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.
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.
This was a prospective study of 180 severely obese patients with biopsy-proven NASH.
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.
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.
Background: As of April 1, 2019, an estimated 103,000 kidney, 13,500 liver, and 3,800 heart transplant (HT) candidates are awaiting transplantation
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.”
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.
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.
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.
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).
“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.
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.
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.
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.
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.