Aspen Webinar 2021 Part 2 -Nonalcoholic Steatohepatitis

From the 2nd lecture of the Aspen Webinar. This blog entry has abbreviated/summarized this presentation. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well. This was a terrific lecture!

NASH Update Stavra Xanthakos

Key points:

  • Lifestyle intervention is 1st line Rx (especially avoiding sugary beverages, and processed foods). This may lead to resolution of NASH in ~29%, fibrosis resolution in 34%; though, only 3% resolved fatty liver
  • Many have progressive disease despite lifestyle treatment recommendations
  • Consider adjunctive treatments if not improving with lifestyle intervention
  • Vitamin E for biopsy-confirmed disease (often for 1-2 years of therapy)
  • Pioglitazone -off-label for adults (18+). Can increase weight; a lot of trials in adults
  • Several phase 3 trials in NASH -GLP1 agonists promising in phase 2 trials
  • GLP1 agents being used in adolescents with T2DM who may also have NASH – monitor liver outcomes
  • Anti-obesity medications may help with weight and perhaps the liver. Approved agents for adolescents include 1) Orlistat -safe, but frequent side effects (eg. Diarrhea, greasy accidents) and 2) Liraglutide -daily SC.  Insurance coverage is limited.
  • Biopsy is important before implementing medications and may influence decision to pursue bariatric surgery.  
  • Fibroscan, if shows no significant fibrosis, can help limit biopsy.
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Related blog posts:

Bariatric Surgery Helps NASH

G Lassailly et al. Gastroenterol 2020; 159: 1290-1301. Bariatric Surgery Provides Long-term Resolution of Nonalcoholic Steatohepatitis and Regression of Fibrosis

This was a  prospective study of 180 severely obese patients with biopsy-proven NASH.

Key findings:

  • NASH: At 5 years after bariatric surgery, NASH was resolved, without worsening fibrosis, in samples from 84% of patients (n = 64; 95% confidence interval, 73.1%-92.2%). 
  • Fibrosis: Fibrosis decreased, compared with baseline, in samples from 70.2% of patients (95% CI, 56.6%-81.6%). Fibrosis disappeared from samples from 56% of all patients (95% CI, 42.4%-69.3%) and from samples from 45.5% of patients with baseline bridging fibrosis. 
Graphic Abstract

My take: This study showed that patients with NASH who underwent bariatric surgery had resolution of NASH in liver samples from 84% of patients 5 years later. The reduction of fibrosis was progressive, beginning during the first year and continuing through 5 years.

Related blog posts:

Renal Disease Associated With Fatty Liver Disease & Dexamethasone-COVID-19 Data

Looking for and managing hypertension has been an important component of care in children and adults with nonalcoholic fatty liver disease (NAFLD)/metabolic syndrome.  In addition, hypertension is frequently associated with renal impairment.

As such, it is perhaps not surprising that in both adults and children, there is a high rate of renal impairment.   The data in children is much more sparse than in adults.  A recent retrospective pediatric cohort study (T Yodoshi et al. J Pediatr 2020; 222: 127-33) adds more information to this problem.

More background information:

  • Chronic kidney disease is highly prevalent in adults with NAFLD: 20-55% (J Hepatol 2020; 72: 785-801; Am J Kidney Dis 2014; 64: 638-52)
  • NAFLD is currently the leading indication for concurrent liver and kidney transplantation
  • In adults, the severity of NAFLD histology is associated with renal impairment
  • The first stage of renal impairment is glomerular hyperfiltration. This is hypothesized to be a precursor of intraglomerular hypertension which leads to albuminuria and glomerular filtration rate (GFR) decline/progressive renal dysfunction
  • Early intervention in high risk patients with angiotensin receptor inhibitors may prevent or delay progressive renal disease

Key findings in 179 patients with biopsy-confirmed NAFLD:

  • 82% non-Hispanic, median age 14 yrs
  • 36 (20%) had glomerular hyperfiltration and 26 (15%) had low GFR (w/in 3 months of liver biopsy) based on Schwartz equation
  • Hyperfiltration was independently associated with higher NAFLD activity score (aOR 2.96)

Discussion:

  • Mechanism: The authors speculate that “it is possible that they [renal and liver disease] are both the end result of the same ‘hit.’ The renin-angiotensin system may play a key role….Notably, there is an ongoing…clinical trial investigating an ATI receptor blocker, losartan, for the treatment of NAFLD in children.” Other potential contributors include fructose and insulin resistance.
  • Limitations: This single center biopsy-confirmed population may not be representative of most children with NAFLD.  Also, as this was a retrospective study, more precise measures of renal function were not available.

My take: This study confirms a high rate of renal dysfunction (35%) in children with NAFLD. As such:

  • Children with NAFLD need to have their blood pressure monitored
  • Clinicians should have a low threshold for nephrology referral if suspected renal impairment.

NEJM Recovery Collaborative Group: July 17, 2020
DOI: 10.1056/NEJMoa2021436: Full Link: Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report

Form NEJM Journal blog:

In the open-label RECOVERY trial, some 2100 U.K. patients hospitalized with COVID-19 were randomized to usual care plus oral or intravenous dexamethasone (6 mg once daily for up to 10 days), and 4300 were randomized to usual care alone.

Among patients on invasive mechanical support at the time of randomization, the mortality rate within 28 days was significantly lower with dexamethasone than with usual care alone (29% vs. 41%). A benefit was also seen among those on oxygen without invasive ventilation (23% vs. 26%). However, among patients not receiving respiratory support, mortality rates did not differ significantly between treatment groups.


Fatty Liver Feast (of Articles): NAFLD 2020

An entire issue of Gastroenterology delved into the topics of “NAFLD 2020.”

This special May 2020 issue provides a comprehensive update on Nonalcoholic Fatty Liver Disease.

Here are a few links to some of the articles:

Related blog posts:

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 Selected Abstracts (Part 1)

Link to full NASPGHAN 2019 Abstracts.

Here are some abstracts that I found interesting at this year’s NASPGHAN meeting:

NAFLD:

  1. Off-label use of topiramate may be helpful in stabilizing weight and improving NAFLD
  2. Socioeconomic barriers are frequent in NAFLD patients (the 2nd poster did not appear to show a control population):

Primary Sclerosing Cholangitis -Use of Vedolizumab for PSC did not appear to help

Eosinophilic Esophagitis

  1. EoE is four times more likely in this cohort with inflammatory bowel disease
  2. 2nd poster describes very early-onset EoE

Inflammatory Bowel Disease:

  1. Use of infliximab in VEO IBD.  Used in 46/122 (38% of patients) and 50% had persistent use 3 years later

Enteral nutrition –poster from our group describing good tolerance of plant-based formula (with Ana Ramirez).

Celiac disease.  This poster indicates low yield of additional serology for celiac disease besides TTG IgA and serum IgA. This includes testing in young patients (< 2 years) with celiac disease.

#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.

 

#NASPGHAN19 Liver Symposium (Part 2)

Although I was unable to attend this year’s liver symposium at NASPGHAN19, I reviewed the lecture notes.  There is some terrific content.  Here are some of the slides (borrowed with permission from NASPGHAN).

Link to complete NASPGHAN Chronic Liver Disease Symposium 2019

SESSION II – FRONTIERS IN LIVER THERAPEUTICS

Keynote Speaker: Outcomes for the future: How do we improve on the status quo? Ronald J. Sokol, MD, FAASLD, Children’s Hospital Colorado  (SLIDES NOT AVAILABLE in onliine handout)

Recognition and stabilization of the pediatric patient with acute liver failure Robert Squires MD Children’s Hospital of Pittsburgh at UPMC

Should I offer treatment for my patients with Hepatitis B or Hepatitis C? Regino P. Gonzalez-Peralta MD, AdventHealth for Children

Are there any medical therapies for NASH?   Marialena Mouzaki, MD, Cincinnati Children’s Hospital Medical Center

This lecture describes a lot of the emerging pharmacologic treatments; none of these are currently recommended.

Improving Fatty Liver Disease Nomenclature

Those who follow this blog regularly know that I have frequently agreed with articles suggesting improving/updating nomenclature for many conditions including the following:

A recent commentary (M Eslam et al. Gastroenterol 2019; 157: 590-3) suggests that fatty liver diseases could use a nomenclature makeover as well.

In pediatrics, the issue of alcoholic and nonalcholic fatty liver disease (NAFLD) overlap is fairly minor in many ways.  In fact, when I am seeing a young teen with NAFLD, parents will often chuckle when I tell them that ‘Johnny’ needs to lay off the booze (now and in the future).  However, it is difficult to fully differentiate nonalcoholic fatty liver disease from alcoholic fatty liver disease, especially in adults.

Full Text: Toward More Accurate Nomenclature for Fatty Liver Diseases

Key points:

  • “Light (1.0-9.9 g/d) or moderate (10.0–29.9 g/d; 10.0–19.9 g/d for women) alcohol consumption in patients with NAFLD is not uncommon…The negative impact of alcohol intake also extends to nonalcoholic steatohepatitis resolution.”
  • “it is time for clinicians to recognize that, within the spectrum of fatty liver disease, there will be patients with true alcohol-related liver disease (AFLD), those with predominant AFLD compounded by metabolic cofactors, those with true NAFLD in whom alcohol consumption is near zero and disease progression is due to metabolic factors, and perhaps a majority with fatty liver disease owing to an abnormal metabolic milieu but with alcohol intake of ≤30 g/d.”
  • ” An updated and more appropriate nomenclature and classification system is required to reflect the nuances of disease etiology within the spectrum of fatty liver disease…”
    • MPFL: metabolic dysfunction predominant fatty liver;
    • APFL, alcohol predominant fatty liver;
    • MPFL/A and MPFL/N: metabolic dysfunction predominant fatty liver with, and without alcohol intake that is anything more than ceremonial
    • APFL/M and APFL/N: alcoholic predominant fatty liver with metabolic dysfunction or with no metabolic dysfunction.

My take: The authors present a good rationale for updating fatty liver disease –will this be adopted?

Related blog posts:

 

NAFLD Outcomes After Bariatric Surgery

A recent systematic review and meta-analysis (Y Lee, et al. Clin Gastroenterol Hepatol 2019; 17: 1040-60) included 32 cohort studies with 3093 liver biopsy specimens from patients with nonalcoholic fatty liver disease (NAFLD).

Key findings:

  • Bariatric surgery resulted in a biopsy-confirmed resolution of steatosis in 66%, inflammation in 50%, ballooning degeneration in 76%, and fibrosis in 40%.
  • Bariatric surgery resulted in worsening features of NAFLD in 12%.
  • The authors note that Roux-en-Y Gastric Bypass (RYGB) “showed greater reduction of liver side effects and higher: resolution of NAFLD.”
  • Jejejnoileal bypass (JIB) and biliopancreatic diversion (BPD) “both have been associated with higher liver function morbidity.”
  • The overall GRADE quality of evidence was considered very low.

My take: Though better studies are needed, the majority of patients’ livers appear to benefit from bariatric surgery.

Related blog posts: