Pancreatic portal hypertension is a distinct type of portal hypertension caused by various pancreatic diseases or by pancreatic surgery. Unlike the far more common portal hypertension driven by cirrhosis of the liver, this variant arises when inflammation, cysts, tumors, or scarring in the pancreas compress or obstruct the splenic vein and neighboring splanchnic vessels. Blood that cannot drain through its usual route finds alternative channels, engorging vessels around the stomach and esophagus and enlarging the spleen. The result is a condition that mimics liver disease on the surface but has an entirely different anatomy and, crucially, a different treatment logic.

The clinical significance of the new consensus lies partly in a quiet epidemiological shift. According to the guideline authors, the detection rate of pancreatic portal hypertension has steadily increased in recent years with the widespread application of advanced imaging techniques and endoscopy. Computed tomography and magnetic resonance imaging now routinely capture the pancreatic region in exquisite detail, while endoscopic ultrasound allows physicians to peer directly at the vessels surrounding the pancreas. Diseases that once went unrecognized are now being identified with growing frequency, making a standardized management framework increasingly urgent.

Yet the condition remains notoriously difficult to catch early. The consensus panel notes that the clinical manifestations of pancreatic portal hypertension are often insidious, compromising early identification. Patients may carry the vascular changes for years without symptoms, and the first warning signs frequently emerge only at an advanced stage. By that point, some complications, such as splenomegaly and upper gastrointestinal bleeding, have already taken hold. Bleeding from engorged gastric varices can be dramatic and life threatening, while an enlarged spleen can trap platelets and complicate the broader management of the underlying pancreatic disease.

To build the guideline, the Chinese Society of Gastroenterology of the Chinese Medical Association invited a panel of skilled experts to participate in a Delphi consensus process, systematically reviewing and discussing the available evidence on the causes, risk factors, clinical manifestations, diagnosis, therapy, and prognostic assessment of pancreatic portal hypertension. The Delphi method is a structured technique for extracting reliable group judgment from a large panel: experts answer questionnaires independently, the results are aggregated and fed back, and the process repeats until statements stabilize. After three rounds of questionnaire surveys and votes, the panel formulated 19 consensus statements to provide clinical guidance on the diagnosis and management of the condition.

The scope of the consensus is deliberately broad. By covering etiology, risk factors, clinical presentation, diagnostic strategy, therapeutic options, and prognostic assessment in a single document, the guideline fills a gap that existing publications on pancreatic diseases or portal hypertension had left open. Although the concept of pancreatic portal hypertension has been recognized in existing guidelines and consensus documents on the management of pancreatic diseases or portal hypertension, its management strategy had never been comprehensively summarized. Clinicians confronting a patient with pancreatic disease and unexplained gastric varices or splenic enlargement have had to piece together guidance from scattered sources, and the new consensus aims to end that improvisation.

Technically, the diagnostic challenge centers on distinguishing pancreatic portal hypertension from cirrhotic portal hypertension and from other causes of splanchnic vein thrombosis. Cross-sectional imaging plays the decisive role: contrast-enhanced computed tomography and magnetic resonance imaging can reveal the obstructing pancreatic lesion, the occluded or compressed splenic vein, and the collateral vessels that betray the redirected blood flow. Endoscopic evaluation identifies the varices that carry bleeding risk, while laboratory findings such as thrombocytopenia from hypersplenism can provide supporting clues. The consensus framework gives clinicians a structured pathway for assembling these pieces into a confident diagnosis, even when the liver itself is entirely healthy.

On the therapeutic side, the management logic differs fundamentally from that of cirrhotic portal disease. Because the obstruction is often localized to the splenic vein, treating the underlying pancreatic lesion can sometimes restore normal venous drainage, and interventions aimed at the vascular obstruction itself, including endovascular approaches, have been explored in the literature. The consensus statements address how to weigh bleeding risk against the risks of intervention, how to manage acute upper gastrointestinal bleeding when it occurs, and how to coordinate vascular care with the treatment of the primary pancreatic condition, whether that is acute pancreatitis, chronic pancreatitis, autoimmune pancreatitis, or a pancreatic tumor.

