Category Archives: Hepatology

Fairness Lost: The Shift in Organ Transplant Practices

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BM Rosenthal et al. NY Times 2/26/25: Organ Transplant System ‘in Chaos’ as Waiting Lists Are Ignored

An excerpt:

The sickest patients are supposed to get priority for lifesaving transplants. But more and more, they are being skipped over…For decades, fairness has been the guiding principle of the American organ transplant system…today, officials regularly ignore the rankings, leapfrogging over hundreds or even thousands of people when they give out kidneys, livers, lungs and hearts…

Last year, officials skipped patients on the waiting lists for nearly 20 percent of transplants from deceased donors, six times as often as a few years earlier. It is a profound shift in the transplant system, whose promise of equality has become increasingly warped by expediency and favoritism…

Under government pressure to place more organs, the nonprofit organizations that manage donations are routinely prioritizing ease over fairness. They use shortcuts to steer organs to selected hospitals, which jockey to get better access than their competitors.

These hospitals have extraordinary freedom to decide which of their patients receive transplants, regardless of where they rank on the waiting lists. Some have quietly created separate “hot lists” of preferred candidates...

More than 100,000 people are waiting for an organ in the United States, and their fates rest largely on nonprofits called organ procurement organizations…

The procurement organization is supposed to offer the organ to the doctor for the first patient on the list. But the algorithms can’t necessarily identify exact matches, only possible ones. So doctors often say no, citing reasons like the donor’s age or the size of the organ…

Until recently, organizations nearly always followed the list. On the rare occasion when they went out of order and gave the organ to someone else, the decision was examined by the United Network for Organ Sharing — the federal contractor that oversees the transplant system — and a peer review committee. Ignoring the list was allowed only as a last resort to avoid wasting an organ...

Procurement organizations regularly ignore waiting lists even when distributing higher-quality organs. Last year, 37 percent of the kidneys allocated outside the normal process were scored as above-average…

Skipping patients is exacerbating disparities in health care. When lists are ignored, transplants disproportionately go to white and Asian patients and college graduates…

How a rare shortcut became routine

In 2020, procurement organizations felt under attack. Congress was criticizing them for letting too many organs go to waste. Regulators moved to give each organization a grade and, starting in 2026, fire the lowest performers... the organizations increasingly used a shortcut known as an open offer. Open offers are remarkably efficient — officials choose a hospital and allow it to put the organ into any patient...

Open offers are a boon for favored hospitals, increasing transplants and revenues and shortening waiting times. When hospitals get open offers, they often give organs to patients who are healthier than others needing transplants…Healthier patients are likelier to help transplant centers perform well on one of their most important benchmarks: the percentage of patients who survive a year after surgery...

It is impossible to gauge whether line-skipping prevents wasted organs. But data suggests it does not. As use of the practice has soared, the rate of organs being discarded is also increasing.

My take: This article was eye-opening for me as I am not actively involved in listing patients for transplantation. I was unaware of this increasing tendency of line-skipping and open source allocation. It is disturbing to see the distribution process undermined in this manner –better oversight is needed to assure fairness for those whose lives are at stake.

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MASH Treatment: Curcumin Shows Promising Results

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G Musso et al. Hepatology 2025; 81: 560-575. Effect of phospholipid curcumin Meriva on liver histology and kidney disease in nonalcoholic steatohepatitis: A randomized, double-blind, placebo-controlled trial

“Let food be thy medicine” is a well-known phrase usually attributed to Hippocrates (though it is unclear if he said this). Regardless, this study indicates that added curcumin in the diet could be beneficial for steatotic liver disease.

Methods: In this double-blind trial, 52 patients with biopsy-proven NASH (71% with stage ≥F2 fibrosis, 58% with stage A2-G2/A2-G3a chronic kidney disease) were randomized 1:1 to receive Meriva 2 g/d (1 g BID) or placebo for 72 weeks. Meriva is a formulation of curcumin extract with phospholipids that has improved oral bioavailability of curcumin metabolites.

Key findings:

  • Sixteen (62%) patients on Meriva (curcumin) versus 3 (12%) patients on placebo had NASH resolution (RR = 5.33)
  • hirteen (50%) patients on Meriva versus 2 (8%) patients on placebo had ≥1 stage fibrosis improvement (RR = 6.50)
  • Eleven (42%) patients on Meriva versus 0 (0%) on placebo had regression of significant liver fibrosis (RR = 18.01)
  • Thirteen (50%) patients on Meriva versus 0 (0%) on placebo had chronic kidney disease regression (RR = 10.71)
  • Compared with placebo, Meriva improved eGFR (difference in adjusted eGFR change: +3.59 [2.96–4.11] mL/min/1.73 m2/y, p = 0.009), fasting glucose(−17 mg/dL; 95% CI = −22, −12), HbA1c (−0.62%; 95% CI = −0.87%, −0.37%), LDL-C (−39 mg/dL; 95% CI = −45, −33), triglycerides (−36 mg/dL, 95% CI = −46, −26), HDL-C (+10 mg/dL; 95% CI = +8, +11), and inflammatory markers
  • The observed benefits were associated with downregulation of hepatic NF-kB which is a proinflammatory transcription factor and a known curcumin target

My take: A larger multicenter study is needed to confirm these promising results. This study shows that dietary changes and lifestyle modification remain important tools in treating MASH (aka NASH).

Related editorial (open access!): S Zelber-Sagi, JM Schattenberg. Hepatology 2025; 81: 399-401. Is curcumin the new kid on the block for the treatment of MASH?

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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.

More Data Indicating GLP-1 Efficacy for MASH

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GI and Hepatology News, Open Access: Watershed Moment’: Semaglutide Shown to Be Effective in MASH (November 2024): “At 72 weeks, a 2.4-mg once-weekly subcutaneous dose of semaglutide demonstrated superiority, compared with placebo, for the two primary endpoints: Resolution of steatohepatitis with no worsening of fibrosis and improvement in liver fibrosis with no worsening of steatohepatitis.”

“ESSENCE (NCT04822181) is an ongoing multicenter, phase 3 randomized, double-blind, placebo-controlled outcome trial studying semaglutide for the potential treatment of MASH.” Cohort: N=1200, biopsy-defined MASH and fibrosis, stages F2 and F3…”After initiation, the semaglutide dosage was increased every 4 weeks up to 16 weeks when the full dose (2.4 mg) was reached.”

Key findings:

  • 62.9% of those in the semaglutide group and 34.1% of those in the placebo group reached resolution of steatohepatitis with no worsening of fibrosis. 
  • 37% of those in the semaglutide group and 22.5% of those in the placebo group had improvement in liver fibrosis with no worsening of steatohepatitis
  • Weight loss was also significant, with a 10.5% reduction in the semaglutide group compared with a 2% reduction in the placebo group
  • No new safety signals were identified
  • Cardiometabolic risk factors improved as well, with changes in blood pressure measurements, hemoglobin A1c scores, and cholesterol values.
  • 20%-40% improvements in liver enzymes and noninvasive fibrosis markers, such as ELF and vibration-controlled transient elastography liver stiffness.

My take: This expected finding indicates that more GLP-1 agents are likely to be approved for MASH treatment. Survodutide received “U.S. FDA Breakthrough Therapy” in October 2024.

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Effectiveness of Xalnesiran in Treating HBV Infection

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JHW Zhang et al. NEJM 391: 2098-2109. Xalnesiran with or without an Immunomodulator in Chronic Hepatitis B

Background: Xalnesiran, a small interfering RNA molecule that targets a conserved region of the hepatitis B virus (HBV) genome and silences multiple HBV transcripts.

Methods: This was a phase 2, multicenter, randomized, controlled, adaptive, open-label platform trial that included the evaluation of 48 weeks of treatment with xalnesiran at a dose of 100 mg (group 1), xalnesiran at a dose of 200 mg (group 2), xalnesiran at a dose of 200 mg plus 150 mg of ruzotolimod (group 3), xalnesiran at a dose of 200 mg plus 180 μg of pegylated interferon alfa-2a (group 4), or a nucleoside or nucleotide analogue (NA) alone (group 5) in participants with chronic HBV infection who had virologic suppression with NA therapy. The primary efficacy end point was hepatitis B surface antigen (HBsAg) loss (HBsAg level, <0.05 IU per milliliter) at 24 weeks after the end of treatment.

Key findings:

In the associated editorial by Janssen et al. (NEJM 2024;391:2163-2168), the authors note that “nucleoside or nucleotide analogues currently form the backbone of therapy for most patients with chronic HBV infection who have access to treatment…However, treatment must be continued on a long-term basis…Although treatment with nucleoside or nucleotide analogues is associated with a decrease in the severity of liver fibrosis and reduction of liver-related complications, the risk of hepatocellular carcinoma persists at the population level because functional cure is not achieved in most patients.”

“Further data are needed on the durability of the effect achieved with new agents that directly interfere with HBsAg production. The results reported by Hou et al. indicate a risk of relapse, undermining the choice of functional cure as an end point for these agents, at least when assessed relatively early after the withdrawal of therapy…Hou et al. observed that functional cure was achieved only in patients with a baseline HBsAg level of less than 1000 IU per milliliter. Although a substantial proportion of patients have similarly low HBsAg levels, patients with higher HBsAg levels have the greatest risk of adverse liver-related outcomes and thus have the most to gain from new therapies.”

My take: While this study represents important progress, it is not likely to change current treatment strategies in the near-term. Even better than treating HBV is preventing HBV. The best strategy for reducing HBV mortality and morbidity still relies of wide-scale use of the highly effective HBV vaccine.

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Teaching an Old Dog a New Trick: Optimizing Thiopurine Therapy in Autoimmune Hepatitis

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Key findings:

  • Over 4 years (N = 146), patients with higher average 6TGN levels were associated with those with stable complete biochemical remission (CBR) (260 pmol/0.2 mL) compared to those failing to maintain CBR (181 pmol/0.2 mL; p = 0.0014) or never achieving CBR (153 pmol/0.2 mL; p < 0.0001), with an optimal 6TGN cutoff of ≥223 pmol/0.2 mL
  • Adding allopurinol to thiopurines in difficult-to-treat patients (N = 36) raised 6TGN (168→321 pmol/0.2 mL; p < 0.0001) and lowered 6MMP (2125→184 pmol/0.2 mL; p < 0.0001), resulting in improved transaminases in all patients and long-term CBR in 75%.
  • Limitation: most of the 337 patients did NOT have sequential azathioprine metabolite monitoring. This could indicate that the 146 patients with sequential monitoring could have a selection bias favoring patients with a more aggressive disease course. Thus, the proposed 6-TGN level of 223 may not be applicable for all patients.

From editorial:

  • “In this issue of Hepatology, “Weltzsch et al1 conducted a multicenter study on the metabolic monitoring of thiopurines in AIH. The authors defined an optimal cutoff of ≥223 pmol/0.2 mL average 6TG level to maintain long-term biochemical remission (BR). Notably, 66% of patients with 6TG levels above this cutoff sustained BR rates. 
  • Allopurinol shifts the thiopurine metabolism toward 6TG production, allowing thiopurine dose reduction to 25%–30%, which improves efficacy and tolerability. (The 100 mg dose of allopurinol had more favorable 6MMP/6TG ratio).
  • However, they note that in a prior study (J Hepatol 2021; 75: 324-32), “patients with subtherapeutic 6TG levels (75–225) achieved similar BR rates (75% vs. 81%, p = 0.589) to those with therapeutic levels (225–450), while experiencing significantly fewer adverse drug reactions (44% vs. 86%, p = 0.0002).”
Proposed Algorithm

My take: This study shows in patients who have not achieved a biochemical remission, optimization of azathioprine dosing with metabolite monitoring improves biochemical remission. In those with low 6TG and low 6MMP, increasing the azathioprine should be considered. In those with low 6TG and high 6MMP, reducing azathioprine and adding allopurinol should be considered.

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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.

Case Study: Elevated Liver Enzymes in Diabetic Ketoacidosis

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Å Sjöholm et al. N Engl J Med 2024;391:1528. Glycogenic Hepatopathy

Case report: “An 18-year-old man with type 1 diabetes mellitus who had been admitted to the hospital with diabetic ketoacidosis had unexpected elevations in aminotransferase levels. Laboratory studies showed a peak alanine aminotransferase level of 972 U per liter.”

“Computed tomography of the abdomen showed hepatomegaly without parenchymal changes (Panel A). A liver biopsy showed swollen hepatocytes with abundant deposition of glycogen in the cytoplasm, as evidenced by positive staining with periodic acid–Schiff (Panel B) and digestion of the deposits after treatment with diastase (Panel C).”

“At follow-up 3 weeks after discharge from the hospital, the patient had been adherent to insulin therapy, and his aminotransferase levels had normalized.”

My take: The potential etiologies for elevated liver enzymes in the setting of diabetic ketoacidosis include glycogenic hepatopathy, ischemic hepatitis, infectious etiologies, autoimmune hepatitis, celiac disease, and steatotic liver disease. This recent case report describes glycogenic hepatopathy. There was not a discussion as to why a CT scan and a liver biopsy were deemed necessary.

Related blog post: Mauriac Syndrome (Glycogenic Hepatopathy)

AASLD Practice Changes for Metabolic Liver Disease in 2024

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V Chen et al. Hepatology 2024; doi: 10.1097/HEP.0000000000001112. Open Access!. Resmetirom therapy for metabolic dysfunction-associated steatotic liver disease: October 2024 updates to AASLD Practice Guidance

Key points:

  • Guidance recommends use of resmetirom (in adults) with F2-F3 fibrosis as determined by “imaging-based NILDAs, such as liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) or magnetic resonance elastography (MRE)…liver biopsy is not typically recommended for fibrosis staging in current clinical practice, [though] histologic examination remains the gold standard to quantify fibrosis.”
  • “Glucagon-like peptide 1 (GLP-1) and GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists are FDA approved for the treatment of type 2 diabetes and overweight/obesity. They reduce the risk of cardiorenal complications in addition to their effects on glycemic control and weight loss.17–25 While these pharmaceutical agents are not currently approved for the treatment of MASH, phase 2 randomized, placebo-controlled clinical trials of liraglutide, semaglutide, and tirzepatide have demonstrated their efficacy in reducing steatohepatitis without worsening fibrosis and, in the case of tirzepatide, decreasing fibrosis without worsening of steatohepatitis as well.”
  • “The most common treatment-emergent adverse events were diarrhea and nausea, which developed in 24% to 34% and 12% to 22% of resmetirom-treated participants, respectively…Development of hypothyroidism requiring levothyroxine replacement occurred in 1.8% of participants receiving resmetirom.”
  • The authors recommend assessing response with bloodwork and noninvasive imaging at 1 yr to help determine if therapy should be continued.

My take: This article provides practical advice for using resmetirom for MASLD.

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Autoimmune Diseases in Patients with Primary Sclerosing Cholangitis Plus One

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A Lundberg Bave et al. Hepatology 2024; 80: 527-535. Autoimmune diseases in primary sclerosing cholangitis and their first-degree relatives

Methods: Using National Swedish registries, the authors evaluated a matched cohort study, 1378 individuals with PSC and 13,549 general population comparators and their first-degree relatives.

Key findings:

  • After excluding inflammatory bowel disease and autoimmune hepatitis, the prevalence of autoimmune disease was 18% in PSC and 11% in comparators, OR: 1.77
  • Highest odds were seen for celiac disease [OR: 4.3], sarcoidosis [OR: 2.74], diabetes type 1 [OR: 2.91], and autoimmune skin disease [OR: 2.15]
  • First-degree relatives of individuals with PSC had higher odds of developing IBD [OR: 3.25], autoimmune hepatitis [OR: 5.94], and any autoimmune disease than relatives of the comparators [OR: 1.34] 

My take: Keep an eye out for other autoimmune diseases in patients (& their 1st-degree relatives) with PSC.

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Briefly noted: BB Lai et al. Hepatology 2024; 80: 511-526. Genotype correlates with clinical course and outcome of children with tight junction protein 2 (TJP2) deficiency–related cholestasis Key finding: “Patients with the TJP2-C genotype carrying PPTMs [predicted protein-truncating mutation] in both alleles had a rapidly progressive course, leading to early decompensation and death if they did not receive timely liver transplantation.”

Metabolite Spectroscopy As a Diagnostic Tool for Autoimmune Hepatitis

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A Dimou et al. Hepatology 2024; 80: 266-277. NMR-based metabolomic signature: An important tool for the diagnosis and study of pathogenesis of autoimmune hepatitis

Methods: The authors examined treatment-naive patients with well-established AIH and compared them to healthy controls and those with other liver diseases.

Key Finding:

  • Fifteen metabolites (out of a total of 52 analyzed) differentiated AIH from disease controls (PBC+chronic viral hepatitis+metabolic dysfunction–associated liver disease) (95% sensitivity and 92% specificity)

In their discussion, the authors review the metabolism of the various metabolites and why they may be altered in AIH. “Our study found that cirrhosis did not seem to affect our results.” In ongoing studies, the authors are trying to determine how these metabolites change with treatment and whether they could be a predictive marker.

My take: Metabolite measurement could be helpful in the diagnosis of AIH as “NMR technology dose not need much sample handling, is highly reproducible, and with low costs.

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Rope-A-Dope with Hepatitis C

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Methods: The authors developed an agent-based model (ABM) “simulating the dynamics of HCV transmission and demographic changes from 2006 to 2030, using data from Ontario, Canada.14 Predicted long-term health outcome effects for current HCV policies (status quo) and those following the implementation of various scale-up interventions were compared to the elimination goals set by the WHO.”

Key findings:

  • Under the current status quo of risk-based screening, we predict the incidence of CHC-induced decompensated cirrhosis, HCC, and liver-related deaths would decrease by 79.4%, 76.1%, and 62.1%, respectively, between 2015 and 2030
  • However, chronic hepatitis C (CHC) incidence would only decrease by 11.1% (WHO goal by 2030 is a reduction of 80%)

From the editorial:

“According to the study by Tian et al,3 the future incidence of HCV infection will be mainly related to HCV transmission, stressing the fact that harm reduction strategies, in addition to the highest treatment rate, are paramount to reducing the further HCV spread and reinfection risk, especially in marginalized populations. In high‐income countries, HCV treatment rates among people who use drugs remain inadequate due to a lack of simplified HCV testing, scale‐up of harm reduction‐based HCV treatment programs, and numerous additional barriers to HCV services.”

“It is not just a matter of time until high-income countries get rid of HCV infection. The ongoing mass screening campaign in Italy shows that having political will and financial coverage is insufficient to achieve the HCV elimination targets. In high-income countries, encouraging and convincing people to get tested is among the most challenging and underrated.”

My take: The development of highly effective HCV treatments has been a remarkable feat, reducing the rate of death and complications from HCV. Nevertheless, it has not brought about a big improvement in HCV transmission. To achieve this, it looks like a vaccine will be necessary. Until then, our fight against HCV is akin to the ‘rope a dope‘ boxing strategy –we are not getting a knock-out anytime soon against this opponent.

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