Tag Archives: NASH

Aspen Webinar 2021 Part 1-COVID-19 and the Liver

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Notes from this year’s Aspen Webinar 2021. This blog entry has abbreviated/summarized some of these presentations. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well. The first talk was excellent.

What’s Hot -COVID-19 and the Liver  William Balistreri

This lecture covered a ton of information and publications with regard to COVID-19 and the liver.

Key points:

  • Numerous studies generally show that liver problems related to COVID-19 are mild, particularly in children
  • Most immunosuppression agents do not worsen outcomes with COVID-19 and should not be reduced in autoimmune hepatitis or liver transplantation; the exception, mycophenolate has been associated with worsened outcomes
  • Cirrhosis is associated with worse outcomes in patients with COVID-19
  • Vaccine response is blunted in immunocompromised patients with 40-50% developing antibody response after two doses of mRNA vaccines and generally lower titers.  3rd dose of vaccine may improve response.

Some of the slides:

Pediatric Data:

Bariatric Surgery Helps NASH

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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:

Liver Shorts -August 2020

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V Cardenas et al. JPGN 2020; 71: 197-202.  Incidence and Sequelae of Liver Injury Among Children Treated for Solid Tumors: Analysis of a Large Single-Center Prospective Cohort

  • Of 1136 solid tumor patients, 160 (14%) experienced liver injury, and the overall frequency of DILI was 4%.
  • DILI was the leading identified cause of liver injury (31%), followed by infection (17%), metastatic/malignant biliary disease (13%), and perioperative liver injury (13%).
  • Most DILI cases (>90%) were mild acute hepatocellular injury episodes that did not result in modification to the chemotherapy plan, and all DILI eventually resolved.

N Kapila et al. Hepatology 2020; 72: 32-41. Full Text Link: Hepatitis C Virus NAT‐Positive Solid Organ Allografts Transplanted Into Hepatitis C Virus–Negative Recipients: A Real‐World Experience

Background: As of April 1, 2019, an estimated 103,000 kidney, 13,500 liver, and 3,800 heart transplant (HT) candidates are awaiting transplantation

Key findings:

  • Seventy‐seven patients who were HCV negative underwent solid organ transplantation from a donor who was HCV viremic. Only one has been a HCV-treatment nonresponder (though several have not completed SVR12).
  • “Our study is the largest to describe a real‐world experience of the transplantation of HCV‐viremic organs into recipients who are aviremic. In carefully selected patients, the use of HCV‐viremic grafts in the DAA era appears to be efficacious and well tolerated.”

M Martinello et al. Hepatology 2020; 72: 7-18. Short‐Duration Pan‐Genotypic Therapy With Glecaprevir/Pibrentasvir for 6 Weeks Among People With Recent Hepatitis C Viral Infection

  • This was an  open‐label, single‐arm, multicenter, international pilot study; adults with recent HCV (duration of infection < 12 months) received glecaprevir/pibrentasvir 300/120 mg daily for 6 weeks.
  • At baseline, median estimated duration of infection was 29 weeks (range 13, 52) and median HCV RNA was 6.2 log10 IU/mL (range 0.9, 7.7). SVR12 in the intention‐to‐treat and per‐protocol populations was achieved in 90% (27/30) and 96% (27/28), respectively.

H Verkade et al. JPGN 2020; 71: 176-83. Systematic Review and Meta-analysis: Partial External Biliary Diversion in Progressive Familial Intrahepatic Cholestasis

  • With regard to  pruritus improvement, 104/155 (67%) were responders, 14/155 (9%) had partial response, and 37/155 (24%) were nonresponders.

K Patel et al. Hepatology 2020; 72: 58-71. Cilofexor, a Nonsteroidal FXR Agonist, in Patients With Noncirrhotic NASH: A Phase 2 Randomized Controlled Trial

  • “Cilofexor for 24 weeks was well‐tolerated and provided significant reductions in hepatic steatosis, liver biochemistry, and serum bile acids in patients with NASH.”

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

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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

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For PDF copy of slides: NAFLD and NASH

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

Epidemiology:

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

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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?

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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

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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?

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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

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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: