty liver disease will most likely die of cardiovascular disease, not liver disease.”

Four principles in treating nonalcoholic fatty liver disease (NAFLD) to address both cardiovascular and liver risks.

  • Target obesity with lifestyle changes and, possibly, bariatric surgery.
  • Target metabolic syndrome to reduce cardiovascular disease risk using medications with additional liver-directed benefits.
  • Target liver disease to prevent progression of steatohepatitis to fibrosis and cirrhosis.
  • Minimize downstream complications such as hepatocellular carcinoma.

More than 60 phase 3 trials are underway –Primary Therapeutic Targets:

  • PPAR signaling (insulin signaling, glucose and lipid metabolism, energy homeostasis, inflammation)
  • FXR signaling (insulin sensitivity, glucogenesis, lipogenesis)
  • ASK1 signaling (apoptosis)
  • CCR2/CCR5 signaling (inflammation and fibrogenesis).

Will Emerging Therapies for Fatty Liver Disease Be Affordable?

With non-alcoholic steatohepatitis (NASH), there are currently no established medical therapies.  However, several candidate medications look promising. However in recent years, many new medications have come with an impressive price tag and this has led to questions about whether emerging therapies for NASH will be affordable.

A recent article looked at the medication Obeticholic Acid, which was approved for treating primary biliary cholangitis.  It is possible that it will be helpful for NASH.  Yet, its cost , currently, is about $70,000 per year

GIHepNews: Despite clinical promise, obeticholic acid may be too expensive for treating NASH

Here’s an excerpt:

In the 72-week Phase II trial, called FLINT, 273 men and women with NASH were randomly assigned to receive OCA or placebo (Lancet 2015;385:956-965). Liver histology improved in 45% of those receiving OCA versus 21% in those receiving sham therapy (P=0.002). An increased risk for pruritus was the most notable adverse event among patients taking OCA (23% vs. 6% for placebo), according to the researchers. Based on the favorable benefit–risk results of the Phase II study, a Phase III trial is ongoing…

The expected benefit of OCA over lifestyle modifications for all the major long-term outcomes, such as decompensated cirrhosis (10% vs. 9.4%), liver-related mortality (9% vs. 8.1%) and transplant-free survival (72.2% vs. 71.5%), were relatively modest, the researchers reported. Those differences resulted in a cost per quality-adjusted life-year saved of $5.2 million with the assumption that 16% of patients would relapse…

 “If the efficacy compared to placebo is of the same order found in the FLINT trial, the current cost of the drug would be prohibitive in a population-based context,” said Dr. Lavine, who was a co-investigator on the trial.

My take: Given the growing burden of NASH, new effective treatments are needed.  In my view, though, cost-effectiveness has to be a consideration.

Prague Castle