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:

Hepatitis C Relapse After Treatment –Spontaneously Cleared in Some

H Kuriry et al. Clin Gastroenterol Hepatol 2021; 19: 2398-2406. Spontaneous Clearance After Relapse Following Direct-Acting Antiviral Treatment for Chronic HCV Infection

This retrospective case-control study identified 93 patients out of 1032 with chronic HCV infection who had a relapse of detectable infection following treatment. Key findings:

  • 12 patients (13%) spontaneously cleared HCV within 6 months after the documented relapse without additional therapy
  • The spontaneous clearers had low levels of HCV RNA (<4 log IU/mL in 11 of 12) and normal levels of alanine aminotransferase at the time of relapse. Low level RNA was identified in only 1 persistent relapser
  • There was no significant difference between the spontaneous clearance group and the SVR12 group in magnitude and breadth of HCV-specific T cell responses
  • The authors note that one limitation of the study was a false positive PCR assay –though this does not negate their message that retesting is important before retreatment
  • The relatively high relapse rate (9%) in this cohort is likely related to the use of first-generation DAA therapy
  • The timing of retesting in the 12 with spontaneous clearance was variable. 7 who had repeat testing at 3 months were all negative.

My take: In those with a low level virological relapse after DAA therapy for HCV, it is a good idea to repeat testing before consideration of further treatment.

Related blog posts:

Huntingdon Lake, Sandy Springs (from Suzan)

Ongoing Hepatitis B Susceptibility in U.S. Adults

H Roberts et al. Hepatology 2021; 74: 2353-2365. Prevalence of HBV Infection, Vaccine-Induced Immunity, and Susceptibility Among At-Risk Populations: US Households, 2013-2018

This article provides some useful trends in Hepatitis B virus (HBV) epidemiology based on NHANES surveys (National Health and Nutrition Examination Survey).  Persons who tested negative for anti-HBc, HBsAg, and anti-HBs were considered susceptible to HBV infection.

Key Findings:

  • The estimated prevalence of persons living with chronic hepatitis B in the USA has remained unchanged at 0.3% since 1999. During 2013-2018, this accounted for 880,000 US residents who were living with chronic HBV infection. It is noted that only a minority of the 11.7 million residents with a history of HBV develop chronic HBV
  • The non-US-born population accounted for 69% (610,000) of persons living with chronic HBV and 70% of this group were Asian. Non-US born population had a 9-fold risk of chronic HBV compared to US-born persons
  • Among adults aged ≥ 25 years who resided in US households, an estimated 155.8 million persons (or 73.4%) were susceptible to HBV infection. Susceptibility was lower in the 25-49 age group (64.8%) compared to the 50 years and older group (81.6%)
  • Despite vaccine recommendations, at risk groups including those using illicit drugs, hx/o MSM, and HCV exposure continue to have high susceptibility; fewer than 25% of adults “deemed to be at high risk for contracting HBV infection had vaccine-induced immunity
  • Overall, vaccine-induced immunity increased to 21.4% (2013-2018) compared to previously 17.9% (2007-2012) in those 25 years and older
  • Limitations: lack of detectable anti-HBs is likely to overestimate susceptibility in those who have previously been vaccinated, participation in NHANES by non-US born persons may have been unequal, and determining timing of HBV acquisition by non-US born persons was not feasible in this study

My take: Lots of adults have chronic HBV and lots more are susceptible. How to identify and encourage adults to avoid vaccine-preventable illnesses is NOT getting easier.

Related blog posts:

From NPR 12/5/21

NY Times: “Who Deserves a Lifesaving Organ?”

NY Times: “Who Deserves a Lifesaving Organ?”

Yesterday’s post discussed policy efforts to help with equitable access for transplantation. This essay explores some of the same issues.

A few excerpts:

  • What makes someone a “good” transplant candidate? Maybe it is inevitable that doctors’ biases creep in when we must make fraught decisions about a scarce resource….
  • A transplant program is also beholden to its metrics. If the one-year survival of transplant recipients is lower than expected or if transplant failure is higher than expected, a program could be put on probation or lose its certification entirely…
  • Social-support requirements vary based on the intensity of the surgery and the length of the required rehabilitation. But in general, a patient is expected to have one to three people who can commit to helping in recovery — driving to appointments, managing medications or responding to overnight emergencies…
  • So much of transplant decision-making is about narrative, which is one reason misconceptions can take hold when patients do not speak English as their primary language. Hispanic patients are about half as likely as their white peers to receive kidney donations from family or friends— a gap that Dr. Juan Carlos Caicedo, an adult and pediatric transplant surgeon who directs the Hispanic Transplant Program at Northwestern Medicine, is working to close. “People will argue that these are not good patients because they don’t follow recommendations, but they are dead wrong,” he told me. “They are great patients, as long as they understand you.”..
  • Change is happening. At my hospital, our lung transplant team is working to identify recipients from underserved communities who can become “ambassadors” to educate others and build trust…
  • Perhaps most important, transplant teams are openly discussing and challenging their assumptions about who makes a “good” transplant candidate. And in doing so, more lives may be saved.
Thanks to Jennifer for this picture