Category Archives: Hepatology

AASLD Guidelines: Challenges of Liver Fibrosis Testing in Pediatrics

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This guideline reviews and recommends blood-based tests as a tool to help determine the likelihood/severity of liver fibrosis in the presence of chronic liver disease. Most of the guideline focuses on adult liver disease. For pediatrics, the guideline makes the following recommendation:

In the pediatric patients with chronic liver disease, AASLD suggests the use of simple, cost-effective, and readily available blood-based NILDA [Non-invasive Liver Disease Assessment], such as APRI or FIB-4, for the detection of advanced fibrosis (F3-4) (ungraded statement).

Technical Remarks:

  • Some blood-based NILDA in children have good accuracy in detecting advanced fibrosis but have difficulty discriminating earlier stages of fibrosis.
  • FIB-4 does not perform as well in children as it does in adults, particularly very young children, due to the inclusion of age in the index.
  • Rapid growth in children and attendant fluctuations in alkaline phosphatase can confound interpretation of blood or collagen-based NILDA tests in pediatric liver disease.
  • There are insufficient biopsy validated data to recommend biomarkers for evaluating fibrosis in pediatric NASH and α1AT at this time.
  • In the pediatric population with CLD, there is growing but insufficient evidence to recommend blood-based NILDA as endpoints to monitor changes in fibrosis over time.

Despite the guidance recommendation, reading the text makes one leery about relying on these tests:

  • For example with biliary atresia: “The utility of APRI to assess or predict liver fibrosis in BA is mixed in the current literature.”
  • “In conclusion, blood-based NILDA tests in children vary widely in their accuracy, even in detecting F3-4 fibrosis, and have difficulty discriminating earlier stages of fibrosis. These tests also have different disease-specific thresholds that correlate with histopathologic fibrosis and differ from adults. APRI and FIB-4 have been the most studied NILDA tests in children, but there is still insufficient evidence to recommend blood biomarkers as endpoints to monitor changes in fibrosis over time. Any blood-based NILDA that includes age (Table 5) should be used cautiously in children.“

My take: This practice guideline, while recommending use of blood-based tests for fibrosis even in the pediatric age group, makes a fairly compelling argument that they are unreliable in children. Elastrography is likely to be more useful, though also imperfect, in the pediatric population.

Algorithm Recommended for Adults:

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Understanding Bleeding Risks in Percutaneous Liver Procedures —Who Needs FFP and Platelet Transfusions

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Background: “The most important factor contributing to bleeding risk in patients with liver disease is related to the presence of portal hypertension rather than coagulation abnormalities.1 The changes in the coagulation system in patients with cirrhosis create a re-balanced state, which is prothrombotic. Despite this well-known pathophysiology and recommendation against routine transfusion of blood products (especially fresh frozen plasma) by major guidelines, platelet and fresh frozen plasma transfusion remain a common practice before percutaneous liver procedures.2,3“

Methods: In this retrospective study from three centers in Spain, the researchers enrolled 1797 adults including 316 with cirrhosis (97% had compensated disease). They established a protocol that allowed, at the discretion of the radiologist, to transfuse patients with FFP or platelets if INR was 1.5 or greater or if platelets were 50,000 or below. The primary outcome of the study was major bleeding, which was defined as a drop in hemoglobin (2 or more units) or a need for transfusion of 2 or more units of blood within 1 week after the procedure. This study enrolled patients who underwent percutaneous liver biopsy (86% of cohort) and percutaneous ablation of liver tumors (14% of cohort). Only 6/25 (24%) with INR >1.5 received FFP. 16/22 (72%) with platelet counts below 50,000 received a platelet transfusion. Overall, 7 patients received FFP (1 with cirrhosis, 6 without) and 35 patients received platelets (16 with cirrhosis, 19 without).

Key findings:

  • Only 14 patients (0.8%) experienced major bleeding after the procedure, and there was no difference between those who had a diagnosis of cirrhosis versus those without cirrhosis. Bleeding occurred in 0.6% of patients with cirrhosis compared to 0.8% of those without.
  • Only 1 patient with an ablation procedure had major bleeding
  • Patients with a diagnosis of cirrhosis were more likely to receive a transfusion of any kind
  • Among those with major bleeding, none met the criteria for transfusion. That is, “no variable was identified to predict the risk of major bleeding.”

My take (borrowed from editorial): This study reinforces the recommendation that “correction of coagulation markers before procedures is unnecessary.”

The editorial notes that “the changes in the coagulation system in patients with cirrhosis
create a re-balanced state, which is prothrombotic.

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Gene Therapy for Alpha-One Antitrypsin Deficiency

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An excerpt from NY Times:

Researchers have corrected a disease-causing gene mutation with a single infusion carrying a treatment that precisely targeted the errant gene.This was the first time a mutated gene has been restored to normal….

The study involved patients who have alpha-1 antitrypsin deficiency, or AATD, a genetic disease that affects an estimated 100,000 Americans…

When the nanoparticles reached the liver, the lipid layer peeled off, releasing the editor — a disabled CRISPR molecule that acted like a GPS for the genome and an enzyme to fix the mutation. The CRISPR molecule crawled along the patient’s DNA until it found the one incorrect letter that needed to be repaired among the three billion DNA letters in the genome. Then the editing enzyme replaced that letter with the correct one… Those who got the highest dose made enough normal alpha-1 antitrypsin to be in a range where no more damage should occur. 

My take: This is exciting news, though, long-term data is needed to determine if this will be a durable cure. Cost/availability will be an important consideration if effective.

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Understanding Fontan-Associated Liver Disease (FALD)

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AJ Gumm, EB Rand. J Pediatr 2025; 277: 114389. Fontan-Associated Liver Disease

This review article provides a lot of useful advice regarding Fontan-Associated Liver Disease (FALD).

Key points:

  • FALD prevalence: “will be 70,000 by 2025, with the mean age of 23 years”
  • Early common manifestations are modest increases in AST and ALT. Elevation of bilirubin is a late finding. Mild elevation of INR is common in range of 1.4 to 1.8.
  • Ascites occurs in 2-17% of patients with FALD but can be due to other etiologies like PLE
  • Annual labs (HFP, GGT, CBC/d, PT/INR, AFP) recommended after 7 years post-Fontan
  • No special diet is recommended but it is worthwhile to avoid fatty liver disease
  • For varices, a TIPS procedure “may precipitate pulmonary hypertension resulting in cardiac failure.” ‘The safety of a nonselective beta-blocker to prevent a variceal bleed has not been established.” It is important to determine if there are cardiac options that could improve portal hypertension.
  • In patients with advanced liver disease, multidisciplinary teams are needed to determine if an isolated liver transplantation versus combined heart and liver transplantation (CHLT) is needed.
  • “If a patient requires a heart transplant, the presence of liver fibrosis or even cirrhosis alone is not an indication for liver transplantation, because cirrhosis has been reported to reverse after isolated heart transplantation in a single provocative case. However, if there is evidence of cirrhosis and liver decompensation, then a CHLT should be considered.”
  • Many hepatologists recommend trending elastography. Many recommend liver biopsy starting after 10 years status post Fontan

When to refer to hepatology:

  1. Concerning labs: high transaminases, GGT or bilirubin; low albumin (if liver-related), high INR (not due to warfarin), and high AFP
  2. Signs of portal hypertension (eg. splenomegaly, varies, reversal of flow on ultrasound)
  3. Liver masses
  4. More than 10 years post-Fontan. “100% of patients with Fontan circulation will develop liver disease in their lifetime”

My take: There is a lot that we do not know about FALD and management is complex due to coexistent abnormal cardiac physiology.

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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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Manuel Antonio National Park, Costa Rica

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)