The panel was large and geographically diverse, drawing gastroenterologists, endoscopists, interventional radiologists, hepatobiliary surgeons, and intensive care specialists from major hospitals across China, from Shenyang in the northeast to Chengdu, Shanghai, Guangzhou, and Xi’an. Corresponding authors include Xingshun Qi of the General Hospital of Northern Theater Command, Hao Wu and Chengwei Tang of West China Hospital, Sichuan University, and Xiaozhong Guo of the General Hospital of Northern Theater Command. Four junior researchers, Xingshun Qi, Yuhang Yin, Zhiyin Huang, and Yuzheng Zhuge, contributed equally to the work, which was partially supported by the National Key R&D Program of China.

The methodological rigor of the consensus reflects modern guideline standards. The panel employed structured evidence frameworks, including PICO and PECO question formats for framing clinical questions, and used the GRADE system for grading the quality of evidence behind each recommendation. Reporting followed the RIGHT checklist for practice guidelines, and the document was appraised with the AGREE II instrument. Literature searches spanned Chinese databases such as CNKI and VIP alongside international sources, ensuring that both Chinese clinical experience and global evidence informed the final statements. The authors declare no competing interests, and the guideline is published under a Creative Commons license allowing free access for clinicians worldwide.

For the international medical community, the significance of the consensus extends beyond China’s borders. Pancreatic portal hypertension is a global condition, arising wherever pancreatitis, pseudocysts, tumors, or pancreatic surgery compromise the splenic vein, and clinicians on every continent face the same diagnostic and therapeutic dilemmas. A comprehensive, openly available framework for the causes, risk factors, clinical manifestations, diagnosis, therapy, and prognostic assessment of the disease gives physicians everywhere a reference point for building their own local protocols. As advanced imaging continues to reveal more cases that once went undetected, the demand for such standardized guidance will only grow, and the 19 statements now offer a foundation that future international guidelines can refine and extend.

Subject of Research: Medicine

Article Title: Chinese consensus on the management of pancreatic portal hypertension

Article References: Qi, X., Yin, Y., Huang, Z., Zhuge, Y., Cai, S., Chen, M., Chen, P., Chen, S., Chen, W., Ding, Z., Du, Y., Guo, G., Guo, W., He, F., He, W., Hu, S., Huang, L., Ke, L., Kong, D., … Tang, C. (2026). Chinese consensus on the management of pancreatic portal hypertension. BMC Medicine. https://doi.org/10.1186/s12916-026-05289-7

Image Credits: AI Generated

DOI: 10.1186/s12916-026-05289-7

Keywords: pancreatic portal hypertension, portal hypertension, consensus, gastrointestinal bleeding, splenomegaly, BMC Medicine, Delphi, pancreatic disease, Chinese, management, pancreatic, portal

The study, published in Frontiers in Gastroenterology, took an unusual two-pronged approach known as triangulation, pairing a Mendelian randomization analysis of large genetic datasets with a retrospective clinical study of patients whose portal pressure was measured directly. The logic behind triangulation is simple but powerful: no single observational study can fully rule out confounding, so researchers seek multiple lines of evidence that rely on different assumptions. If independent methods converge on the same answer, the conclusion becomes far harder to dismiss as an artifact of bias.

Mendelian randomization exploits a quirk of biology: genes are randomly allocated at conception and remain fixed throughout life. By using genetic variants that predict dietary fat intake as instruments, researchers can approximate a randomized trial of lifelong eating habits without actually assigning diets. Because the genes are inherited randomly, they are largely immune to the confounding factors that plague ordinary nutrition studies, such as obesity, insulin resistance, or the tendency of advanced liver disease itself to change what people eat. The method rests on three assumptions: the genetic variants must be strongly associated with the exposure, must not be linked to confounders, and must influence the outcome only through the exposure.

In practice, the team drew on genome-wide association study data covering 268,922 people of European ancestry, selecting 18 independent single nucleotide polymorphisms associated with fat intake as a percentage of total energy consumption. These instruments were strong by conventional standards, with a mean F-statistic of 34.2 against the threshold of 10 usually required, though together they explained only 2.8 percent of the variation in dietary fat. The primary analysis, an inverse variance weighted method, found that each standard deviation increase in genetically predicted fat intake was associated with 28 percent higher odds of portal hypertension, an odds ratio of 1.28 with a 95 percent confidence interval of 1.15 to 1.42 and a p-value of 1.0 times ten to the minus five.

Crucially, the association held up across every complementary method the team applied. The weighted median estimator, which remains valid even if up to half of the instruments are faulty, produced an odds ratio of 1.23. MR-Egger regression, designed to detect directional pleiotropy, where variants affect the outcome through pathways other than the exposure, yielded 1.35, and its intercept test showed no evidence of such pleiotropy. Cochran’s Q statistic found no significant heterogeneity among the SNP estimates, and the MR-PRESSO outlier-detection procedure identified no pleiotropic outliers, with the outlier-corrected estimate virtually identical to the original. A leave-one-out analysis confirmed that no single genetic variant was driving the result, and a Steiger directionality test verified that the causal arrow runs from diet to disease rather than the reverse. An independent FinnGen analysis of nearly 400,000 Finns, using liver cirrhosis as a surrogate endpoint with zero participant overlap, replicated the direction and significance of the effect.

The clinical arm of the study grounded these genetic findings in measurable physiology. The researchers retrospectively studied 72 patients with chronic liver disease who underwent hepatic venous pressure gradient, or HVPG, measurement at a tertiary hepatology center between 2021 and 2023. HVPG, the difference between wedged and free hepatic venous pressures, is the gold standard for assessing portal pressure, with values above 5 mmHg defining portal hypertension and values at or above 10 mmHg defining clinically significant disease. Dietary intake was assessed with a validated 168-item food frequency questionnaire administered by trained staff, and a high-fat diet score from 0 to 10 was calculated from consumption of red and processed meats, high-fat dairy, fried foods, cooking oils, and nuts and seeds.

The correlation was striking. The high-fat diet score correlated with HVPG at r = 0.700, and patients in the highest tertile of fat intake had a mean HVPG of 14.53 mmHg, compared with 12.29 mmHg in the moderate group and 9.37 mmHg in the low-fat group, a gap of roughly 5 mmHg between the extremes. The clinical stakes of that gap are considerable, because each 1 mmHg increase in HVPG is associated with approximately 10 to 15 percent higher risk of variceal bleeding, and even reductions of 2 to 3 mmHg are considered clinically meaningful. Nearly 94 percent of the high-fat diet group had clinically significant portal hypertension, versus only about 42 percent of the low-fat group.

Importantly, the association survived statistical adjustment. In a multivariate linear regression controlling for age, sex, BMI, bilirubin, albumin, and platelet count, each one-point increase in the high-fat diet score predicted a 0.85 mmHg increase in HVPG, and a partial correlation adjusting for BMI alone remained significant. That finding suggests dietary composition matters beyond its effect on body weight, consistent with emerging evidence that saturated and trans fats can exert direct hepatotoxic effects independent of overall adiposity. The regression model explained 62.3 percent of the variance in HVPG, and cross-validation and bootstrap correction confirmed it retained good predictive performance despite the modest sample size.

The authors stress that they did not directly test mechanisms, but several plausible biological pathways could connect fatty diets to raised portal pressure, all drawn from prior literature and acknowledged as speculative. Hepatic steatosis, the accumulation of fat inside liver cells, may increase intrahepatic vascular resistance by compressing sinusoids and reducing vascular compliance. Lipotoxicity from saturated fatty acids can trigger oxidative stress, endoplasmic reticulum stress, and activation of hepatic stellate cells, the cells that drive fibrosis. High-fat diets may also disrupt the gut microbiome and increase intestinal permeability, flooding the liver with bacterial endotoxin and fueling inflammation, while the associated insulin resistance can raise hepatic vascular tone by impairing nitric oxide signaling.

The study has real limitations, and the researchers are candid about them. Mendelian randomization captures the effect of lifelong genetic predisposition, which may not translate directly into the benefits of moderate dietary changes adopted in adulthood. The genetic analysis was restricted to people of European ancestry, the dietary data relied on self-reported questionnaires, and the clinical cohort was small and drawn from a single center with a retrospective design. The diet score also did not distinguish saturated from unsaturated fats. Even so, the convergence of genetic and clinical evidence on the same conclusion gives the finding unusual weight, and the authors argue it provides a rationale for testing dietary fat reduction as a potential adjunctive strategy for managing portal hypertension, pending confirmation in prospective intervention trials. For now, the message is a cautious one: what lands on the plate may help determine the pressure inside the portal vein.

Subject of Research: Causal relationship between high-fat diet and portal hypertension assessed by Mendelian randomization and clinical HVPG measurement

Article Title: High-fat diet and portal hypertension: a triangulation approach combining Mendelian randomization with retrospective clinical analysis

Article References: Xu, Y., Yang, S., Li, Y., Han, Q., & Wang, W. (2026). High-fat diet and portal hypertension: a triangulation approach combining Mendelian randomization with retrospective clinical analysis. Frontiers in Gastroenterology, 5, Article 1927449. https://doi.org/10.3389/fgstr.2026.1927449

Image Credits: AI Generated

DOI: 10.3389/fgstr.2026.1927449

Keywords: portal hypertension, high-fat diet, Mendelian randomization, hepatic venous pressure gradient, liver disease, causal inference, NAFLD, cirrhosis, GWAS, dietary fat, triangulation, hepatology

The review, led by Professor Hong You and Dr. Bingqiong Wang of the Liver Research Center at Beijing Friendship Hospital, Capital Medical University, examines evidence on recompensation across the major causes of cirrhosis. Published in the journal Portal Hypertension & Cirrhosis, the work synthesizes data on how often recompensation occurs, what criteria should define it, which factors predict it, what is known about its biological basis, and how patients who recover should be monitored over the long term. The authors’ central proposal is that recompensation should be recognized as a distinct, treatment-related disease state rather than treated as a vague synonym for improvement.

The shift in thinking rests on a growing body of evidence that effective treatment of the underlying cause of cirrhosis can allow some patients to regain liver function and resolve the complications that defined their decompensation. In viral hepatitis, potent antiviral therapy can suppress replication and reduce inflammation; in alcohol-related liver disease, sustained abstinence can remove the ongoing injurious stimulus; in autoimmune and cholestatic conditions, targeted immunosuppression or other therapies can alter disease activity. When the driver of scarring is controlled, the liver’s residual regenerative capacity can, in a subset of patients, translate into measurable clinical recovery.

Yet recovery, the authors emphasize, is neither automatic nor uniform. Under the Baveno VII consensus, an international framework widely used in hepatology, recompensation is defined by three requirements: control of the underlying cause of cirrhosis, sustained resolution of decompensation events without the need for supportive treatment such as diuretics or non-selective beta-blockers, and stable improvement in liver function. Meeting these criteria is demanding, and the new review makes clear that many patients who improve do not fully satisfy them, while others who do may later lose that status.

How often does recompensation actually occur? A meta-analysis of 27 studies encompassing 9,063 patients found a pooled prevalence of approximately 35 percent, though the figure varied dramatically by etiology. Around 50 percent of patients with hepatitis B virus-related cirrhosis achieved recompensation, compared with only about 15 percent of those with primary biliary cholangitis. In one hepatitis B study, 56.2 percent of 283 treatment-naive patients receiving the antiviral drug entecavir met Baveno VII criteria after 120 weeks of therapy. Among patients with alcohol-related cirrhosis, a multicenter study reported that 31.1 percent achieved recompensation. These numbers suggest that recompensation is far from rare, but also far from universal.

The likelihood of recovery depends on more than simply eliminating the cause. Better baseline liver function, fewer previous decompensation events, and a lower burden of portal hypertension, the elevated pressure in the venous system that drains the gut through the liver, were generally associated with a greater chance of recompensation. The meta-analysis illustrated this gradient starkly: cohorts with a mean Model for End-Stage Liver Disease score below 15 had a pooled recompensation rate of 48 percent, whereas cohorts with scores of 15 or higher achieved only 19 percent. In other words, the reserve remaining in the liver at the moment treatment begins shapes how much recovery is possible.

Intriguingly, clinical improvement appears to be mirrored by measurable biological change. In a small group of 19 patients with alcohol-related cirrhosis who had paired hemodynamic measurements, the median hepatic venous pressure gradient, a direct readout of portal pressure, fell from 19 to 9 mmHg after sustained recovery. That decline represents a substantial hemodynamic improvement and suggests that fibrosis regression and reductions in vascular resistance within the scarred liver can accompany the resolution of clinical complications. However, the same body of data carries a cautionary note: 59 percent of 29 evaluated patients retained clinically significant portal hypertension despite their overall improvement, meaning that the vascular complications of cirrhosis can persist even when the surface picture looks favorable.

Perhaps the most consequential argument in the review is that recompensation can be unstable. In a hepatitis B cohort, 86.8 percent of patients who achieved recompensation by Week 120 maintained it during extended follow-up, but 13.2 percent developed hepatocellular carcinoma, experienced further decompensation, or died. Another study identified unstable recompensation in 24.3 percent of patients. The prognostic separation between recovery states is striking: five-year rates of hepatocellular carcinoma or all-cause mortality were 10.1 percent for stable recompensation, 14.7 percent for unstable recompensation, and 27.3 percent for persistent decompensation. Recovery clearly improves outcomes compared with continued decompensation, but it does not restore the risk profile of a never-decompensated liver.

Recompensation reflects meaningful improvement after effective treatment, but it should not automatically be interpreted as complete reversal of cirrhosis, Professor You cautions. Recognizing it as a distinct treatment-related state, she argues, may help clinicians describe recovery more consistently and identify the patients who remain at risk even after their complications resolve. Dr. Wang reinforces the point from the patient-care perspective: people who improve after cirrhosis treatment may still carry residual risks from portal hypertension, limited hepatic reserve, and liver cancer, so continued surveillance remains important even when clinical signs of decompensation have disappeared. The message for survivors of decompensation is one of cautious optimism rather than discharge from care.

To organize these observations, the authors propose a four-state framework describing where a patient with cirrhosis may sit after the underlying cause has been brought under control: compensated cirrhosis, stable recompensation, unstable recompensation, or persistent decompensation. Such a taxonomy could standardize how clinical trials enroll and stratify patients, how guidelines frame follow-up intervals, and how physicians communicate prognosis. The authors are careful to note that the framework requires prospective validation, particularly in causes of cirrhosis other than hepatitis B, where the evidence base is strongest. Future research, they write, should establish objective markers that distinguish stable from unstable recovery, validate expanded criteria, clarify the mechanisms of fibrosis regression and portal-pressure reduction, and determine whether different recovery trajectories demand different monitoring strategies. If validated, the concept of recompensation as a formal disease state could reshape both research design and everyday hepatology practice for millions of patients living with treated cirrhosis.

Subject of Research: Recompensation as a treatment-related disease state in cirrhosis after control of the underlying cause

Article Title: Recompensation may represent a new treatment-related state in cirrhosis

Article References: Recompensation may represent a new treatment-related state in cirrhosis. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: cirrhosis, recompensation, liver disease, portal hypertension, decompensation, hepatitis B, hepatocellular carcinoma, fibrosis regression, Baveno VII, liver function, alcohol-related cirrhosis, disease state framework

Schistosomiasis mansoni remains a major public health burden in endemic regions of Brazil and other parts of the world where the parasite’s larvae, released from freshwater snails, penetrate human skin during contact with contaminated water. While the acute phase of infection often produces only vague symptoms, the long-term consequences can be severe. Eggs deposited by adult worms in the mesenteric veins trigger a chronic inflammatory reaction in the liver, leading over years to periportal fibrosis, a fibrotic thickening around the portal tracts that distorts the organ’s vascular architecture. Unlike the cirrhosis produced by alcohol or viral hepatitis, schistosomal liver damage typically spares the hepatocytes themselves, but the fibrotic obstruction of portal blood flow drives the pressure inside the portal vein dangerously upward.

The clinical stakes of this process are considerable. Portal hypertension in schistosomiasis manifests as splenomegaly, the development of collateral blood vessels, and ultimately esophageal varices that can rupture and cause life-threatening upper gastrointestinal bleeding. Detecting periportal fibrosis early, and gauging how far it has advanced, is therefore essential for deciding which patients need closer surveillance or intervention. The reference standard for assessing this fibrosis in the field is abdominal ultrasound interpreted according to the Niamey classification, a scoring system that grades the periportal thickening from pattern A, essentially normal, through patterns B and C for mild involvement, to patterns D and E for moderate and advanced disease, and pattern F for the most severe fibrotic distortion. Ultrasound, however, requires trained examiners and equipment that are not always available in the rural areas where the disease is most prevalent.

The ELF test was developed as a noninvasive alternative for quantifying liver fibrosis in conditions such as chronic hepatitis C and nonalcoholic fatty liver disease. It combines the serum concentrations of three markers of fibrotic remodeling: hyaluronic acid, a component of the extracellular matrix that accumulates as fibrosis progresses; tissue inhibitor of metalloproteinases 1, or TIMP-1, which reflects the inhibition of matrix-degrading enzymes; and procollagen III amino-terminal peptide, known as PIIINP, a byproduct of new collagen synthesis. An algorithm converts the three measurements into a single ELF score, with higher values indicating more extensive fibrosis. Because the test uses a standard blood sample and a validated analytical platform, it could in principle be deployed in settings where imaging expertise is scarce.

Despite this potential, few studies had examined whether the ELF score performs meaningfully in schistosomiasis mansoni, whose fibrotic pattern differs fundamentally from the cirrhotic scarring for which the test was calibrated. The new study, led by Rebecca Dantas Thorp and colleagues at institutions in Pernambuco, Brazil, set out to determine whether serum ELF values correlate with the periportal fibrosis pattern established by the Niamey ultrasound classification, and whether the score relates to a history of upper gastrointestinal bleeding, the most feared complication of advanced disease.

The researchers conducted a cross-sectional, bidirectional analytical study enrolling patients from an endemic area and from a reference outpatient clinic dedicated to schistosomiasis care. In total, 196 patients were evaluated, 58 percent of them women, with a mean age of 45.04 years and a standard deviation of 15.30 years. Each participant completed a structured questionnaire capturing sociodemographic and clinical information, including any prior episodes of upper gastrointestinal bleeding, and provided blood samples for ELF determination. A single examiner performed all ultrasound examinations, an approach that eliminated interobserver variability and ensured that the Niamey patterns were assigned consistently across the cohort.

The distribution of fibrosis severity in the study population spanned the full range of the Niamey scale. Eighteen patients showed pattern A plus B, indicating no or minimal periportal thickening, while 64 fell into pattern C, 56 into pattern D, 49 into pattern E, and 9 into pattern F, the most advanced category. When the researchers compared median ELF values across these groups, a clear gradient emerged: the median score rose from 8.36 in patients with pattern A plus B, to 8.40 in pattern C, 8.64 in pattern D, 8.99 in pattern E, and 9.75 in pattern F. This monotonic increase was statistically significant, with a p value of 0.0021, indicating that the probability of observing such a pattern by chance alone was low.

The team then tested whether the ELF score could discriminate between broader categories of fibrosis severity. It could. The test differentiated patients without periportal fibrosis from those with mild, moderate, and advanced disease when the Niamey patterns were grouped as A plus B versus C versus D versus E plus F, with a p value of 0.0024. It also distinguished patients with advanced fibrosis from those without fibrosis or with moderate fibrosis: the comparison of A plus B versus E plus F yielded a p value of 0.0464, and the comparison of C plus D versus E plus F was even stronger, at p equal to 0.0007. In practical terms, this means the blood test reliably flagged the patients whose livers had reached the stage of fibrosis most likely to produce clinically significant portal hypertension.

One result, however, tempered the enthusiasm. When the researchers compared mean ELF values between patients with and without a history of upper gastrointestinal bleeding, they found no statistically significant difference. This suggests that while the ELF score tracks the structural progression of periportal fibrosis as seen on ultrasound, it does not by itself identify which patients have already experienced variceal hemorrhage. Bleeding risk in schistosomiasis depends not only on the degree of fibrosis but also on the size and wall tension of the collateral vessels, factors that a fibrosis marker measured in serum cannot directly capture. The authors therefore position the ELF test as a complement to, rather than a replacement for, clinical assessment and endoscopic or imaging surveillance of varices.

Nevertheless, the study’s conclusion is significant for a disease that continues to affect millions of people in poverty-stricken rural communities. The ELF test demonstrated potential as a tool for assessing periportal fibrosis in patients with schistosomiasis mansoni, because it could differentiate those with minimal fibrosis from those with moderate or advanced fibrosis using nothing more than a blood sample. As a pilot study with a modest sample size and a cross-sectional design, it cannot yet establish whether serial ELF measurements can monitor fibrosis progression in individual patients over time, or whether the score predicts future decompensation. Those questions will require longitudinal cohorts and validation in other endemic regions. But if larger studies confirm these findings, the ELF score could become a practical, scalable screening instrument, allowing health systems in endemic areas to reserve scarce ultrasound resources for patients whose blood tests signal advancing disease, and to intervene before portal hypertension claims another life.

Subject of Research: Use of the Enhanced Liver Fibrosis serum score to assess periportal fibrosis severity in schistosomiasis mansoni

Article Title: Evaluating periportal fibrosis in schistosomiasis mansoni using the ELF [Enhanced Liver Fibrosis] score: A pilot study

Article References: Thorp, R. D., Batista, A. D., Mariz, C. A., de Araújo, L. R. M. G., Diniz, G. T. N., Barreto, A. V. M. S., de Morais, C. N. L., Silva, P. C. V., Domingues, A. L. C., & Lopes, E. P. (2026). Evaluating periportal fibrosis in schistosomiasis mansoni using the ELF [Enhanced Liver Fibrosis] score: A pilot study. PLOS Neglected Tropical Diseases, 20(10), e0014775. https://doi.org/10.1371/journal.pntd.0014775

Image Credits: AI Generated

DOI: 10.1371/journal.pntd.0014775

Keywords: schistosomiasis mansoni, periportal fibrosis, ELF score, liver fibrosis, Niamey classification, portal hypertension, ultrasound, biomarkers, neglected tropical diseases, Brazil, noninvasive diagnostics, PLOS Neglected Tropical Diseases

The clinical starting point was a group of patients whose stomachs suffer as a consequence of their livers. The team enrolled 111 patients with hepatitis B-related liver cirrhosis or hepatic failure at the Third Affiliated Hospital of Sun Yat-sen University between January 2022 and August 2024, alongside 118 control subjects. Using the gastrointestinal symptom rating scale, a validated 15-item questionnaire, the researchers found that patients with liver disease scored significantly higher overall than controls, 51.49 versus 42.40, with heartburn, acid reflux, nausea, bloating and diarrhea all markedly more frequent. Endoscopy told a matching story: the diseased mucosa showed more erosion and bleeding, and statistical analysis confirmed that mucosal lesions correlated with higher symptom scores, while normal mucosa tracked with lower scores.

Why would a congested stomach become a hypoxic one? The explanation is vascular. In portal hypertension and hepatic failure, restricted blood flow through the portal vein causes gastric venous congestion, and the oxygen supply to the epithelium falls behind demand. Using Hypoxyprobe-1 staining, the team demonstrated that hypoxia was indeed present in the gastric epithelium of these patients. In parallel, they established a mouse model of portal hypertension by partially ligating the portal vein, and again the hypoxia signal rose in step with a quantified gastric injury index. Crucially, the transcription factor HIF-1α, the master regulator of the cellular response to low oxygen, accumulated in the nuclei of epithelial cells in both human and mouse tissue, poised to reprogram gene expression.

That reprogramming showed up first as a metabolic shift. RNA sequencing of clinical gastric samples revealed enrichment of glycolysis and anaerobic metabolism pathways, and untargeted metabolomics of epithelial cells from the mouse model confirmed the biochemical signature: lactic acid rose while isocitric acid and citric acid, intermediates of the mitochondrial citric acid cycle, fell. This is the classic Warburg-like pattern in which cells, deprived of the oxygen needed for oxidative phosphorylation, burn glucose to lactate instead. In the short term this is a survival strategy, but the study suggests that under sustained hypoxia it becomes pathological, feeding a vicious cycle of metabolic disorder, reactive oxygen species generation and cell death.

The central molecular discovery concerns FUNDC1, an outer mitochondrial membrane protein previously known to help build mitochondria-associated ER membranes, or MAMs. These contact sites are far more than structural curiosities: they regulate calcium transfer from the ER to mitochondria, lipid exchange and mitochondrial dynamics. The researchers found that HIF-1α binds directly to a hypoxia-responsive element in the FUNDC1 promoter, driving its transcription, and that a second, post-transcriptional layer reinforces this. The m6A methyltransferase METTL3 chemically modified FUNDC1 messenger RNA, and the RNA-binding protein IGF2BP3, the most upregulated m6A reader in cirrhotic gastric tissue, recognized and stabilized that modified transcript. In mice carrying a mutant METTL3, FUNDC1 upregulation was blunted, confirming the epitranscriptomic mechanism.

With FUNDC1 elevated, the ER and mitochondria embraced more tightly. Transmission electron microscopy showed expanded contact zones in epithelial cells from portal hypertensive mice and from cirrhotic patients, and a proximity ligation assay for the IP3R2–VDAC1 tethering pair quantified the same increase. Coimmunoprecipitation confirmed that FUNDC1, IP3R2, VDAC1 and GRP75 formed complexes under hypoxic conditions. Truncation experiments pinpointed amino acids 7 to 48 of FUNDC1 as the domain essential for MAMs formation, a detail the authors highlight as a blueprint for designing inhibitors that could block the tethering interface specifically.

The consequences of this hyper-tethering were metabolic and oxidative. Seahorse extracellular flux analysis showed that epithelial cells under hypoxia had reduced maximal respiration, increased proton leak, elevated non-mitochondrial oxygen consumption and heightened basal and compensatory glycolysis, all of which were reversed when FUNDC1 was knocked down. Levels of electron transport chain subunits NDUFA9, SDHA, cytochrome b and ATP5A fell, along with ATP production. Meanwhile, mitochondrial superoxide, lipid peroxidation products such as 4-HNE and malondialdehyde, and oxidized mitochondrial DNA all climbed, while antioxidant defenses, superoxide dismutase activity and the glutathione redox ratio, collapsed. Calcium handling was also disturbed, with both cytosolic and mitochondrial calcium rising and membrane potential falling.

The final executioner in the cascade was NINJ1, a transmembrane protein that has recently emerged as the mediator of plasma membrane rupture during lytic cell death. In its inactive state NINJ1 is scattered across the membrane; when activated it oligomerizes into polymers that lyse the membrane and spill cellular contents. The team found NINJ1 oligomerization increased in gastric tissue from cirrhotic and hepatic failure patients, alongside elevated cleaved caspase-3 and cleaved caspase-1, markers of apoptosis and pyroptosis. Silencing NINJ1 in mice with portal hypertension reduced lactate dehydrogenase release, a readout of membrane permeabilization, restored epithelial viability and lessened mucosal injury. Notably, NINJ1 blockade did not change caspase activation, indicating it acts at the terminal step of membrane rupture rather than upstream of cell death signaling.

Two intervention experiments tied the whole axis together and pointed toward the clinic. Mito-TEMPO, a mitochondria-targeted antioxidant, suppressed NINJ1 oligomerization, reduced LDH release and protected the gastric mucosa in the mouse model, placing mitochondrial reactive oxygen species upstream of NINJ1 activation. The HIF-1α inhibitor PX-478 suppressed FUNDC1 expression and attenuated injury. Confocal imaging also showed that fragmented mitochondrial DNA released under oxidative stress colocalized with NINJ1, hinting at a direct or indirect role for escaping mtDNA in activating the rupture machinery, though the authors acknowledge the precise mechanism remains unresolved.

The authors are candid about limitations. The partial portal vein ligation model mechanically constricts the portal vein without reproducing hepatic parenchymal injury, systemic inflammation or the other comorbidities of clinical cirrhosis, and only knockdown rather than tissue-specific knockout approaches were used. Yet the reversibility of the pathway is encouraging: because MAMs remodeling is dynamic rather than covalent, targeted disruption of excessive ER-mitochondria tethering, inhibition of METTL3 or IGF2BP3 with emerging small molecules, or blockade of NINJ1 oligomerization with monoclonal antibodies could, in principle, interrupt the cycle before irreversible tissue damage sets in. If those strategies survive preclinical and clinical testing, the humble contact points between two organelles may become the address at which doctors finally treat the stomach’s silent suffocation.

Subject of Research: The FUNDC1–MAMs–NINJ1 signaling axis in hypoxia-induced gastric mucosal injury

Article Title: Mitochondria-associated endoplasmic reticulum membranes facilitate gastric epithelial injury in hypoxia-induced gastric mucosal lesions

Article References: Tan, S., Luo, J., Ou, X., Guo, X., Ke, B., & Tan, S. (2026). Mitochondria-associated endoplasmic reticulum membranes facilitate gastric epithelial injury in hypoxia-induced gastric mucosal lesions. Journal of Advanced Research. https://doi.org/10.1016/j.jare.2026.10.007

Image Credits: AI Generated

DOI: 10.1016/j.jare.2026.10.007

Keywords: hypoxia, gastric mucosal injury, mitochondria-associated ER membranes, FUNDC1, HIF-1α, m6A methylation, METTL3, IGF2BP3, NINJ1, portal hypertension, mitochondrial oxidative stress, plasma membrane rupture