Category Archives: Hepatology

More Data on Fazisiran for Alpha-One Antitrypsin

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About two years ago, the NEJM published a phase 2 study of Fazisiran for Alpha-One Antitrypsin Deficiency (see: RNA Interference (Fazirsiran) for Liver Disease Associated with Alpha-1-Antitrypsin Deficiency). Now a larger placebo-controlled study which randomized 40 patients to subcutaneous placebo or fazirsiran 25/100/200 mg has been published:

VG Clark et al. Gastroenterol 2024; (in press). DOI:https://doi.org/10.1053/j.gastro.2024.06.028 Fazirsiran for Adults with Alpha-1 Antitrypsin Deficiency Liver Disease: A Phase 2 Placebo Controlled Trial (SEQUOIA)

Key findings:

  • At Week 16, least-squares mean percent declines in serum Z-AAT concentration were −61%, −83% and −94% with fazirsiran 25/100/200 mg, respectively, versus placebo (all P< .0001)
  • Efficacy was sustained through Week 52. At post-dose liver biopsy, fazirsiran reduced median liver Z-AAT concentration by 93% compared with an increase of 26% with placebo
  • All fazirsiran-treated patients had histological reduction from baseline in hepatic globule burden
  • Portal inflammation improved in 5/12 and 0/8 patients with baseline score >0 in the fazirsiran and placebo groups, respectively
  • Histological METAVIR score improved by >1 point in 7/14 and 3/8 patients with fibrosis >F0 at baseline in the fazirsiran and placebo groups, respectively

My take: This is an exciting development for patients with A1AT-associated liver disease. Longer duration data is needed to confirm whether fazirsiran will be a useful therapeutic agent for A1AT deficiency. If effective, selecting patients who benefit from treatment will need to be determined.

Prevalence of Steatotic Liver Disease in U.S. And Risk of Complications

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M Kalligeros et al. Clin Gastroenterol Hepatol 2024; 22: 1330-1332. Prevalence of Steatotic Liver Disease (MASLD, MetALD, and ALD) in the United States: NHANES 2017-2020

9698 participants in NHANES during the 2017-2020 cycle completed a transient elastography examination. After excluding patients less than 18 years, these were the key findings:

  • 37.87% had steatotic liver disease
  • 32.45% had MASLD
  • 2.56% had MetALD
  • 1.17% and ALD

Limitations: database study, lack of liver biopsy, reliance on self-reports of alcohol consumption

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M-H Lee et al. Clin Gastroenterol Hepatol 2024; 22: 1275-1285. Open Access! Chronic Viral Hepatitis B and C Outweigh MASLD in the Associated Risk of Cirrhosis and HCC

Methods: 336,866 adults aged ≥30 years were prospectively enrolled in a health screening program between 1997–2013

Key findings:

  • 122,669 (36.4%) had MASLD. Over a mean follow-up of 15 years, 5562 new cases of cirrhosis and 2273 new cases of HCC were diagnosed.
  • Hazard ratios for HCC were 8.86 for MASLD with HBV or HCV, compared with non-SLD without HBV or HCV
  • Hazard ratios for HCC were 8.81 for HBV or HCV with non-SLD (SLD), and 1.52 for MASLD without HBV or HCV

My take: MASLD significantly increased cirrhosis and HCC risks; however the risk of HBV or HCV was much greater. The high prevalence rates of MASLD guarantees a huge need for liver disease management for the foreseeable future.

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What Can Go Wrong with Living Liver Transplantation for the Donor

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J Xiao et al. Liver Transplantation 2024; 30: 493-504 The incidence of adverse outcome in donors after living donor liver transplantation: A meta-analysis of 60,829 donors

This meta-analysis consisted of eighty-seven articles involving 60,829 living liver donors.

Key findings:

  • The overall pooled incidence of complications in LDLT donors was 24.7%
  • The incidence of minor complications was 17.3%
  • The incidence of major complications was 5.5%
  • The overall incidence of donor mortality was 0.06% in 49,027 individuals**. 
  • Psychological complications 7.6% were the most common complications among LDLT donors. This was followed by wound-related complications 5.2%
  • Table 2 (below) gives an extensive list of potential complications and their incidences in this cohort

**In the discussion, the authors note that “donor mortality is a devastating outcome in LDLT…Our study found that Asian countries reported a lower rate…For example, in Japan, the rate of donor mortality was 0.3 deaths per 1000 donors, while in the United States and Europe, donor mortality rates were 1.7 and 2.3 deaths per 1000 donors, respectively. While this observation may be attributed to greater experience in LDLT in Asian centers, it is also possible that underreporting in Asian centers might play a role. Mortality in donors…may result in the suspension or termination of an LDLT program.”

My take: Even with potential underreporting, this study highlights the very real risks associated with trying to save a life via LDLT.

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Resmetirom (Rezdiffra) -FDA Approved for MASH with Moderate to Advanced Fibrosis

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3/14/24: FDA Approves First Treatment for Patients with Liver Scarring Due to Fatty Liver Disease

An excerpt:

“At 12 months, liver biopsies showed that a greater proportion of subjects who were treated with Rezdiffra achieved NASH resolution or an improvement in liver scarring as compared with those who received the placebo. A total of 26% to 27% of subjects who received 80 milligrams of Rezdiffra and 24% to 36% of subjects who received 100 milligrams of Rezdiffra experienced NASH resolution and no worsening of liver scarring, compared to 9% to 13% of those who received placebo and counseling on diet and exercise…n addition, a total of 23% of subjects who received 80 milligrams of Rezdiffra and 24% to 28% of subjects who received 100 milligrams of Rezdiffra experienced an improvement in liver scarring and no worsening of NASH, compared to 13% to 15% of those who received placebo, depending on each pathologist’s readings.”

“The most common side effects of Rezdiffra included diarrhea and nausea. Rezdiffra comes with certain warnings and precautions, such as drug-induced liver toxicity and gallbladder-related side effects. Use of Rezdiffra should be avoided in patients with decompensated cirrhosis.”

My take: It is good to finally have an FDA-approved medication for MASH (in adults). My speculation is that medications which achieve persistent weight loss will have a more pronounced effect on liver health and overall health.

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How Trientine and Penicillamine Work: Cool Visual Study

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FT Kirk et al. Hepatology 2024; 79: 1065-1074. Open Access! Effects of trientine and penicillamine on intestinal copper uptake: A mechanistic 64Cu PET/CT study in healthy humans

Background: Trientine (TRI) and D-penicillamine (PEN) are used to treat copper overload in Wilson disease. Their main mode of action is thought to be through the facilitation of urinary copper excretion. In a recent study, TRI was noninferior to PEN despite lower 24-hour urinary copper excretion than PEN.

Key findings and conclusions:

  • “TRI inhibits intestinal copper absorption, in addition to its cupriuretic effect. In contrast, PEN has modest effects on the intestinal copper absorption. This may explain why TRI and PEN are equally effective although urinary copper excretion is lower with TRI.”
  • ” TRI (n=8) reduced hepatic 64Cu activity 1 hour after 64Cu dose from 6.17 (4.73) to 1.47 (2.97) standard uptake value, p<0.02, and after 15 hours from 14.24 (3.09) to 6.19 (3.43), p<0.02, indicating strong inhibition of intestinal 64Cu absorption.”
  • “PEN (n=8) slightly reduced hepatic standard uptake value at 15 hours, from 16.30 (5.63) to 12.17 (1.44), p<0.04.”
  • “The study questions whether the same therapeutic targets for 24-hour urinary excretion apply to both drugs.”

My take: This is a cool study!

Related blog post: Practice Guidance on Wilson Disease (AASLD) (2023)

Is First Line Therapy for Autoimmune Hepatitis Changing? CAMARO Study Results

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RJ Snijders et al. J Hepatol 2024; 80: 576-585. Open Access! An open-label randomised-controlled trial of azathioprine vs. mycophenolate mofetil for the induction of remission in treatment-naive autoimmune hepatitis

Methods: In this 24-week, prospective, randomised, open-label, multicentre superiority trial, 70 patients (mean age 57.9 years) with treatment-naive AIH received either MMF or azathioprine, both in combination with prednisolone. The primary endpoint was biochemical remission (BR) defined as normalisation of serum levels of alanine aminotransferase and IgG after 24 weeks of treatment.

Treatment dosing in study (Table S2):

Key findings:

  • 56.4% of the MMF group and 29.0% of the azathioprine group achieved BR
  • No serious adverse events occurred in patients who received MMF (0%) but serious adverse events were reported in four patients who received azathioprine (12.9%) (p = 0.034)

Excerpts from the discussion:

  • “The evidence for the current standard induction therapy in AIH with azathioprine and prednisolone is limited and stems from the early seventies of the last century.”
  • “Patients assigned to azathioprine were significantly more prone to discontinuing treatment because of intolerance or SAEs, with nausea and vomiting as the main reasons for cessation of treatment.”
  • “MMF exhibits high teratogenicity. MMF should not be used during pregnancy and may only be used with strict contraceptive measures in women of childbearing age and men planning to father a child, as its use is absolutely contraindicated during pregnancy.”
  • “In addition, MMF must be administered twice daily, while azathioprine is given as a single dose daily…relevant for a disease that requires lifelong treatment.”

My take: This study needs to be replicated in the pediatric age group. Though many patients have some frequent side effects with MMF, the overall safety (and possibly effectiveness) appears improved with MMF compared with azathioprine.

Disclaimer: This blog, 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. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog 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.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Algae and Liver Cancer

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M Ledenko, SO Antwi, T Patel. Hepatology 2024; 79: 575-588. Geospatial analysis of cyanobacterial exposure and liver cancer in the contiguous United States

Cyanobacteria are commonly found in water bodies and their production of hepatotoxins can contribute to liver damage.

Methods: Across the contiguous United States, regions with high cyanobacteria exposure (CE) counts in water bodies were identified using satellite remote sensing data. The data were geospatially mapped to county boundaries, and disease mortality and incidence rates were analyzed.

Key findings:

  • There was a highly significant spatial association between CE, liver disease, and liver cancer. In Figure 4, the counties in the top half of CE had higher liver cancer. The mean CE 569.6 in the top half compared with median counts of CE of 319.5 in the bottom half of CE
  • Counties with CE exceeding the 80Th percentile for >8 or more years had as significantly higher liver cancer age-adjusted incidence rate (mean 9.48) compared with that did so for 5 or fewer years (mean=8.79)
  • Hot spots of CE and mortality were identified along the Gulf of Mexico, eastern Texas, Louisiana, and Florida, and cold spots across the Appalachians. 
  • Cyanotoxins were detected in 62% of US counties using remote sensing.

My take: This study shows an association between areas with higher CE exposure and increased risk of liver cancer. This could be mediated via contaminated water exposure.

Resmetirom for MASH

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SA Harrison et al. NEJM 2024; 390: 497-509. A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis

This “MAESTRO-NASH” study enrolled 966 adult patients biopsy-confirmed NASH (now termed MASH) and a fibrosis stage of F1B, F2, or F3. Approximately 60% of each arm had F3 fibrosis. Patients were randomly assigned in a 1:1:1 ratio to receive once-daily d resmetirom at a dose of 80 mg or 100 mg or placebo; Resmetirom is an oral, liver-directed, thyroid hormone receptor beta–selective agonist.

Key findings:

  • MASH “resolution with no worsening of fibrosis was achieved in 25.9% of the patients in the 80-mg resmetirom group and 29.9% of those in the 100-mg resmetirom group, as compared with 9.7% of those in the placebo group (P<0.001)”
  • “Fibrosis improvement by at least one stage with no worsening of the NAFLD activity score was achieved in 24.2% of the patients in the 80-mg resmetirom group and 25.9% of those in the 100-mg resmetirom group, as compared with 14.2% of those in the placebo group (P<0.001)”
  • “Levels of a broad range of atherogenic lipids and lipoproteins, including LDL cholesterol, non-HDL cholesterol, triglycerides, apolipoprotein B, and lipoprotein(a), appeared to be reduced by resmetirom relative to placebo, findings consistent with those of earlier studies.18,19“
  • Diarrhea and nausea were more frequent in the resmetirom group compared to placebo, though there were no differences in serious adverse effects. Patients in the 100 mg group were more likely to discontinue treatment (~7%) compared to 2% in the other two groups.
  • “In this trial, achievement of a 30% reduction in hepatic fat (MRI-PDFF) or a 120% increase in the sex hormone–binding globulin level appeared to be associated with biopsy responses.”

In their discussion, the authors note that “Noninvasive testing to identify patients with NASH for treatment and to monitor treatment response will be important in clinical practice in which liver biopsy is infrequently used.”

The associated editorial by Kenneth Cusi (pg 559-561) notes the following:

  • Resmetirom had neutral effects on body weight and insulin resistance. 
  • “Treatment affected the pituitary–thyroid hormone axis, with prohormone free T4 levels decreasing by approximately 17 to 21% and mean thyrotropin levels also decreasing.” It is unclear if this has any long-term significance (long-term data needed). ”Careful surveillance to detect early endocrine disease that is related to potential thyroid, gonadal, or bone disease appears warranted to avoid any potential risks from long-term treatment.”
  • When subtracting the placebo effect, he notes that “approximately 2 of 10 patients treated will have NASH resolution and approximately 1 of 10 patients treated will have fibrosis improvement.” Thus, combination therapy may be needed.

My take: This study brings us a step closer to having a medication which can improve MASH as currently there are no FDA-approved medications. My speculation is that medications which achieve persistent weight loss will have a more pronounced effect on liver health and overall health.

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Eradicating Hepatitis C Dependent on Congressional Action

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Francis Collins, NY Times 11/28/23: We Are Squandering One of the Most Important Medical Advances of the 21st Century

An excerpt:

Congress has an opportunity to turn this ongoing human tragedy into a public health advancement, by providing support for a five-year project to eliminate hepatitis C in the United States...

Each year, about 15,000 Americans die from hepatitis C, many in their 40s and 50s. Given the safe and effective cure available for the last nine years, the correct number of deaths in 2023 should be zero...

In March, President Biden came out in favor of a five-year program to put the United States on track to eliminate hepatitis C…The plan includes an innovative approach to provide broad access to curative medications, modeled on a successful effort in Louisiana. Under this approach, sometimes known as the “Netflix model,” a drug company or companies agree to provide full access to medications for a population in need in exchange for a set lump sum payment. In the current proposal, the populations who would have access to free hepatitis C drugs are Medicaid enrollees, the uninsured, Native Americans, and those in the prison and jail systems. If structured correctly, many more people can get lifesaving care and the cost per cure drops significantly…the plan also includes training, technical support and resources for primary care offices, federally qualified health centers, drug treatment centers, and jails and prisons…

An expert group has estimated that a national initiative to end hepatitis would save society more than $18 billion in health care costs over the next decade, with $13.3 billion of that savings accruing to the federal government.

My take: The advent of safe and effective hepatitis C medications has helped many. Particularly with the challenge of more infections due to intravenous drug use, it will take a concerted effort to eliminate this infection.

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How to Improve the Gift of Life

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MS Cattral et al. Gastroenterol 2023; 165: 1315-1317. Open access (PDF)! Anonymous Living Donor Liver Transplantation: The Altruistic Strangers

This commentary, from Toronto General Hospital practitioners, discusses the increasing use of anonymous living liver donation (ALLD) in North America and donor altruism which is a term coined and popularized by the French philosopher Auguste Comte in the 1800s. Altruism is the principle and moral practice of concern for the welfare or happiness of others.

Key points:

  • Living-donor liver transplantation (LDLT) … in Toronto currently makes up 30% of adult and 80% of pediatric liver transplants.
  • Over the past 4 years, ALLD activity has doubled and now accounts for 15% of our yearly LDLT activity (80–85/year). Similar rates of growth in ALLD have occurred in the USA, whereas it remains rare outside of North America
  • The Canadian system provides several important advantages for anonymous donors: publicly funded health care that covers the cost of the donor assessment, surgery, and
    postoperative care; supportive employers and social programs that minimize financial losses; and a provincially funded program (Prelod) that reimburses incidental costs related to travel, accommodation, and meals up to $6000.
  • Important steps toward supporting living donation have been taken in the USA, such as the development of the National Living Donor Assistance Center as well as the Patient Protection and Affordable Care Act, which makes it illegal for insurance companies to deny
    health coverage to living donors…
  • Donors in the USA, however, still face significant obstacles to obtaining life insurance, long term care insurance, and disability insurance. Notably, the National Living Donor Protection act, which aims to rectify this problem (https://www.congress.gov/bill/117th-congress/
    house-bill/1255/text    ) has yet to move through Congress despite pressure from the transplant community

My take: It is definitely a good idea to promote living donors by removing insurance obstacles/discrimination

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