Favorite Posts 2022

Thank you to those who have helped me this past year with this blog –colleagues, friends and family. Wishing all of you a good 2023. Here are some of my favorite posts from this past year:

GI:

Nutrition:

Liver:

Endoscopy:

Health Policy:

Humor:

New Age for Hepatitis B Therapies

M-F Yuen et al. NEJM 2022; 387; 1957-1968. Efficacy and Safety of Bepirovirsen in Chronic Hepatitis B Infection

This study is nicely summarized in a “quick take” video and also reviewed in an accompanying editorial by J Hoofnagle (pages: 1996-1998).

In this phase 2b, randomized, investigator-unblinded trial involving 457 participants with chronic HBV infection (1/2 receiving nucleotide analogue (NA) therapy), the authors evaluated bepirovirsen is an antisense oligonucleotide that targets all hepatitis B virus (HBV) messenger RNAs and acts to decrease levels of viral proteins.

Background: HBV infection affects 4% of worldwide population and has a prevalence of 0.3% in the U.S. Worldwide, HBV causes more than 1/2 million deaths each year.

Key finding:

Mechanism of Action: Bepirovirsen is an antisense oligonucleotide that targets all hepatitis B virus (HBV) messenger RNAs and acts to decrease levels of viral proteins.

Current therapies (like entecavir and tenofovir) are able to suppress viral replication but have low rates of clearance of HBsAg and most often HBV relapses when medications are stopped. This is due to covalently closed circular DNA which can persist in hepatocytes despite these medications.

In Dr. Hoofnagle’s editorial, he notes that bepirovirsen is one of several RNA-based HBV therapies that are being pursued. There are also “the more malleable small interfering RNA molecules (“-sirans”) are currently in early-phase clinical trials.”

My take: While these studies point to new therapies for those afflicted with HBV infection, the best strategy for reducing HBV mortality and morbidity still relies of wide-scale use of the highly effective HBV vaccine.

A Purple Liver

G Jiang et al. Clin Gastroenterol Hepatol 2022; https://doi.org/10.1016/j.cgh.2022.05.036.Open Access! A Purple Liver

In this case report, a 38 yo was incidentally discovered to have a purple liver while undergoing surgery for cholelithiasis. A diagnosis of Dubin-Johnson syndrome was made. It “is a benign autosomal-recessive liver disease with clinical manifestations of chronic or intermittent conjugated hyperbilirubinemia. It is caused by mutations in the ABCC2 gene leading to MRP2 [multidrug resistance-associated protein 2] dysfunction or deletion.”

Related blog posts

Liver Briefs: MMF & Less Food Allergies, Losartan for NAFLD (negative trial), Another Pangenomic HCV Treatment for Adolescents

If you have not seen this video from 2014 (42 seconds), I recommend it for a good laugh. I’ve seen it many times and I think it is funny every time.

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S Haflidadottir et al. JPGN 2022; 75: 138-144. Mycophenolate Mofetil Use Is Associated With Reduced Incidence of Food Allergy in Liver Transplanted Children. N=107. Key finding: Children treated with MMF in addition to tacrolimus 1 year after transplantation reported less food allergy (12.5% vs 37.8%, P = 0.003) and sensitization to food allergens one year after transplantation (8.9% vs 17.8%, P = 0.02) than those not receiving MMF. The effect of MMF was not due to reduced trough levels of tacrolimus.

MB Vos et al. Hepatology 2022; 76: 429-444. Open access: Randomized placebo-controlled trial of losartan for pediatric NAFLD Key finding: Losartan did not significantly reduce ALT in children (n=83) with NAFLD when compared with placebo in this multicenter, double-masked, placebo-controlled, randomized clinical trial

G Indoli et al. Hepatology 2022; 76: 445-455. Sofosbuvir-velpatasvir-voxilaprevir in adolescents 12 to 17 years old with HCV infection All patients (n = 21) were naïve to HCV DAAs, and none had cirrhosis. Key finding: 100% of patients (21 of 21) reached SVR12 (8 week treatment course)

Westchester Lagoon off of the Tony Knowles Coastal Trail, Anchorage AK

RNA Interference (Fazirsiran) for Liver Disease Associated with Alpha-1-Antitrypsin Deficiency

P Strnad et al. NEJM 2022; 387: 514-524. Fazirsiran for Liver Disease Associated with Alpha1-Antitrypsin Deficiency

Background: “Z-AAT accumulation has been correlated with liver fibrosis, a finding that suggests that reducing Z-AAT production may improve hepatic phenotypes…RNA interference (RNAi) is a naturally occurring cellular mechanism that regulates gene expression. Fazirsiran (previously ARO-AAT) is an investigational RNAi therapeutic that contains a synthetic, double-stranded, small interfering RNA duplex conjugated to N-acetylgalactosamine, which binds to the hepatocyte asialoglycoprotein receptor to facilitate endosomal uptake and intracellular delivery…Fazirsiran causes degradation of AAT and Z-AAT messenger RNA, thus reducing both AAT and Z-AAT protein synthesis in hepatocytes.” Fazirsiran has already shown effectiveness in a mouse model and had an adequate safety profile in a phase 1 study with healthy volunteers.

Methods: Phase 2, open-label, multicenter trial enrolled adults with the PI ZZ genotype and liver fibrosis. They received fazirsiran subcutaneously on day 1 and week 4 and then every 12 weeks

Key findings:

  • All the patients had reduced accumulation of Z-AAT in the liver (median reduction, 83% at week 24 or 48)
  • Fibrosis regression was observed in 7 of 15 patients and fibrosis progression in 2 of 15 patients after 24 or 48 weeks
  • There were no adverse events leading to trial or drug discontinuation. Four serious adverse events (viral myocarditis, diverticulitis, dyspnea, and vestibular neuronitis) resolved. Most common adverse events were arthralgia and transient increase in creatinine kinase (each in 4 patients). It was noted that there was a gradual decrease in mean FEV1 through week 52 but no evidence that this was due to fazirsiran treatment.

The authors note that reduction in Z-AAT accumulation is expected to yield clinical benefit since the liver is a regenerative organ.

My take: This is an exciting development for patients with AAT-associated liver disease but a larger, placebo-controlled treatment trial with longer duration is needed to confirm whether fazirsiran will be a useful therapeutic agent for AAT deficiency.

After reviewing this study, I contacted one of the authors (Dr. Teckman) to find out about the status of pediatric studies. His response:

  • A larger, phase III study is going to start enrolling soon (for adults) to better define the risks, benefits, dose, length of therapy and patient selection which will hopefully lead to full FDA approval. The next phase of fazirsiran for adults will have many sites and St Louis will be one. Patients are welcome to contact me.
  • Trials with fazirsiran for children are being designed. Time frame 1-3 years. Other drugs are also close to opening studies for kids, as well.
  • Several other drugs that appear promising for AAT are also in phase I, II, soon III. That’s great news. I commonly refer patients to “clinicaltrials.gov” but they can contact me or the Alpha-1 Foundation for information.
  • All patients should read the extensive and very informative patient literature on the Alpha-1 Foundation web site; www.alpha1.org.
  • All patients should enroll in the Alpha-1 Registry. This is a scientific, IRB approved registry which is non-interventional and does not commit patients to anything, but which will permit them to be contacted and kept informed about potential trials. It is for anyone who carries any number of many abnormal genotype; ZZ, SZ, MZ, null, etc.
  • All eligible people who are anywhere near a site should be enrolled in the Childhood Liver Disease Research Network; www.childrennetwork.og. This is a non-interventional, NIH- sponsored network which studies pediatric liver disease. ZZ and SZ patients ages 0 years to 25 years can enroll. You do not need to change doctors or care sites. Many patients stay with their docs they have but contribute to the study once a year.

Related blog posts:

  • Alpha-1-Antitrypsin Deficiency (review May 2020). 35% of adults with ZZ genotype show clinically-significant liver fibrosis. Risk factors for advanced fibrosis: male gender, metabolic syndrome/obesity, and alcohol consumption.
  • Liver Shorts March 2020 (A1AT Heterozygosity worsens NAFLD/contributes to cirrhosis)

Withdrawal of Chronic Hepatitis B Therapy

G Hirode et al. Gastroenterol 2022; 162: 757-771. Off-Therapy Response After Nucleos(t)ide Analogue Withdrawal in Patients With Chronic Hepatitis B: An International, Multicenter, Multiethnic Cohort (RETRACT-B Study)

Methods: This cohort study included patients (n=1552) with virally-suppressed chronic hepatitis B (CHB) who were hepatitis B e antigen (HBeAg)–negative (and without advanced liver disease) and stopped nucleos(t)ide analogue (NA) therapy

Key findings:

  • Cumulative probability of HBsAg loss was 3.2% at 12 months and 13.0% at 48 months of follow-up
  • HBsAg loss was higher among Whites (vs Asians: subdistribution hazard ratio, 6.8; P < .001) and among patients with HBsAg levels <100 IU/mL at end of therapy (vs ≥100 IU/mL: subdistribution hazard ratio, 22.5; P < .001)

My take: This study identifies subsets with HBeAg-negative CHB who may benefit from NA therapy cessation.

Related blog posts:

Why Do Some People Recover from Acute Liver Failure and Some People Don’t?

Briefly noted: T Lin et al. Hepatology 2022; 322-337. Open Access: Follistatin-controlled activin-HNF4α-coagulation factor axis in liver progenitor cells determines outcome of acute liver failure

Design: After preliminary work in 19 patients with acute liver failure (ALF) and in a zebrafish model, a prospective clinical study followed up 186 patients with cirrhosis for 80 months to observe the relevance of follistatin (FST) levels in prevalence and mortality of acute-on-chronic liver failure.

Key findings: Recovered patients with ALF robustly express HNF4α in either LPCs (liver progenitor cells) or remaining hepatocytes. Serum FST levels could predict the incidence and mortality of acute-on-chronic liver failure.

Implication of study: “Our results indicate that serum FST levels might be a surrogate marker reflecting the extent of hepatocyte death and hepatic insulin resistance, which point to the danger of coagulopathy and clinical deterioration. The hypothesis requires further confirmation in the future.”


Hormone-controlled activin-HNF4α-coagulation factor axis in LPCs

How Often Does Liver Disease Develop in Healthy Young Males…Over 65 Year Study Period

J Uhanova et al. Clin Gastroenterol Hepatol 2021; 19: 2417-2424. Chronic Liver Disease and Metabolic Comorbidities in Healthy Young Males Followed for 65 Years: The Manitoba Follow-up Study

Methods: 3,983 air force men were enrolled in the Manitoba Follow-up Study in 1948. The comprehensive database on results of routine physicals and health encounters was examined for evidence of chronic liver disease (CLD) and metabolic syndrome (MetS). 

Key findings:

  • 5.2% of men developed CLD and 6.4% MetS
  • Among the 206 with CLD, 162 (79%) were diagnosed with CLD as a non-terminal event; however, CLD was clinically significant with 50.5% (n=104) with cirrhosis (of whom 56 had hepatic decompensation)
  • The most common etiologies for CLD were alcohol-related liver disease (32.5%, n=67) and fatty liver disease (20%, n=41); chronic viral hepatitis (B & C) accounted for 4.4% (n=9). In 20%, the etiology was not specified
  • The relative risk of mortality in men with vs. without CLD was 3.33 (95% CI – 2.83 to 3.91, p < .0001)
  • An increasing gradient of risk for CLD was apparent with increasing numbers of MetS components; the HR of 3.67, 5.97 and 14.3 for IR/DM (insulin resistance /diabetes mellitus), IR/DM + one component, and IR/DM + two or more components respectively

Discussion –The authors note that the lifetime risk of CLD was much higher in NHANES studies (11.8% to 14.8% prevalence); this is attributed to active surveillance for liver disease in the NHANES study (and different study population). It is also likely that there is a substantially increased risk over the last 65 years due to factors like increasing rates of obesity as well as possibly higher rates of alcohol use and infections.

My take: Among healthy 18 year old males, a substantial number develop chronic liver disease, much of which could be prevented by limiting alcohol intake and maintaining a healthy diet/exercise.

Related blog posts:

Intracostal Waterway near Siesta Key, FL

Changes in Latitudes and Changes in Autoimmune Liver Disease

GJ Webb et al. Clin Gastroenterol Hepatol 2021; 19: 2587-2596. Open Access: The Epidemiology of UK Autoimmune Liver Disease Varies With Geographic Latitude

Methods: A retrospective cohort study using anonymized UK primary care records (2002-2016). All adults without a baseline diagnosis of AILD (autoimmune liver disease) were included and followed up until the first occurrence of an AILD diagnosis, death, or they left the database.

AIH, autoimmune hepatitis; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis

Key findings:

  • 1314 incident cases of PBC, 396 of PSC, and 1034 of AIH. Crude incidences were as follows: PBC, 2.47 (95% CI, 2.34–2.60); PSC, 0.74 (95% CI, 0.67–0.82); and AIH, 1.94 (95% CI, 1.83–2.06) per 100,000 per year.
  • A more northerly latitude was associated strongly with incidence of PBC: 2.16 to 4.86 from 50°N to 57°N (P = .002) and incidence of AIH: 2.00 to 3.28 (P = .003), but not incidence of PSC: 0.82 to 1.02 (P = .473)
  • After adjustments, PBC was more frequent in smokers than those who had never smoked at 3.40 (3.03–3.77) per 100,000/y and 1.96 (1.80–2.12) cases per 100,000/y; there was a lower incidence of PSC in smokers 0.47 (0.33–0.61) per 100,000/y compared with those who had never smoked 0.95 (0.83–1.07) per 100,000/y. For AIH, there was no difference between current smokers and those who had never smoked

The authors speculate in the discussion about potential reasons why latitude could correlate with disease incidence. Some potential explanations include sunlight/vitamin D metabolism (though this is at odds with the fact that those with increased skin pigmentation are NOT at increased risk), environmental exposures (related to geology, diet, air quality) or unrecognized genetic tendency based on geography.

My take: In the UK, there is an association between a more northernly latitude and both PBC and AIH.

Related blog post: Aspen Webinar 2021 Part 5 -Autoimmune Liver Disease & PSC

Figure 2

Mortality Risk With Autoimmune Hepatitis

R Sharma et al. Clin Gastroenterol Hepatol 2021; 19: 2636-2647. Open Access PDF: Increased Mortality Risk in Autoimmune Hepatitis: A Nationwide Population-Based Cohort Study With Histopathology

In this nationwide population-based cohort study in Sweden from 1969-2017 of 6,016
adults with histologically-confirmed AIH (all 18 years or older) and 28,146 matched general population, key findings:

  • 3,185 individuals with AIH died (41.4/1000 person-years) compared with 10,477 reference individuals (21.9/1000 person-years)
  • The 10-year cumulative incidence of death was 32.3% (95%CI [ 31.1-33.6) for AIH individuals and 14.1% (95%CI [ 13.7-14.5) for reference individuals
  • AIH individuals with cirrhosis on biopsy had a high risk of death (HR [ 4.55; 95%CI [ 3.95-5.25), while mortality risks for patients with noncirrhotic fibrosis (HR, 2.68) and inflammation without fibrosis (HR, 2.18) were similar to overall risk
  • In this cohort, 13.7% had cirrhosis at diagnosis (lower than other studies)

My take: In this study over nearly 50 years, AIH was associated with “a 2-fold increased risk of death. Risks were particularly high in individuals with cirrhosis, portal hypertension (HR, 7.55), and overlap with cholestatic liver disease.”

Related blog posts: