Nutrition Reviews in Gastroenterology, SERIES #29

Nutrition Management for Functional Dyspepsia

December 2025 • Volume XLIX, Issue 12
Sophia Scattaglia,Nancee Jaffe

Read Article

Functional dyspepsia (FD) is a common disorder of the gut-brain interaction characterized by bothersome symptoms including postprandial fullness, early satiation, epigastric pain, and epigastric burning, without structural disease. Despite its frequency, the exact prevalence of FD remains poorly understood. There is a significant overlap of FD with other common gastrointestinal disorders, including irritable bowel syndrome (IBS), gastroparesis (GP), and gastroesophageal reflux disease (GERD). This review aims to explore the most studied dietary interventions for managing FD symptoms, including the low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) diet, gluten-free diet (GFD), and traditional dietary advice (TDA). Furthermore, this review will discuss the efficacy of alternative nutrition therapies including STW-5, caraway oil, artichoke leaf extract, and ginger. To support clinical practice, this review will also provide clinical pearls and practical tools designed to enhance symptom management and optimize patient care for those living with FD.

What is Functional Dyspepsia? 

Dyspepsia is a Greek term: dys- (meaning “bad” or “impaired”) and pepsis (meaning “digestion”).1 Although dyspeptic symptoms can be associated with an underlying organic pathology—such as peptic ulcer disease, gastroesophageal reflux disease, or malignancy — more than 75% cases have no organic cause and are therefore labeled as functional dyspepsia (FD).2

According to the Rome IV criteria, FD encompasses chronic or recurrent upper abdominal symptoms, including postprandial fullness, early satiation, epigastric pain, or burning, in the absence of structural disease that could explain these complaints.³ The Rome IV criteria further subdivide FD into two clinically meaningful subtypes—Postprandial Distress Syndrome (PDS) and Epigastric Pain Syndrome (EPS)—which reflect differences in symptom patterns, timing in relation to meals, and severity (See Table 1). While patients may exhibit overlapping features, identifying the subtype can guide management strategies.

Furthermore, symptoms of FD that extend beyond the ROME IV criteria tend to be specific to each subtype (See Table 2). Patients may not experience all the listed symptoms, but clear patterns differentiate EPS from PDS when assessed in this context.

Background and Statistics

Although FD is a common disorder of the gut-brain interaction (DGBI), little is known about its prevalence.4 A global systematic review and meta-analysis of 256,915 participants from 40 countries (1990–2022) found functional dyspepsia (FD) affected 7–12% of people.5The Rome criteria for diagnosing functional dyspepsia have become increasingly rigorous as subclassifications have evolved, making prevalence under Rome IV lower than under previous Rome iterations. Dyspepsia is more common in women, smokers, in developing countries vs. developed countries, and those taking non-steroidal anti-inflammatory drugs.5,6 Dyspepsia is estimated to cost the United States healthcare service over $18 billion per annum and societal costs are likely to be double this with 2–5% of patients taking time off work because of symptoms.7-8

Table 1. ROME IV Criteria for Functional Dyspepsia and Subtypes3

Functional Dyspepsia includes one or more of the following symptoms:
1. Bothersome postprandial fullness  
2. Bothersome early satiation  
3. Bothersome epigastric pain  
4. Bothersome epigastric burning

In the absence of structural disease that is likely to explain the symptoms. Symptoms must be chronic or recurrent, with onset at least six months prior to diagnosis and persistence for the previous three months.
Functional Dyspepsia is further classified into two subtypes: Postprandial Distress Syndrome (PDS) and Epigastric Pain Syndrome (EPS).3  PDS diagnosis must include one or both of the following for at least three days per week:   
1. Bothersome postprandial fullness
(i.e., severe enough to impact usual activities)  
2. Bothersome early satiation
(i.e., severe enough to prevent finishing a meal of usual size)

EPS diagnosis must include one or both of the following at least 1 day per week:   
3. Bothersome epigastric pain
(i.e., severe enough to impact usual activities)  
4. Bothersome epigastric burning
(i.e., severe enough to impact usual activities)

Possible Overlap between Functional Dyspepsia and Other Gastrointestinal Disorders

Various research studies have been conducted over the years to explore the overlap among FD and other gastrointestinal disorders, including gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), and gastroparesis (GP). 

Gastroesophageal Reflux Disease

FD and GERD often present with overlapping symptoms including upper abdominal bloating, epigastric pain, regurgitation, and heartburn.9-10 A systematic review and meta-analysis examined the overlap between FD and GERD and found that 41.15% of patients with GERD also experienced FD symptoms. Similarly, 31.32% of patients with FD also experienced GERD-like symptoms.9 Research has shown that there is similarity in pathophysiological mechanisms as well. A well-known mechanism in FD, impaired gastric accommodation, has been associated with more frequent transient lower esophageal sphincter relaxation (TLESRs) episodes.9 Additionally, both impaired gastric accommodation and TLESRs can increase stomach pressure, promoting acid reflux.10 Other potential overlapping pathways include esophageal acid exposure, delayed gastric emptying, and visceral hypersensitivity.9

Irritable Bowel Syndrome

In a multicenter, 12-month longitudinal study involving 807 individuals diagnosed with IBS according to the Rome IV criteria, 208 participants (25.8%) had coexisting PDS, 60 (7.4%) had EPS, and 178 (22.1%) had both PDS and EPS.11 Participants with IBS and PDS, as well as those with both PDS and EPS, reported a significantly greater impact on daily activities, defined as interference ≥ 50% of the time, compared to those with IBS alone (73.8% for IBS and PDS, 72.7% for IBS, PDS, and EPS, vs. 50.5% for IBS alone; p < 0.001). Patients with overlapping PDS and EPS were more likely to see their physician about their symptoms and underwent a higher number of IBS treatments compared to those with IBS alone.

Table 2. Other Symptoms of Postprandial Distress Syndrome and Epigastric Pain Syndrome 

Other Symptoms of PDSOther Symptoms of EPS
Postprandial epigastric pain or burningPain may be induced by ingestion of a meal, relieved by ingestion of a meal, or may occur while fasting
Postprandial epigastric bloatingEpigastric bloating
Postprandial belchingExcessive belching
Postprandial nausea Nausea 

Gastroparesis 

GP is a neuromuscular disorder that is classified by delayed gastric emptying, with more than 60% of food remaining in the stomach at 2 hours and/or more than 10% at 4 hours.12 Recent studies have shown that delayed gastric stomach emptying is also present in 25-37% of patients with FD.12 Bloating, postprandial fullness, early satiety, and epigastric pain are symptoms commonly experienced by both patients with FD and GP; however, nausea and vomiting are hallmarks for GP alone.13 Pasricha et al.conducted a prospective study of 944 patients for 48 weeks to study the relationship between FD and GP.14 Out of the total patients, 720 (76%) were diagnosed with GP and 224 (24%) with FD. By 48 weeks, 41% of patients had a revised diagnosis: 42% of those initially diagnosed with GP were reclassified as FD, whereas 37% with FD initially were now diagnosed with GP.This diagnostic shift reflects the clinical overlap between these two disorders and the hypothesis that gastric emptying studies alone may not be an accurate marker for distinguishing between the two.

Self-Reported Dietary Triggers

In a study of over 200 patients with FD, an increase in all FD symptoms occurred within 15 minutes of eating a meal in 79% of patients, showing that diet is a significant contributor to symptoms.15 Studies on self-reported food and lifestyle triggers show that fatty foods, acidic foods, spicy foods, wheat products, watermelon, and fruit juices are the most common reported.16  However, some studies suggest that spicy foods may actually improve symptoms. In a small randomized controlled trial of 30 individuals with functional dyspepsia, red pepper powder significantly improved overall symptom scores, including reductions in epigastric pain, fullness, and nausea compared to placebo.17 In a cross-sectional survey of 121 patients with FD, 55% listed FODMAPs as the most reported trigger which included wheat, fruit juices, and watermelon.18

Current Evidence from Studied Diet Interventions

There have been several dietary approaches explored for the treatment of FD including the  traditional dietary advice (TDA), gluten-free diet (GFD), and the low FODMAP diet (LFD), though evidence at this time is limited.

Traditional Dietary Advice

The recommendations under TDA include eating small, frequent meals, avoiding perceived dietary triggers such as alcohol, caffeine, chocolate, spicy or acidic foods, and high-fat foods, consuming food slowly and chewing thoroughly, and not eating 3 hours before bed. Recent research has explored the relationship between symptom exacerbation and some of the foods listed above, including high-fat food and spicy foods. High-fat foods have been shown to delay gastric emptying, impair gastric motility, and increase post-meal fullness in patients with FD.19

Capsaicin, the chemical compound found in higher concentrations in chili peppers, has been shown to lead to more symptoms in individuals with FD when compared to healthy controls or placebo.19 Capsaicin activates the transient receptor potential vanilloid-1 (TRPV1) receptors, leading to a burning sensation. Capsaicin can also result in chemical hypersensitivity, which can trigger upper gastrointestinal symptoms in individuals with FD.20 The genetic variation of the TRPV1 gene, G315 polymorphism, is inversely correlated with FD, though research has shown that gene variations were unable to predict the severity of FD symptoms based on questionnaires.

Gluten-Free Diet

Hosseinian et al. conducted a systematic review including information on the impact of gluten on FD symptoms across 27 studies, with a meta-analysis on 5 RCTs.21 The meta-analysis showed that there was a statistically significant increase in the severity of epigastric pain (weight mean difference (WMD) = 0.46; 95% CI), bloating (WMD = 0.67; 95% CI), and early satiety (WMD = 0.91; 95% CI) following gluten-consumption of 0.5-32 gram per day.21 These findings suggest relief of FD symptoms associated with avoiding or reducing gluten. Refractory functional dyspepsia (RFD) is defined by symptoms that continue despite medical interventions or Helicobacter pylori (H. pylori) eradication. 

The presence of non-celiac gluten sensitivity (NCGS) in 77 patients with RFD was investigated in a randomized, double-blind, placebo-controlled trial.22 Each patient followed the GFD for 6 weeks, in which 27 patients (35%) showed symptom improvement. Of the 27 patients that were then assigned to a gluten or placebo challenge, 5 patients (6.4% of the total sample) reported intestinal and/or extra intestinal symptoms after gluten exposure. The most common symptoms reported included postprandial fullness (100%), epigastric pain/burning (80%), fatigue (80%), headache (80%), and musculoskeletal pain (60%). Patients were monitored for three months following the study and three additional patients reported symptom recurrence with gluten consumption. Due to the overlap seen between NCGS and FD, the GFD may be an effective dietary recommendation in symptom management for a subset of patients with FD in which there is a clinical concern for NCGS.22

Low Fodmap Diet 

In a single-blind prospective study, Goyal et al.evaluated the efficacy of the LFD and TDA.23 During the study, the Short-Form Nepean Dyspepsia Index (SF-NDI) was used to measure symptomatology in 105 patients with FD (54 assigned to LFD, 51 assigned to TDA), with each subject completing either one of the two diets for 4 weeks (phase I). The participants following the LFD were then advised to follow the reintroduction phase of the LFD for 4-12 weeks (phase II). The baseline SF-NDI scores improved significantly with both diets (LFD: 66.7% improvement [36/54]; TDA: 56.9% improvement [29/51]; p = 0.32). Patients with bloating and PDS had significantly greater improvements with the LFD versus TDA at 4 and 12 weeks (p = 0.04), despite improvements in overall symptomatology in both diets.23 While not statistically significant, there was a trend towards improvement in EPS patients with TDA. 

The effectiveness of the LFD was compared to standard dietary advice (SDA), like the recommendations under TDA, in an observational study.24 Of the 59 patients with FD, 40 followed the LFD and 19 were assigned to SDA. The Structured Assessment of Gastrointestinal Symptoms (SAGIS) was used to collect data on epigastric and overall gastrointestinal symptoms. The results showed a greater reduction in epigastric scores in the LFD compared to SDA (p = 0.032). Additionally, there were greater reductions in postprandial pain, excessive belching, and bloating in the LFD (p < 0.05). When looking at overall gastrointestinal symptoms, there was statistically significant improvement in the LFD group compared with the standard dietary advice (p = 0.026). 

Preliminary results seen in an abstract from the University of Leuven showed that 62% of 25 patients with FD experienced a statistically significant improvement in symptoms following a 6-week low FODMAP diet. Improvements were observed in both overall and individual symptom scores, including upper abdominal bloating, early satiety, and postprandial fullness. Following the 6-week intervention, patients followed a blinded reintroduction phase, which revealed variability in the specific FODMAPs that triggered symptom recurrence. Mannitol and galacto-oligosaccharides triggered symptom recurrence in 29% of the patients, followed by fructans (21%), sorbitol (14%), fructose (14%) and lactose (12%).25 It is important to note that fructans are found in many gluten-containing grains. Researchers who have studied the GFD in FD have noted that it is not clear whether fructans or gluten is the culprit for triggering dyspeptic symptoms.21

Complementary and Alternative Therapies 

According to American College of Gastroenterology (ACG) and the Canadian Association of Gastroenterology (CAG) guidelines, the quality of evidence supporting complementary and alternative nutrition therapies for FD management is of poor quality.26 The available evidence on the therapeutic benefits of caraway oil, STW5, artichoke leaf extract, and ginger in management of FD will be reviewed.

Caraway Oil

Caraway oil has been hypothesized to increase gastric accommodation, and L-menthol is an antispasmodic whose action includes modulation of gastric sensory nerves, thereby promoting smooth muscle relaxation. The combination of these agents may exert a prokinetic effect and reduce visceral hypersensitivity. A meta-analysis and systematic review of five randomized controlled trials involving 578 patients showed that the combination of caraway oil and L-menthol resulted in statistically significant improvement in overall FD symptoms, specifically with a reduction in epigastric pain. While these results are promising, limitations identified from this study include a short treatment duration of only four weeks, an insufficient sample size to be able to evaluate publication bias adequately, and potential differences in patient diagnosis due to the lack of using validated criteria among all studies.27It should be noted that peppermint is not appropriate for all patients, including those with hiatal hernia, GERD, gallbladder disorders, and those that are pregnant and lactating.28,29

STW-5

Efficacy of STW-5, a nine-herb preparation, was tested in an 8-week double-blind, placebo-controlled RCT of 315 patients with FD. In the treatment group, the therapeutic effect was seen as early as within 2 weeks, with symptom improvement of 57%, which increased to 86% by week 4. However, the number of responders in the placebo group was similar to the STW-5 group, respectively 72.2% versus 78.3%. Overall, in comparison to the placebo group, the GIS score improved significantly in the STW-5 group during the course of treatment (p < 0.05).30 Furthermore, a meta-analysis of three RCTs demonstrated that STW-5 provided a statistically significant benefit over placebo in reducing postprandial fullness, early satiety, and epigastric pain.31 It should be noted that case reports of liver injury with use of this product have been reported and close monitoring with a medical professional is recommended if considering use of STW-5.32

Artichoke Leaf

Artichoke (Cynara scolymus) leaf extract (ALE), long used for dyspepsia, has been shown to have lipid-lowering, antioxidant, and antispasmodic effects. The effectiveness of ALE in managing FD was evaluated in a six-week, double-blind, placebo-controlled study involving 247 patients with FD. Participants received either ALE preparation or a placebo, and the effectiveness of ALE was assessed using a four-point patient-rated scale of overall symptom change. Dyspeptic symptoms and quality of life were also evaluated using the Nepean Dyspepsia Index (NPI). After six weeks, the ALE group showed significantly greater symptom improvement than placebo (p < 0.01), with notable reductions in early satiety, flatulence, and fullness compared to placebo (all p < 0.05), and enhanced quality of life scores (p < 0.01).33 However, evidence is too limited at this time to make clinical recommendations. 

More recently, the effectiveness of ALE in the management of FD has been evaluated in combination with ginger (Zingiber officinalis). In addition to its well-known anti-nausea and antiemetic effects, ginger has also been shown to enhance gastric motility. The efficacy of a combination of ALE and ginger was explored in a 4-week, double-blind, placebo-controlled trial including 126 adults diagnosed with FD. Participants took two capsules daily; 65 received the supplement containing ginger and ALE, while 61 received the placebo. After two weeks, there were significant improvements in FD symptoms in the supplementation group compared to the placebo group (p = 0.017). These results remained consistent at the 4-week mark. Specifically, there were significantly greater improvements in nausea, epigastric fullness, epigastric pain, and bloating in the supplementation group when compared to the placebo (p < 0.001, p < 0.001, p < 0.002, p = 0.017, respectively).34 

Ginger

Ginger alone also has been studied in the context of stomach emptying, with results showing that 3 pills daily equaling 1200mg could increase gastric emptying and stimulate antral contractions, though its impact on FD symptoms is conflicting.35-36 In all but one of the studies, there were no adverse events noted. In the oldest of the studies, adverse events were classified as gastrointestinal, identified as mild to moderate and resolved on their own by the end of the study. 

Practical Applications

When selecting dietary or complementary interventions for FD, tailoring recommendations to the patient’s specific symptom profile can improve effectiveness. The following points highlight how current evidence can guide clinical decision-making:

Patients experiencing bloating and PDS may benefit more from an LFD than a TDA.

Individuals with postprandial pain, excessive belching, and bloating are the most likely to experience meaningful symptom relief from an LFD.

Given the overlap between NCGS and FD, a GFD may help manage symptoms in patients for whom NCGS is a clinical concern.

Although evidence is not statistically significant, patients with EPS may notice some improvement with a TDA.

Caraway oil, based on limited data, may reduce FD symptoms—particularly epigastric pain.

STW-5 may help alleviate postprandial fullness, early satiety, and epigastric pain; however, it may not be appropriate for all patients and has been linked to possible liver-related adverse effects.

Ginger and artichoke extracts may provide relief for FD symptoms; however, current evidence is limited and insufficient to support routine clinical use. 

References

References
1. Brun R, Kuo B. Functional dyspepsia. Therap Adv
Gastroenterol. 2010;3(3):145-164.
2. Talley NJ. Functional dyspepsia: advances in diagnosis and
therapy. Gut Liver. 2017;11(3):349-357.
3. The Rome Foundation. Rome IV Criteria. Rome Foundation.
Published 2021. https://theromefoundation.org/rome-iv/
rome-iv-criteria/
4. Francis P, Zavala SR. Functional Dyspepsia. In: StatPearls
[ I n t e r n e t ] . Treasure Island, (FL): StatPearls
P u b l i s h i n g ; 2025 Jan–. Updated 2024 Jun 8. Available
from: https://www.ncbi.nlm.nih.gov/books/NBK554563/
5. Lee K, Kwon CI, Yeniova AÖ, et al. Global prevalence of
functional dyspepsia according to Rome criteria, 1990–
2020: a systematic review and meta-analysis. Sci Rep.
2024;14(1):4172.
6. Ford AC, Marwaha A, Sood R, et al. Global prevalence
of, and risk factors for, uninvestigated dyspepsia: a metaanalysis.
Gut. 2015;64(7):1049-1057.
7. Lacy BE, Weiser KT, Kennedy AT, et al. Functional dyspepsia:
the economic impact to patients. Aliment Pharmacol
Ther. 2013;38(2):170-177.
8. Moayyedi P, Lacy BE, Andrews CN, et al. ACG and
CAG clinical guideline: management of dyspepsia. Am J
Gastroenterol. 2017;112(7):988-1013.
9. Geeraerts A, Van Houtte B, Clevers E, et al. Gastroesophageal
reflux disease–functional dyspepsia overlap: do birds of a
feather flock together? Am J Gastroenterol. 2020;115(8):1167-
1182.
10. Byun SY, Jung KW. Overlap between gastroesophageal
reflux disease and functional dyspepsia: do we need a
new management paradigm? J Neurogastroenterol Motil.
2025;31(2):129.
11. Barberio B, Sinagra E, Palumbo D, et al. Overlap of Rome
IV irritable bowel syndrome and functional dyspepsia and
effect on natural history: a longitudinal follow-up study. Clin
Gastroenterol Hepatol. 2022;20(2):e89-e101.
12. Egboh SM, Duncanson K, Potter M, et al. Functional
dyspepsia and gastroparesis: are they distinct disorders, a
spectrum of diseases or one disease? eGastroenterology.
2025;3(1):e100119.
13. Parkman HP, Hasler WL, Fisher RS. American
Gastroenterological Association technical review on the
diagnosis and treatment of gastroparesis. Gastroenterology.
2004;127(5):1592-1622
14. Pasricha PJ, Grover M, Yates KP, et al. Functional dyspepsia
and gastroparesis in tertiary care are interchangeable
syndromes with common clinical and pathologic features.
Gastroenterology. 2021;160(6):2006-2017.
15. Bisschops R, Karamanolis G, Arts J, et al. Relationship
between symptoms and ingestion of a meal in functional
dyspepsia. Gut. 2008;57(11):1495-1503.
16. Duboc H, Latrache S, Nebunu N, Coffin B. The Role of Diet
in Functional Dyspepsia Management. Front Psychiatry.
2020;11:23.
17. Pesce M, Cargiolli M, Cassarano S, et al. Diet and functional
dyspepsia: Clinical correlates and therapeutic perspectives.
World J Gastroenterol. 2020;26(5):456-465.
18. Cooke ZM, Resciniti SM, Wright BJ, et al. Association
between dietary factors, symptoms, and psychological factors
in adults with dyspepsia: a cross-sectional study.
Neurogastroenterol Motil. 2023;35(12):e14684.
19. Gkolfakis P, Arvanitakis M, Triantafyllou K. Food, dietary
patterns, or is eating behavior to blame? Analyzing the association
between functional dyspepsia and dietary habits: A
narrative review. Nutrients. 2023;15(6):1544.
20. Lee S-Y, Masaoka T, Han HS, et al. A prospective study
on symptom generation according to spicy food intake
and TRPV1 genotypes in functional dyspepsia patients.
Neurogastroenterol Motil. 2016;28(9):1401-1408.
21. Hosseinian SZ, Haghighatdoost F, Hajihashemi P, Adibi
P. Effects of gluten on dyspeptic symptoms: a systematic
review and meta-analysis of clinical trials. Nutr Rev.
2023;82(1):9-33.
22. Shahbazkhani B, Fanaeian MM, Farahvash MJ, et al.
Prevalence of Non-Celiac Gluten Sensitivity in Patients with
Refractory Functional Dyspepsia: a Randomized Doubleblind
Placebo Controlled Trial. Sci Rep. 2020;10(1):2401.
23. Goyal O, Nohria S, Batta S, et al. Low FODMAP diet versus
traditional dietary advice for functional dyspepsia: a
randomized controlled trial. J Gastroenterol Hepatol. 2021.
24. Staudacher HM, Nevin AN, Duff C, Kendall BJ, Holtmann
GJ. Epigastric symptom response to low FODMAP dietary
advice compared with standard dietetic advice in individuals
with functional dyspepsia. Neurogastroenterol Motil.
2021;33(11):e14148.
25. Tack J, Tornblom H, Tan VPY, Carbone F. Evidence-based
and emerging dietary approaches to upper disorders of gut–
brain interaction. Am J Gastroenterol. 2022;117(6):965-972.
26. Moayyedi PM, Lacy BE, Andrews CN, Enns RA, Howden
CW, Vakil N. ACG and CAG Clinical Guideline: Management
of Dyspepsia. Am J Gastroenterol. 2017;112(7):988–1013.
27. Li J, Lv L, Zhang J, et al. A combination of peppermint
oil and caraway oil for the treatment of functional dyspepsia:
a systematic review and meta-analysis. Evid Based
Complement Alternat Med. 2019;2019:7654947.
28. Fifi AC, Axelrod CH, Chakraborty P, Saps M. Herbs and
spices in the treatment of functional gastrointestinal disorders:
a review of clinical trials. Nutrients. 2018;10(11):1715.
29. Kligler B, Chaudhary S. Peppermint oil. Am Fam Physician.
2007;75(7):1027–1030.
30. von Arnim U, Peitz U, Vinson B, et al. STW 5, a phytopharmacon
for patients with functional dyspepsia: results of a
multicenter, placebo-controlled double-blind study. Am J
Gastroenterol. 2007;102(6):1268-1275.
31. Melzer J, Rösch W, Reichling J, Brignoli R, Saller R.
Meta-analysis: phytotherapy of functional dyspepsia with
the herbal drug preparation STW 5 (Iberogast). Aliment
Pharmacol Ther. 2004;20(11-12):1279-1287.
32. Leroy A, Perrin H, Porret R, et al. Iberogast®-induced
acute liver injury—a case report. Gastro Hep Advances.
2022;4:601–603.
33. Holtmann G, Adam B, Haag S, Collet W, Grünewald E,
Windeck T. Efficacy of artichoke leaf extract in the treatment
of patients with functional dyspepsia: a six-week
placebo-controlled, double-blind, multicentre trial. Aliment
Pharmacol Ther. 2003;18(11-12):1099-1105.
34. Giacosa A, Guido D, Grassi M, et al. The Effect of Ginger
(Zingiber officinalis) and Artichoke (Cynara cardunculus)
Extract Supplementation on Functional Dyspepsia:
A Randomised, Double-Blind, and Placebo-Controlled
Clinical Trial. Evid Based Complement Alternat Med.
2015;2015:915087.
35. Wu KL, Rayner CK, Chuah SK, et al. Effects of ginger
on gastric emptying and motility in healthy humans. Eur J
Gastroenterol Hepatol. 2008;20(5):436-440.
36. Hu ML, Rayner CK, Wu KL, et al. Effect of ginger on gastric
motility and symptoms of functional dyspepsia. World J
Gastroenterol. 2011;17(1):105-110.

Download Tables, Images & References

Frontiers in Endoscopy, Series #101

Topical Endoscopic Hemostatic Agents for Gastrointestinal Bleeding

December 2025 • Volume XLIX, Issue 12
Magnus Chun,Douglas G. Adler

Read Article

Background

Gastrointestinal bleeding (GIB) is associated with significant morbidity and mortality. Despite improved endoscopic practices for GIB, approximately 8-15% of patients fail primary endoscopic therapy, which includes injection, thermal, and mechanical therapy. These techniques require precise localization of the bleeding source and may not be as effective in patients with lesions that are difficult to access, have tumor-associated bleeding, or broad based bleeding sources. Additionally, a high level of endoscopic expertise is required for these modalities which may not be available at smaller hospitals. 

Recently, topical endoscopic hemostatic agents were introduced to treat GIB. These agents have had promising results as salvage therapy or even as primary therapy without requiring precise localization or extensive technical expertise.3, There are five approved agents (Table 1): hemostatic agent TC-325 (HemosprayTM, Cook Medical Inc, Winston-Salem, North Carolina, US), synthetic self-assembling peptide agent (PuraStatTM, 3D-Matrix, Europe Ltd., France), EndoclotTM (Endoclot Plus Inc., Santa Clara, California, US) polysaccharide hemostatic system (PHS), biocompatible natural polymer UI-EWD (NexpowderTM, NextBiomedical Co., Incheon, South Korea) and erythrocyte protein network (Ankaferd Blood StopperTM, ABS, Ankaferd Health Products Ltd., Turkey).

Table 1. Summary of Topical Endoscopic Hemostatic Agents 

Agent/Trade Name Composition Mechanism of Action Approved Application 
TC-325 (HemosprayTM) Granular mineral-based Absorbs water and activates the clotting cascade to form a mechanical tamponade Peptic ulcer disease, variceal GIB, lower GIB, tumor bleeding 
PuraStatTM Synthetic self-assembling peptide agent Peptide solution forms a 3-dimensional nano-fiber hydrogel scaffold of beta-sheets Bleeding secondary to therapeutic endoscopic procedures 
EndoclotTM Absorbable starch-based modified polysaccharide Absorbs water and concentrates platelets and clotting factors to create a mechanical tamponade Peptic ulcer disease, malignant tumors, esophageal ulcers, esophagitis, post-interventional bleeding 
UI-EWD (NexpowderTM) Biocompatible natural polymer Forms adhesive hydrogel in presence of water Prophylaxis post-intervention, Peptic ulcer disease, malignant tumors, and post-interventional bleeding 
Ankaferd Blood StopperTM Erythrocyte protein network Encapsulated protein network provides focal points for erythrocyte aggregation Only approved in Turkey:  non-variceal upper GIB (Case reports: peptic ulcer disease, malignant GIB, esophageal variceal bleeding and post-polypectomy bleeding)

Topical endoscopic hemostatic agents are intended to control active non-variceal GIB (NVGIB) by delivering a substance over the bleeding site through a catheter via the endoscope working channel. The main advantage of topical agents is that less precision is required when applying the agent to the bleeding site. This allows for treatment of lesions that may be difficult to access or refractory to standard therapy. Although recent studies have shown that hemostatic agents were effective in NVGIB, there had been reports of high re-bleeding rates.5 Topical agents can also be used prophylactically to reduce the risk of bleeding following polypectomy, endoscopic mucosal resection (EMR), or endoscopic submucosal dissection (ESD). These agents can also be used to treat or reduce the risk of sphincterotomy bleeding during endoscopic retrograde cholangiopancreatography (ERCP). 

This manuscript aims to discuss the efficacy, safety, advantages, and disadvantages of the FDA-approved topical endoscopic hemostatic agents.

Hemostatic agent TC-325/Hemospray

Hemostatic agent TC-325 is a metabolically inert, nontoxic, granular mineral-based inorganic powder that when in contact with blood will induce hemostasis by absorbing water and activating the clotting cascade. As a result, a mechanical tamponade and adhesive barrier form over the bleeding site. Hemospray is deployed through the endoscope-integrated catheter in short bursts when a compressed carbon dioxide propellant is activated by the device’s trigger.

Hemospray has been shown to be successful in controlling bleeding from peptic ulcer disease, variceal GIB, and lower GIB as both monotherapy and as an adjunctive therapy to conventional therapy.8,9,10,11 (Figures 1 and 2) Sung et al. and Kwek et al. reported hemostasis in 90% of patients with monotherapy and 100% of patients as an adjunctive therapy., In another study, Ibrahim et al. reported 100% hemostasis in nine patients treated with monotherapy. In regards to lower GIB, Hemospray was effective in achieving hemostasis for spurting post-polypectomy bleeding that did not respond to clipping. Additionally, in a systematic review and meta-analysis by Facciorusso et al., the immediate hemostasis rate for Hemospray monotherapy in 8 studies with 175 patients was 96.2% (95% CI 93.5-99.7%). Bleeding from gastrointestinal tumor may sometimes be diffuse and lack a specific target suitable for endoscopic hemostasis. In these cases, Hemospray is a good option to provide short-term hemostasis. In a large multicenter study conducted by Pittayanon et al., they found that hemostasis was achieved with Hemospray in 98% of cases. 

However, the downside of Hemospray monotherapy is that studies show high rebleeding rates at 7 days typically ranging between 15-49%.12,,, Facciorusso et al. found that there was a 9.8% (95% CI 3.8-15.8%) pooled 7-day rebleeding rate and a 12.3% (95% CI 6.0-18.7%) pooled 30-day rebleeding rate. A study by Cahyadi et al. found even higher rebleeding rates at 3 days (43.1%) and at 7 days (49.0%). This is likely due to the fact that while Hemospray induces coagulation, it generally does not treat the underlying cause of a bleed. Recent guidelines published in the Annals of Internal Medicine recommend that Hemospray be used only as a temporizing measure when primary endoscopy therapy fails and should not be used as a monotherapy due to the high re-bleeding rates. 

Hemospray can often limit endoscopic visualization after deployment, and when it is used before other hemostatic agents, there may be a risk of obscuring the boundaries of a lesion (making it more difficult to implement other hemostatic options if they are needed). As Hemospray is sprayed, the cloud of powder can temporarily fill the endoscopic field of view and if the endoscope’s tip is too close to the site of application, the powder can adhere directly to the lens. To avoid this, we recommend releasing the powder in short 1- to 2- second bursts and maintaining the endoscope’s tip at least 1-2 cm away from the lesion.

PuraStat

PuraStat is a biocompatible synthetic peptide gel consisting of a repeating sequence of the amino acids Arginine, Alanine, and Aspartic Acid. Once Purastat gel comes in contact with blood, the peptide solution is neutralized to form a 3-dimensional nano-fiber hydrogel scaffold of beta-sheets. This structure, similar to the extracellular matrix, forms a physical barrier over the bleeding vessel or bleeding site to achieve hemostasis.

PuraStat is currently intended for prophylaxis of bleeding secondary to therapeutic endoscopic procedures such as endoscopic submucosal dissection (ESD) or endoscopic mucosal resection (EMR), although it has been used in a wide variety of contexts. (Figures 3 and 4) Prior studies have shown that post-ESD, there was a smaller mean number of any secondary temporizing measures required when PuraStat was used initially compared to the control group without PuraStat (1.0±1.4 vs 4.9±5.2, p<0.001), demonstrating the efficacy of PuraStat in managing intraoperative bleeding. , In a study by Uraoka et al., only 1 out of 51 included patients had post-ESD bleeding after being treated with PuraStat. However, Gomi et al. 2024, in a more recent and larger study of 101 patients, did not find that PuraStat was associated with improved rates of post-ESD bleeding, highlighting the need for further research in this area. 

The efficacy of PuraStat in managing post-sphincterotomy bleeds has also been studied. Ogura et al. found that 98% of patients achieved complete cessation of bleeding with PuraStat monotherapy. Kishore et al. found that 96.5% (95% CI: 92.3-100) of patients achieved complete cessation of bleeding with PuraStat monotherapy, with a rebleeding rate of 3.10% (95% CI: 0.50-5.60). 

Furthermore, in a recent meta-analysis, three studies showed PuraStat to be effective in both primary and rescue hemostasis for bleeds caused by peptic ulcer disease, large polyps, tumors, and capillary lesions. 20,,, For primary hemostasis, the pooled immediate hemostasis rate was 87% (95% CI 75%-94%) and the pooled rebleeding rate within 30 days was 10% (95% CI: 6%-16%).20,26,27,28  In Bianchi et al.’s study, 111 patients were included with an initial hemostatic success rate of 94% (95% CI 88-99%). When used as a secondary hemostatic product, PuraStat had a hemostatic success rate of 75% (95% CI 59-91%). The rebleeding rates at 3 and 7 days were 9% and 15% after primary use and 13% and 19% after secondary use, respectively. The overall rebleeding rate at 30 days was 16%.20 

In comparison with Hemospray, PuraStat is a transparent hemostatic agent that does not compromise endoscopic visualization after deployment. This makes it possible to check post-therapy bleeding status and continue further interventions, if needed. It is already prepared for the endoscopist in a single prefilled, ready-to-use syringe and deployed through the endoscopic catheter. Given that PuraStat is a gel, it is also highly versatile and can be used in narrow spaces where the bleeding site is difficult to reach with a hemoclip or a thermal probe.  

However, similar to Hemospray, the downside of PuraStat is it has a high rebleeding rate of 10%-15% at 7 days if used as monotherapy.20, 26 This is a drawback of hemostatic agents in general given they can only bind to sites with active bleeding for 12-24 hours. However, one recent retrospective study showed there was no statistical significant differences in rebleeding (p=0.64) or mortality (p=0.69) when comparing initial PuraStat use and the standard care (i.e. injection, hemoclips, etc.). 

Endoclot

Endoclot is a starch-derived compound consisting of biocompatible absorbable hemostatic polysaccharide that when in contact with blood, will rapidly absorb water. This causes a high concentration of clotting factors, red blood cells, and platelets to accumulate at the bleeding site accelerating the hemostasis process.3 Afterwards, the polysaccharide will form a gelled, adhesive matrix providing a mechanical barrier to seal and potentially protect the wound site from further bleeding.

Endoclot is indicated as either monotherapy or rescue therapy for both upper and lower GIB, with studies showing efficacy in hemostasis for peptic ulcer disease, malignant tumors, esophageal ulcers and esophagitis, as well as post-interventional bleeding. ,,,, In a recent meta-analysis of 5 studies and 398 patients, the immediate hemostasis rate for any GIB after Endoclot monotherapy was 86% (95% CI: 80%-90%), with a rebleeding risk within 30 days of 10% (95% CI 6%-16%).26 In a recent multicenter analysis of 43 patients by Hagel et al., the immediate hemostasis rate was 81.8% when Endoclot was used as a salvage therapy. In one study, among patients with tumor bleeding, there was a 0% rebleeding rate after treatment with Endoclot as monotherapy.35 

Furthermore, Endoclot is delivered differently compared to other hemostatic agents. Hemospray is delivered at high pressure with a carbon dioxide cartridge which can be advantageous in situations with high pressure bleeding. However, the high-pressure application from the carbon dioxide can potentially cause tissue injury as well. Two studies have shown perforation in their patient cohort after Hemospray application due to high-pressure carbon dioxide application.35, In contrast, the pressure at which Endoclot is sprayed is much lower making it more suitable for localized bleeding lesions and has lower risks of causing tissue injury.

The main disadvantage of Endoclot, similarly to other hemostatic agents, is the risk of rebleeding due to low binding times of the adhesive matrix to the bleeding site. Limited studies report the advantages and disadvantages of Endoclot compared to other forms of hemostatic agents. Beg et al. reported on the use of Endoclot by novice operators. In their study, assisting nurses who had no specific training using Endoclot had success and ease of use when it was applied.32 

Nexpowder

Nexpowder is a biocompatible natural polymer composed of oxidized dextran and succinic anhydride that gets converted to adhesive hydrogel when in contact with water. It then forms a mechanical barrier at bleeding site(s) to promote hemostasis.39 It is deployed by insoluble air propellant and uses a pre-installed battery as its power source, allowing air pressure generated from the air pump in the delivery system’s spray body to provide a force to move the powder into the delivery catheter.39 The advantage of Nexpowder is that it does not require active bleeding to work which allows it to have a potential role in prophylaxis post-procedural. However, most studies show promising results for Nexpowder as a role in primary hemostasis or prophylaxis post-intervention as well.,,

Nexpowder is indicated as either monotherapy or rescue therapy for both upper and lower GIB, with studies showing efficacy in hemostasis for peptic ulcer disease, malignant tumors, and post-interventional bleeding.40,41,42 It can also be used as prophylaxis post-intervention.40,42 In a recent meta-analysis of 3 studies and 114 patients, the immediate hemostasis rate for any GIB after Nexpowder monotherapy was 96% (95% CI: 91%-99%), with a rebleeding risk within 30 days of 8% (95% CI 3%-20%).26 Shin et al. found that there was immediate hemostasis in 100% (n=23) of their patient cohort when using Nexpowder monotherapy for active bleeds secondary to luminal malignant tumors. However, there was a high rate of rebleeding within 1 month in 26.1% and 22.5% of their patients when using Nexpowder as monotherapy and salvage therapy, respectively.42 All three studies used Nexpowder post-intervention as a prophylaxis for acute bleeding.40,41,42 

One advantage of Nexpowder is it has a lower rebleeding rate within 30 days (8%) compared to other hemostatic agents (subgroup differences: p < 0.01).26 In a study conducted by Park et al., they found that only 2 out of 54 patients (3.7%) had rebleeding within 30 days after using Nexpowder as a monotherapy.41 In another study, Park et al. used a second-look endoscopy after 24 hours of applying the Nexpowder as a monotherapy and saw that the hydrogel from Nexpowder was still attached to the bleeding site in 69% of their patients 24 hours later.40 Shin et al. found that the when using Nexpowder as a monotherapy, the hydrogel was reported to be present at 70.2% of sprayed bleeding sites using second-look endoscopy at 24 hours. 

Ankaferd Bloodstopper

Ankaferd Bloodstopper (ABS) is a hemostatic agent only approved in Turkey and Bosnia-Herzegovina and composed of a mixture of plants, including Thymus vulgaris, Glycrrhiza glabra, Vitis vinifera, Alpinia officinarum, and Urtica dioica. The mechanism of action of ABS is it rapidly forms an encapsulated protein network that provides multiple focal points for erythrocyte and leukocyte aggregation, including fibrinogen, which, in turn, induces protein aggregation., ABS is a topical powder application that is sprayed via a catheter through the working channel of the endoscope. ABS is currently approved in Turkey and Bosnia-Herzegovina for upper and lower GIB that is only refractory to conventional hemostatic measures.3

There has been a relative paucity of studies analyzing the effectiveness and safety of ABS monotherapy and salvage therapy. No safety concerns have been reported to date. A case series of 27 patients with active, non-variceal GIB showed an immediate hemostasis rate of 73% when ABS was used as a monotherapy and 100% when used in combination with standard therapy.46 Rebleeding within 48 hours was seen in 15.8% of patients with ABS monotherapy and 33.3% with ABS salvage therapy. There are multiple case reports of the success of immediate hemostasis using ABS monotherapy in patients with peptic ulcer disease, malignant GIB, esophageal variceal bleeding and post-polypectomy bleeding.,,,,,,, 

Conclusion

Topical hemostatic agents have been shown to be effective in hemostasis for gastrointestinal bleeding, especially when used in combination with conventional methods or as salvage therapy. Limited studies have demonstrated high primary hemostasis rates in both upper and lower GIB when used as monotherapy but with some risk of rebleeding. Topical hemostatic agents are simple to use and do not require a high level of endoscopic expertise to employ.   

References

1 Lau JY, Barkun A, Fan DM, Kuipers EJ, Yang YS, Chan
FK. Challenges in the management of acute peptic ulcer bleeding.
Lancet. 2013 Jun 8;381(9882):2033-43. doi: 10.1016/S0140-
6736(13)60596-6. PMID: 23746903.
2 Barkun A, Bardou M, Marshall JK, Nonvariceal Upper GI Bleeding
Consensus Conference Group. Consensus recommendations for
managing patients with nonvariceal upper gastrointestinal bleeding.
Ann Intern Med. 2003;139(10):843- 857.
3 Bustamante-Balén M, Plumé G. Role of hemostatic powders in
the endoscopic management of gastrointestinal bleeding. World J
Gastrointest Pathophysiol. 2014 Aug 15;5(3):284-92. doi: 10.4291/
wjgp.v5.i3.284. PMID: 25133029; PMCID: PMC4133526.
4 Barkun AN, Moosavi S, Martel M. Topical hemostatic agents: a
systematic review with particular emphasis on endoscopic application
in GI bleeding. Gastrointest Endosc 2013; 77: 692–700
5 Chen YI, Barkun AN. Hemostatic powders in gastrointestinal bleeding:
A systematic review. Gastrointest Endosc Clin N Am 2015; 25:
535–552
6 Giday SA, Kim Y, Krishnamurty DM, Ducharme R, Liang DB, Shin
EJ, Dray X, Hutcheon D, Moskowitz K, Donatelli G, Rueben D,
Canto MI, Okolo PI, Kalloo AN. Long-term randomized controlled
trial of a novel nanopowder hemostatic agent (TC-325) for control
of severe arterial upper gastrointestinal bleeding in a porcine model.
Endoscopy 2011; 43: 296-299 [PMID: 21384319 DOI: 10.1055/s-
0030-1256125]
7 Ibrahim M, El-Mikkawy A, Mostafa I, Devière J. Endoscopic
treatment of acute variceal hemorrhage by using hemostatic
powder TC-325: a prospective pilot study. Gastrointest Endosc.
2013;78(5):769-773.
8 Sung JJY, Luo D, Wu JCY, et al. Early clinical experience of
the safety and effectiveness of Hemospray in achieving hemostasis
in patients with acute peptic ulcer bleeding. Endoscopy.
2011;43(4):291-295.
9 Kwek BEA, Ang TL, Ong PLJ, et al. TC-325 versus the conventional
combined technique for endoscopic treatment of peptic ulcers
with high-risk bleeding stigmata: A randomized pilot study. J Dig
Dis. 2017; 18(6):323-329
10 Ibrahim M, El-Mikkawy A, Mostafa I, Devière J. Endoscopic
treatment of acute variceal hemorrhage by using hemostatic
powder TC-325: a prospective pilot study. Gastrointest Endosc.
2013;78(5):769-773.
11 Iveković H, Bilic B, Markos P, Rustemovic N, Ostojic R,
Mönkemüller K. Successful use of Hemospray to control refractory
post-polypectomy bleeding. Endoscopy. 2015;47:E466-E467
12 Facciorusso A, Bertini M, Bertoni M, Tartaglia N, Pacilli M, Ramai
D, Mohan BP, Chandan S, Ambrosi A, Sacco R. Effectiveness
of hemostatic powders in lower gastrointestinal bleeding: a
systematic review and meta-analysis. Endosc Int Open. 2021
Aug;9(8):E1283-E1290. doi: 10.1055/a-1495-4764. Epub 2021 Jul
16. PMID: 34447877; PMCID: PMC8383089.
13 Pittayanon R, Rerknimitr R, Barkun A. Prognostic factors affecting
outcomes in patients with malignant GI bleeding treated with
a novel endoscopically delivered hemostatic powder. Gastrointest
Endosc. 2018;87(4):994-1002
14 Smith LA, Stanley AJ, Bergman JJ, et al. Hemospray application in
nonvariceal upper gastrointestinal bleeding: results of the Survey to
Evaluate the Application of Hemospray in the Luminal Tract. J Clin
Gastroenterol. 2014;48(10):e89-92.
15 Cahyadi O, Bauder M, Meier B, Caca K, Schmidt A. Effectiveness
of TC-325 (Hemospray) for treatment of diffuse or refractory upper
gastrointestinal bleeding – a single center experience. Endosc Int
Open. 2017;5(11):E1159-E1164
16 Sinha R, Lockman KA, Church NI, Plevris JN, Hayes PC. The
use of hemostatic spray as an adjunct to conventional hemostatic
measures in high-risk nonvariceal upper GI bleeding (with video).
Gastrointest Endosc. 2016;84(6):900-906.e3.
17 Cahyadi O, Bauder M, Meier B, Caca K, Schmidt A. Effectiveness
of TC-325 (Hemospray) for treatment of diffuse or refractory upper
gastrointestinal bleeding – a single center experience. Endosc Int
Open. 2017 Nov;5(11):E1159-E1164. doi: 10.1055/s-0043-118794.
Epub 2017 Nov 8. PMID: 29124127; PMCID: PMC5677459.
18 Barkun AN, Almadi M, Kuipers EJ et al. Management of nonvariceal
upper gastrointestinal bleeding: guideline recommendations
from the International Consensus Group. Ann Intern Med 2019; 171:
805–822
19 Barkun AN, Moosavi S, Martel M. Topical hemostatic agents: a
systematic review with particular emphasis on endoscopic application
in GI bleeding. Gastrointest Endosc. 2013;77(5):692-700.
20 Branchi F, Klingenberg-Noftz R, Friedrich K, Bürgel N, Daum
S, Buchkremer J, Sonnenberg E, Schumann M, Treese C, Tröger
H, Lissner D, Epple HJ, Siegmund B, Stroux A, Adler A, Veltzke-
Schlieker W, Autenrieth D, Leonhardt S, Fischer A, Jürgensen C,
Pape UF, Wiedenmann B, Möschler O, Schreiner M, Strowski
MZ, Hempel V, Huber Y, Neumann H, Bojarski C. PuraStat in
gastrointestinal bleeding: results of a prospective multicentre observational
pilot study. Surg Endosc. 2022 May;36(5):2954-2961. doi:
10.1007/s00464-021-08589-6. Epub 2021 Jun 15. PMID: 34129089;
PMCID: PMC9001238.
21 Subramaniam S, Kandiah K, Chedgy F, Fogg C, Thayalasekaran S,
Alkandari A, Baker-Moffatt M, Dash J, Lyons-Amos M, Longcroft-
Wheaton G, Brown J, Bhandari P. A novel self-assembling peptide
for hemostasis during endoscopic submucosal dissection: a randomized
controlled trial. Endoscopy. 2021;53:27–35. doi: 10.1055/a-
1198-0558.
22 Uraoka T, Uedo N, Oyama T, Saito Y, Yahagi N, Fujimoto A,
Kawahara Y, Mabe K, Hikichi T, Yamamoto Y, Tajiri H. Efficacy and
Safety of a Novel Hemostatic Peptide Solution During Endoscopic
Submucosal Dissection: A Multicenter Randomized Controlled
Trial. Am J Gastroenterol. 2023;118:276–283. doi: 10.14309/
ajg.0000000000002060.
23 Uraoka T, Ochiai Y, Fujimoto A, Goto O, Kawahara Y, Kobayashi
N, Kanai T, Matsuda S, Kitagawa Y, Yahagi N. A novel fully synthetic
and self-assembled peptide solution for endoscopic submucosal
dissection-induced ulcer in the stomach. Gastrointest Endosc.
2016 Jun;83(6):1259-64. doi: 10.1016/j.gie.2015.11.015. Epub 2015
Dec 1. PMID: 26608126.
24 Takeshi Ogura, Saori Ueno, Atsushi Okuda, Nobu Nishioka,
Masanori Yamada, Masahiro Yamamura, Nobuhiro Hattori,
Junichi Nakamura, Kimi Bessho, Hiroki Nishikawa, Step-Up
Strategy for Endoscopic Hemostasis Using PuraStat After
Endoscopic Sphincterotomy Bleeding (STOP Trial), Techniques
and Innovations in Gastrointestinal Endoscopy, Volume 26, Issue
3, 2024, Pages 224-229, ISSN 2590-0307, https://doi.org/10.1016/j.
tige.2024.03.005. (https://www.sciencedirect.com/science/article/
pii/S2590030724000199)
25 Kishore, Mehwish MD,*; Khan, Zarak H. MD; Puli, Srinivas MD.
S132 Meta-Analysis and Systematic Review of the Emerging use
of PuraStat as Hemostatic Agent for Post-Sphincterotomy Bleeding.
The American Journal of Gastroenterology 119(10S):p S99, October
2024. | DOI: 10.14309/01.ajg.0001028896.06269.e4
26 Alali AA, Moosavi S, Martel M, Almadi M, Barkun AN.
Topical hemostatic agents in the management of upper gastrointestinal
bleeding: a meta-analysis. Endosc Int Open. 2023 Apr
24;11(4):E368-E385. doi: 10.1055/a-1984-6895. PMID: 37102185;
PMCID: PMC10125779.
27 de Nucci G, Reati R, Arena I, Bezzio C, Devani M, Corte CD,
Morganti D, Mandelli ED, Omazzi B, Redaelli D, Saibeni S, Dinelli
M, Manes G. Efficacy of a novel self-assembling peptide hemostatic
gel as rescue therapy for refractory acute gastrointestinal bleeding.
Endoscopy. 2020 Sep;52(9):773-779. doi: 10.1055/a-1145-3412.
Epub 2020 Apr 21. PMID: 32316041.
28 Labianca O, Sica M, Zulli C et al. Use of Purastat in management
of gastro-intestinal bleeding: out experience. Endoscopy 2021; 53:
S97-S98
29 Chen YI, Barkun AN. Hemostatic Powders in Gastrointestinal
Bleeding: A Systematic Review. Gastrointest Endosc Clin N Am.
2015 Jul;25(3):535-52. doi: 10.1016/j.giec.2015.02.008. Epub 2015
Apr 18. PMID: 26142037.
30 Ballester R, Costigan C, O’Sullivan AM, Sengupta S, McNamara D.
Efficacy and applications for PuraStat® use in the management of
unselected gastrointestinal bleeding: A retrospective observational
study. World J Gastrointest Endosc. 2025 Mar 16;17(3):98021.
doi: 10.4253/wjge.v17.i3.98021. PMID: 40125508; PMCID:
PMC11923975.
31 AMP technology. Polymer Solution for hemostasis. 2011. Available
from: http: //endoclot.com/technology.html. Last accessed:
September 2025
32 Beg S, Al-Bakir I, Bhuva M, Patel J, Fullard M, Leahy A. Early
clinical experience of the safety and efficacy of EndoClot in the
management of non-variceal upper gastrointestinal bleeding. Endosc
Int Open. 2015 Dec;3(6):E605-9. doi: 10.1055/s-0034-1393087.
Epub 2015 Nov 27. PMID: 26716120; PMCID: PMC4683139.
33 Kim YJ, Park JC, Kim EH, Shin SK, Lee SK, Lee YC. Hemostatic
powder application for control of acute upper gastrointestinal bleed28
ing in patients with gastric malignancy. Endosc Int Open. 2018
Jun;6(6):E700-E705. doi: 10.1055/a-0593-5884. Epub 2018 May
25. PMID: 29868635; PMCID: PMC5979193.
34 Prei JC, Barmeyer C, Bürgel N, Daum S, Epple HJ, Günther U,
Maul J, Siegmund B, Schumann M, Tröger H, Stroux A, Adler A,
Veltzke-Schlieker W, Jürgensen C, Wentrup R, Wiedenmann B,
Binkau J, Hartmann D, Nötzel E, Domagk D, Wacke W, Wahnschaffe
U, Bojarski C. EndoClot Polysaccharide Hemostatic System in
Nonvariceal Gastrointestinal Bleeding: Results of a Prospective
Multicenter Observational Pilot Study. J Clin Gastroenterol. 2016
Nov/Dec;50(10):e95-e100. doi: 10.1097/MCG.0000000000000615.
PMID: 27552329.
35 Hagel AF, Raithel M, Hempen P, Preclik G, Dauth W, Neurath
MF, Gschossman J, Konturek PC, Albrecht H. Multicenter analysis
of endoclot as hemostatic powder in different endoscopic settings
of the upper gastrointestinal tract. J Physiol Pharmacol. 2020
Oct;71(5). doi: 10.26402/jpp.2020.5.06. Epub 2021 Jan 16. PMID:
33475093.
36 Park JC, Kim YJ, Kim EH, Lee J, Yang HS, Kim EH, Hahn KY,
Shin SK, Lee SK, Lee YC. Effectiveness of the polysaccharide
hemostatic powder in non-variceal upper gastrointestinal bleeding:
Using propensity score matching. J Gastroenterol Hepatol. 2018
Aug;33(8):1500-1506. doi: 10.1111/jgh.14118. Epub 2018 Mar 5.
PMID: 29415371.
37 Yau AH, Ou G, Galorport C, Amar J, Bressler B, Donnellan F,
Ko HH, Lam E, Enns RA. Safety and efficacy of Hemospray®
in upper gastrointestinal bleeding. Can J Gastroenterol Hepatol.
2014 Feb;28(2):72-6. doi: 10.1155/2014/759436. PMID: 24501723;
PMCID: PMC4071892.
38 Vitali F, Naegel A, Atreya R, Zopf S, Neufert C, Siebler J, Neurath
MF, Rath T. Comparison of Hemospray® and Endoclot™ for the
treatment of gastrointestinal bleeding. World J Gastroenterol. 2019
Apr 7;25(13):1592-1602. doi: 10.3748/wjg.v25.i13.1592. PMID:
30983819; PMCID: PMC6452236.
39 Bang B, Lee E, Maeng J, Kim K, Hwang JH, Hyon SH, Hyon W,
Lee DH. Efficacy of a novel endoscopically deliverable muco-adhesive
hemostatic powder in an acute gastric bleeding porcine model.
PLoS One. 2019 Jun 11;14(6):e0216829. doi: 10.1371/journal.
pone.0216829. PMID: 31185029; PMCID: PMC6559629.
40 Park JS, Bang BW, Hong SJ, Lee E, Kwon KS, Kim HK, Shin
YW, Lee DH. Efficacy of a novel hemostatic adhesive powder in
patients with refractory upper gastrointestinal bleeding: a pilot study.
Endoscopy. 2019 May;51(5):458-462. doi: 10.1055/a-0809-5276.
Epub 2019 Jan 10. PMID: 30630195.
41 Park JS, Kim HK, Shin YW, Kwon KS, Lee DH. Novel hemostatic
adhesive powder for nonvariceal upper gastrointestinal bleeding.
Endosc Int Open. 2019 Dec;7(12):E1763-E1767. doi: 10.1055/
a-0982-3194. Epub 2019 Dec 10. PMID: 31828214; PMCID:
PMC6904239.
42 Shin J, Cha B, Park JS, Ko W, Kwon KS, Lee JW, Kim HK, Shin
YW. Efficacy of a novel hemostatic adhesive powder in patients with
upper gastrointestinal tumor bleeding. BMC Gastroenterol. 2021 Jan
28;21(1):40. doi: 10.1186/s12876-021-01611-0. PMID: 33509102;
PMCID: PMC7842074.
43 Shin YW, Bang BW, Kwon K, et al. Endoscopic application of
new hemostatic powder in gastrointestinal bleeding. Endoscopy.
2018;50;OP006
44 Beyazit Y, Kurt M, Kekilli M, Goker H, Haznedaroglu IC.
Evaluation of hemostatic effects of Ankaferd as an alternative medicine.
Altern Med Rev. 2010 Dec;15(4):329-36. PMID: 21194248.
45 Haznedaroglu BZ, Haznedaroglu IC, Walker SL, Bilgili H,
Goker H, Kosar A, Aktas A, Captug O, Kurt M, Ozdemir O,
Kirazli S, Firat HC. Ultrastructural and morphological analyses
of the in vitro and in vivo hemostatic effects of Ankaferd Blood
Stopper. Clin Appl Thromb Hemost. 2010 Aug;16(4):446-53. doi:
10.1177/1076029609343706. Epub 2009 Oct 14. PMID: 19833624.
46 Gungor G, Goktepe MH, Biyik M, Polat I, Tuna T, Ataseven H,
Demir A. Efficacy of ankaferd blood stopper application on non-variceal
upper gastrointestinal bleeding. World J Gastrointest Endosc.
2012 Dec 16;4(12):556-60. doi: 10.4253/wjge.v4.i12.556. PMID:
23293725; PMCID: PMC3536852.
47 Ozaslan E, Purnak T, Yildiz A, Haznedaroglu IC. The effect of a
new hemostatic agent for difficult cases of non-variceal gastrointestinal
bleeding: Ankaferd blood stopper. Hepatogastroenterology.
2010 Mar-Apr;57(98):191-4. PMID: 20583410.
48 Yarali N, Oruc M, Bay A, Dalgic B, Bozkaya IO, Arıkoglu T, Kara
A, Tunc B. A new hemostatic agent–Ankaferd blood stopper: management
of gastrointestinal bleeding in an infant and other experiences
in children. Pediatr Hematol Oncol. 2010 Nov;27(8):592-6.
doi: 10.3109/08880018.2010.503337. Erratum in: Pediatr Hematol
Oncol. 2014 Feb;31(1):107. Ankoglu, Tugba [corrected to Arıkoglu,
Tugba]. PMID: 20863156.
49 Kurt M, Akdogan M, Onal IK, Kekilli M, Arhan M, Shorbagi A,
Aksu S, Kurt OK, Haznedaroglu IC. Endoscopic topical application
of Ankaferd Blood Stopper for neoplastic gastrointestinal bleeding:
A retrospective analysis. Dig Liver Dis. 2010 Mar;42(3):196-9. doi:
10.1016/j.dld.2009.05.006. Epub 2009 Jun 21. PMID: 19540818.
50 Zulfikar OB, Emiroglu HH, Kebudi R. Nasogastric application of
topical Ankaferd Blood Stopper for bleeding from primary esophageal
adenocarcinoma in a child with disseminated intravascular
coagulation. Dig Liver Dis. 2011 Mar;43(3):247-8. doi: 10.1016/j.
dld.2010.10.002. Epub 2010 Dec 21. PMID: 21177146.
51 Tuncer I, Doganay L, Ozturk O. Instant control of fundal variceal
bleeding with a folkloric medicinal plant extract: Ankaferd Blood
Stopper. Gastrointest Endosc. 2010 Apr;71(4):873-5. doi: 10.1016/j.
gie.2009.08.021. Epub 2009 Nov 17. PMID: 19922917.
52 Ozaslan E, Purnak T, Yildiz A, Haznedaroglu IC. Bleeding due to
slippage of elastic band during variceal ligation: successful use of
Ankaferd blood stopper. Indian J Gastroenterol. 2010 Jul;29(4):166-
8. doi: 10.1007/s12664-010-0043-y. Epub 2010 Sep 3. PMID:
20814774.
53 Kurt M, Onal I, Akdogan M, Kekilli M, Arhan M, Sayilir A, Oztas
E, Haznedaroglu I. Ankaferd Blood Stopper for controlling gastrointestinal
bleeding due to distinct benign lesions refractory to
conventional antihemorrhagic measures. Can J Gastroenterol. 2010
Jun;24(6):380-4. doi: 10.1155/2010/896819. PMID: 20559581;
PMCID: PMC2898493.
54 Karaman A, Torun E, Gürsoy S, Yurci A, Ozbakir O. Efficacy
of Ankaferd Blood Stopper in postpolypectomy bleeding. J
Altern Complement Med. 2010 Oct;16(10):1027-8. doi: 10.1089/
acm.2010.0089. PMID: 20954959.

Download Tables, Images & References

Bacterial Translocation and Biliary Atresia in Infants

Biliary atresia (BA) is a fibro-obliterative disease process of unknown etiology affecting the biliary tract in infants. BA eventually leads to cirrhosis and is the leading cause of liver transplantation in infants. Since changes in the intestinal microbiome are associated with chronic liver disease in adults, the authors of this study looked for similar issues occurring in infants with BA. Research previously done by this group has demonstrated increased alpha-diversity of pathogenic intestinal bacteria with an associated decrease in potential beneficial bacteria in children with BA who had underwent hepatoportoenterostomy (the “Kasai procedure” (KP)) and had worse surgical outcomes. This current study evaluated gut bacterial translocation and intestinal barrier function in children with BA.

Infants with BA were recruited in a prospective manner and were assessed at 6 weeks, 12 weeks, and 24 weeks post-KP. Prior to KP, all infants had standard blook work and demographics obtained. They also underwent liver biopsies to assess for fibrosis. After KP, standard blood work for liver disease as well as hepatic elastography studies were obtained. Additionally, blood and stool specimens were obtained to assess for intestinal barrier function and evidence of bacterial translocation.  

A total of 55 infants with BA were recruited for the study for which 33 infants had no jaundice at 6 months after KP while the rest of the patient group continued to have jaundice. Patient demographics were similar between the two groups. Liver transplantation occurred in 24 of the 55 infants by 2 years of age for which 91% of those infants requiring liver transplantation had no clearance of jaundice by 6 months after KP. At least one episode of cholangitis occurred with 26 of the 55 infants by 6 months after KP for which 64% of these specific infants were still jaundiced at 6 months after KP.  

A comparison occurred between patients who were cleared of jaundice after KP and those that did not clear jaundice after KP. Although markers for intestinal barrier function and bacterial translocation were similar between the two patient groups prior to KP, differences were noted very soon after KP. At 6 weeks post KP, intercellular adhesion molecule 1 (ICAM-1), interleukin-4 (IL-4), and claudin-3 were significantly elevated in the patient group with continuing jaundice after KP.  By 12 weeks post KP, ICAM-1, IL-8, IL-1ß, and claudin-3 were significantly elevated in the patient group with continuing jaundice after KP. By 24 weeks post KP, ICAM-1, IL-2, IL-6, IL-8, IL-1ß, tumor necrosis factor alpha (TNF-ɑ), and vascular cell adhesion molecule 1 (VCAM-1) were significantly elevated in the patient group with continuing jaundice after KP.

Univariate analysis done at 6 weeks post KP demonstrated that elevated levels of total bilirubin, serum aspartate aminotransferase (AST), ICAM-1, and claudin-3 were significantly associated with persistent jaundice. A multivariate analysis demonstrated that elevated levels of ICAM-1 and claudin-3 were significantly associated with jaundice at 24 weeks post KP. VCAM-1, ICAM-1, TNF-ɑ, lipopolysaccharide (LPS), and intestinal fatty acid binding protein (IFABP) all increased significantly from before KP to 24 weeks post KP in patients who remained jaundiced. A significant correlation of total bilirubin levels after KP was found with ICAM-1 levels at 6 weeks post KP; with ICAM-1, IL-8, IL-1ß levels at 12 weeks post KP; and with ICAM-1, IL-8, IL-1ß, IL-6, IL-2, and VCAM-1 levels at 12 weeks post KP.

In terms of fibrosis correlation, only ICAM-1 was significantly associated with an elevated AST-to-platelet ratio prior to KP although liver histology prior to KP was not associated with ICAM-1 levels. ICAM-1 and VCAM-1 were significantly associated with an elevated AST-to-platelet ratio and liver stiffness measured by elastography at 6 weeks post KP.  IL-1ß, TNF-ɑ, IL-8, IL-4, and IL-2 were significantly associated with an elevated AST-to-platelet ratio at 12 weeks post KP.  Only ICAM-1 was associated with an elevated liver stiffness measurement as measured by elastography at 24 weeks post KP. D-lactate (used to demonstrate bacterial translocation) was significantly associated with hepatic fibrosis only at 12 weeks post KP.

In terms of markers of bacterial translocation and inflammation, lipopolysaccharide binding protein (LBP) levels were significantly correlated with IL-6 and TNF-ɑ at 6 weeks post KP; were significantly correlated with D-lactate and ICAM-1 at 12 weeks post KP; and were significantly correlated with IL-6 and IL-17 at 24 weeks post KP. Using 16S rRNA amplicon sequencing, the most common bacteria identified in fecal specimens at all time points post KP included Enterococcus, Clostridium, Fusobacterium,and 10 other bacterial species. Finally, elevated fecal calprotectin levels were significantly associated with severity of jaundice in infants at 24 weeks post KP.

This study demonstrates that gut inflammation and potential bacterial translocation into the bloodstream of infants with BA who undergo KP may be associated with worse surgical outcomes. The authors point out that claudin-3, which is a biomarker for tight junction integrity, may be an effective screening tool to determine potential outcomes after KP in children with BA.

Jain V, Nulty J, Alexander E, Buford C, Davenport M, Chokshi S, Riva A, Dalby M, Verma A, Hall L, Yuksel M, Dhawah A. Claudin-3, Lipopolysaccharide Binding Protein, and Jaundice Clearance in Infants with Biliary Atresia. Journal of Pediatrics 2025; 286: 114703.

Using H. pylori Antibiotic Sensitivity to Drive Treatment in Children

Helicobacter pylori (H. pylori) is a gram-negative bacteria associated with gastric infections worldwide. Besides causing gastritis and peptic ulcer disease, a chronic infection by this bacterium can lead to gastric adenocarcinoma and MALT lymphoma. Antibiotic therapy is essential for curing this infection, and it would be especially important to identify a correct antibiotic regimen as H. pylori is associated with a high rate of antibiotic resistance. The authors of this study evaluated the efficacy of susceptibility-guided treatment (SGT) compared to empirical therapy (ET) for H. pylori.

This retrospective study occurred at a single tertiary care children’s hospital in the United States.  All included patients had a history of a biopsy-proven initial H. pylori infection and had received antibiotic treatment. All patients were treated for H. pylori using the 2016 Joint ESPGHAN / NASPGHAN guidelines for treatment of H. pylori in children (see https://www.naspghan.org/files/Joint_ESPGHAN_NASPGHAN_Guidelines_for_the.33.pdf).

All patients treated either by ET or by SGT underwent testing for H. pylori eradication by either fecal antigen screening or by repeat esophagogastroduodenoscopy (EGD) with biopsy.

A total of 238 patients were diagnosed with an initial H. pylori infection over a 5-year period (2019 to 2024). After excluding patients who had received no therapy, had no H. pylori culture sent, or had a culture with no bacterial growth, a total of 218 patients were left for which 95 patients underwent ET and 123 patients underwent SGT. Mean patient age was 13.6 ± 4.8 years, and 50.9% of patients were male. The most common endoscopic finding was gastritis in 92.7% of patients with 100% of patients having gastritis on histology. Antibiotic resistance was present in 45.5% of H. pylori cultures with the most common single antibiotic resistance being clarithromycin at 26.8%. The most common dual antibiotic resistance was clarithromycin and metronidazole at 10.6%. No cultures demonstrated resistance to tetracycline. The most common treatment for H. pylori in the study was clarithromycin-based triple therapy which was used in 41.3% of patients. Subsequent eradication was achieved in 80.7% of patients.

Age, sex, and ethnicity were not associated with antibiotic treatment failure in patients treated with either ET or SGT. However, patients categorized as “white” had significantly higher eradication rates. Treatment failure rates were significantly higher in those infections associated with amoxicillin resistance as well as in infections associated with clarithromycin-metronidazole dual resistance. Amoxicillin use was significantly associated with eradication while a history of prior amoxicillin, clarithromycin, and metronidazole use were significantly associated with treatment failure.  

Eradication was significantly higher in those patients treated using SGT (89.4%) compared to ET (70.2%). Univariate analysis demonstrated that patients who received amoxicillin during therapy, received clarithromycin during therapy, received metronidazole during therapy, or had received any of these three antibiotics in the past were significantly less likely to achieve eradication with no other factors reaching significance. Multivariate analysis demonstrated that amoxicillin use was the sole factor associated with H. pylori eradication.  

This study clearly demonstrates that H. pylori eradication was superior when using SGT. Amoxicillin bacterial resistance and prior use of antibiotics seemed to be a significant issue in preventing eradication in this patient population. Obtaining H. pylori cultures to drive directed antibiotic therapy is recommended and should be more widely available.

Chan C, Bousvaros A, Goldsmith J, Liu E, Bonilla S. Antimicrobial Susceptibility-Guided Treatment is Superior to Empiric Therapy for Helicobacter pylori Infection in Children. Journal of Pediatric Gastroenterology and Nutrition. 2025; 81: 1133-1141.

Liver Disorders, SERIES #20

Beyond Jaundice Part 2: Recognizing Dermatologic Findings in Chronic Liver Diseases

November 2025 • Volume XLIX, Issue 11
Olivia Babich,Alexandra Savage,Tavankit Singh

Read Article

Chronic liver disease is often accompanied by cutaneous findings indicative of underlying pathology. However, in addition to the many widely-known and recognizable dermatologic manifestations, there exists a multitude of subtle, lesser-known findings which warrant increased attention. Recognition of these dermatologic findings is invaluable, as they contribute to the diagnostic picture and can aid in prioritization of the differential diagnosis. It is vital for providers across specialties to be able to recognize and describe such lesions in order to help reduce diagnostic delay and hasten time to treatment. In this article, we present the associated cutaneous findings for common liver diseases including autoimmune hepatitis, Wilson’s disease, hemochromatosis, alpha-1 antitrypsin deficiency, primary biliary cholangitis, primary sclerosing cholangitis, and metabolic dysfunction-associated steatotic liver disease.

Introduction

Liver disease continues to have a significant impact on public health, both in the United States and globally.1 In the United States, chronic liver disease and cirrhosis represent the 10th leading cause of death, just behind kidney disease and diabetes, and continue to account for a significant portion of overall healthcare expenditures.2–4 Given the pathophysiology of liver diseases, dermatologic manifestations are both common and multitudinous. These cutaneous findings are crucial to identify, given that they may represent some of the earliest indicators of underlying dysfunction.6 For providers outside of the specialty of dermatology, learning how to both recognize and accurately describe lesions is paramount to ensuring timely diagnosis. In this review, we present associated cutaneous findings of several common forms of chronic liver disease with discussion of lesion description, etiopathogenesis, and significance. Also included are brief summaries regarding appropriate management of dermatologic lesions. 

Autoimmune Hepatitis 

Vitiligo

In patients with autoimmune hepatitis (AIH), there is significant overlap with other autoimmune disorders. Following autoimmune thyroid disease, skin diseases are most commonly-reported.7,8 Vitiligo is the most well-known of these associations, as ~23% of patients with vitiligo have a comorbid autoimmune disease. Patients with more extensive vitiligo tend to have a greater likelihood of being diagnosed with at least one comorbid autoimmune disease.9 Multiple case reports have documented AIH occurring in association with vitiligo, and a 2017 systematic review identified vitiligo as having a particularly strong association with type 2 AIH.10–12 Vitiligo presents as depigmented, coalescing macules and patches with well-defined borders, more common in sun-exposed areas or regions prone to repetitive trauma such as intertriginous skin [Figure 1]. Vitiligo treatment is varied and may include topical treatments such as corticosteroids, calcineurin inhibitors, ruxolitinib cream, UVB phototherapy, depigmentation therapy, or surgical approaches involving grafting.13

Pyoderma gangrenosum

Pyoderma gangrenosum is a neutrophilic dermatosis which occurs in association with systemic disease in at least 50% of cases. Upregulation of several proinflammatory and chemotactic cytokines including interleukin-8 have been identified in affected skin.14 Lesions begin as single, small papules/pustules before rapidly developing into large, painful ulcers with violaceous, undermined borders and surrounding erythema. Ulcers often feature a purulent, exudative base which can develop into exuberant granulation tissue over several weeks [Figure 2]. Multiple case reports have described the association of pyoderma gangrenosum with AIH, noting its development even in periods of quiescent disease.15–17 Recommended laboratory investigations in pyoderma patients consequently include liver function tests and a full hepatitis panel.18 Treatment requires expert wound care and pain management. Early, uncomplicated wounds may be treated with topical corticosteroids or tacrolimus ointment. As lesions progress, systemic steroids as well as biologics may be utilized. Patients should be referred to dermatology for optimal management.19

Hemochromatosis

Hyperpigmentation/bronzing

Hemochromatosis is an autosomal recessive condition involving mutations to the HFE gene which ultimately leads to iron overload with deposition in tissues. Over 90% of patients with hemochromatosis develop skin hyperpigmentation. This pigmentation has a particular bronze hue, leading to coining of the term “bronze diabetes” to describe hemochromatosis. Hyperpigmentation often develops several years prior to other disease features, and may be the only sign of disease. Pigmentation is common on sun-exposed skin, and may be most evident on the face and dorsal hands [Figure 3].20 Treatment for pigmentary changes is the same as treatment for hemochromatosis as a whole; regular phlebotomy/venesection has been shown to gradually reverse cutaneous bronzing.21

Alopecia

Cases of alopecia areata, alopecia universalis, and scarring alopecia have all been reported in patients with hemochromatosis. In one study, 62% of patients reported partial hair loss while 12% noted complete hair loss.22 Alopecia areata involves acute-onset, focal hair loss in well-demarcated round patches. Broken hair strands that appear to thin as they enter the scalp, or “exclamation point hairs”, may be observed at the periphery of bald patches [Figure 4]. It may be advantageous to collect iron studies in alopecia patients at greater risk for hemochromatosis such as those with a family history and the typical demographic profile.23 Regarding treatment, topical immunotherapies such as diphenylcyclopropenone, topical or intralesional corticosteroids, and/or phlebotomy have been shown to provide satisfactory results in hemochromatosis patients.21

Table 1. Liver Diseases and Associated Dermatologic Manifestations

Liver DiseaseAssociated Dermatologic Findings
Autoimmune HepatitisVitiligo Pyoderma gangrenosum
HemochromatosisHyperpigmentation/bronzing Alopecia Ichthyosis Koilonychia
Wilson’s DiseaseLower extremity hyperpigmentation Azure lunulae
Alpha-1 Antitrypsin DeficiencyPanniculitis
Primary Biliary CholangitisPruritis: excoriations, post-inflammatory hyperpigmentation, butterfly sign Xanthomas: xanthelasma palpebrarum, tuberous, tendinous, xanthoma striata palmaris Extrahepatic autoimmune disease: systemic sclerosis, psoriasis, Sjögren’s syndrome
Primary Sclerosing CholangitisInflammatory bowel disease overlap: erythema nodosum, pyoderma gangrenosum
Metabolic Dysfunction-Associated
Steatotic Liver Disease		Psoriasis  Acanthosis nigricans 

Ichthyosis

Ichthyosiform changes have been noted as a prominent skin finding in patients with hemochromatosis. A 2024 systematic review found that 46/100 hemochromatosis patients reported ichthyosis-like changes of the skin.21 Pathogenesis involves transepidermal water loss and compensatory epidermal hyperproliferation as a result of impaired barrier function. The appearance of this cutaneous finding in hemochromatosis patients is similar to ichthyosis vulgaris, with extremely dry, thickened skin and “fish-like” scales [Figure 5]. Treatment may include salt water baths, exfoliation to remove scale, and moisturizing creams containing agents such as alpha-hydroxy acids, salicylic acid, or high-dose urea applied to damp skin. Topicals may be used alone or in combination with retinoids to help promote skin cell turnover.24

Koilonychia

Koilonychia is an upward eversion of the latero-distal nail plate with central depression. Nails are thin, brittle, and commonly referred to as “spoon-shaped” or concave [Figure 6]. Adult-onset koilonychia may be associated with iron deficiency anemia or hemochromatosis; this should prompt further investigation via a complete blood count and ferritin level in those without a clearly associated illness.25 Koilonychia has been noted in approximately 49% of hemochromatosis patients, and may occur at any point during the disease course. Koilonychia is treated by addressing its underlying cause, though phlebotomy in the case of hemochromatosis does not appear to have a significant effect.22

Wilson’s Disease

Lower extremity hyperpigmentation

Patchy hypermelanotic pigmentation has been reported as being the most distinctive cutaneous manifestation of Wilson’s disease. A prospective study of patients with Wilson’s disease found that ~30% developed hyperpigmentation.26 This form of hyperpigmentation presents as grey-brown, coalescing macules/patches with a rippled appearance over the anterior aspect of the lower extremities, though more diffuse hyperpigmentation has also been reported.27–29 Cutaneous changes are found more frequently in patients with hepatic Wilson’s disease, and histopathological analysis shows increased melanin deposition with normal iron and copper content.30 A 2022 paper by Tiwari at al. suggests that hyperpigmentation could be an early sensitive marker for Wilson’s disease. Cutaneous lesions may improve with chelating agents, though most case reports note persistent hyperpigmentation despite treatment.31

Azure lunulae

Azure lunulae, or “blue nails”, were first described in 1958 by Drs. Beam and McKusick as a distinctive and diagnostic sign of Wilson’s disease.32 While no longer considered “diagnostic”, azure lunulae are reported to occur in ~10% of patients with Wilson’s disease, and may aid in its detection.33 Azure lunulae describes a bluish, non-blanching discoloration that is restricted to the nail lunula, the visible part of the distal nail matrix that extends past the proximal nail fold [Figure 7]. In a 2020 case report, the authors noted that these nail changes served as an important diagnostic clue which led them to consider and ultimately diagnose a 24-year-old patient with Wilson’s disease.34 The exact pathophysiology behind azure lunulae is unclear, and there is no specific treatment.

Alpha-1 Antitrypsin Deficiency 

Panniculitis

In the 1930s, the first association was made between panniculitis and alpha-1-antitrypsin deficiency (A1AD). While rare, over 120 additional cases have since been reported.35 This association may be explained by the same protease/antiprotease imbalance that causes A1AD lung disease, wherein increased activity of proteolytic enzymes leads to localized tissue destruction. Supporting this claim is the fact that A1AD panniculitis has been shown to improve with intravenous alpha-1 antitrypsin augmentation therapy (IV-AAT), plasma exchange, and liver transplant.36,37 A1AD panniculitis is considered “necrotizing panniculitis”, and begins with painful, erythematous nodules – typically of the proximal extremities – which develop into large, ulcerated lesions that produce an oily, yellow exudate [Figure 8]. A1AD panniculitis possesses distinct histopathological features, and analysis of plasma alpha-1 antitrypsin levels in all cases of necrotizing panniculitis has been recommended. Patients should be referred to dermatology for histopathologic investigation and clinical correlation.38 Dapsone is widely recommended as first-line therapy given its efficacy and affordability, though tetracycline antibiotics –specifically doxycycline or minocycline – may also be effective given their anti-collagenase activity. Still, IV-AAT remains the most efficacious overall treatment, especially in severe or refractory cases.35

Primary Biliary Cholangitis 

Pruritis: excoriations, post-inflammatory hyperpigmentation, butterfly sign

Pruritis is noted by 50-75% of patients with primary biliary cholangitis (PBC) as being their first or most prominent symptom. Pruritis can lead to several cutaneous findings including excoriations, post-inflammatory hyperpigmentation, and the classic “butterfly sign.”39 Post-inflammatory hyperpigmentation is a temporary pigmentation that follows injury to the skin. It is primarily observed in darker skin types, and takes on the size/shape of the original injury, such as excoriations from excessive scratching. The “butterfly sign” was first described by hepatologist Dr. Telfer Reynolds when he noticed a butterfly-shaped sparing of skin on the back of a patient with PBC who had generalized pruritus. This rash is actually the result of post-inflammatory hyperpigmentation, as the butterfly-shaped area of relative hypopigmentation represents a region of the back that the patient is unable to scratch [Figure 9].40 Beyond treatment of underlying PBC, daily application of SPF 50+ sunscreen is important for minimizing further darkening. A variety of topical treatments are also available to lighten hyperpigmented lesions, including hydroquinone, tretinoin cream, and corticosteroids. For severe or refractory cases, consider chemical peels or laser therapy.41

Xanthomas: xanthelasma palpebrarum, tuberous, tendinous, xanthoma striata palmaris

Dyslipidemia is a common feature of PBC, seen in 75% of patients as a result of multiple factors including accumulation of lipoprotein X. As a result, patients may present with similar types of xanthomas as seen in types II-III hyperlipidemia, such as xanthelasma palpebrarum, tuberous xanthomas, tendinous xanthomas, or xanthoma striatum palmare.42 Xanthelasma palpebrarum are most common, seen as soft, yellow-orange macules, papules, or plaques around the medial canthus of the upper eyelid [Figure 10]. Palmar xanthomas (xanthoma striata palmaris) present as yellow-orange accentuations of the palmar and wrist creases. Tuberous xanthomas are firm, painless, red-yellow single nodules or multilobulated masses that develop over the knees, elbows, or heels. Tendinous xanthomas present as slowly enlarging subcutaneous nodules typically attached to extensor tendons on the dorsal hands or on the achilles tendons. They are smooth, firm, and mobile, with normal overlying skin [Figure 11]. Xanthomas may improve with treatment of underlying hypercholesterolemia. However, other treatments can include topical trichloroacetic acid, electrodessication, cryotherapy, laser vaporization, or excision.42,43

Extrahepatic autoimmune disease: systemic sclerosis, Sjögren’s syndrome, psoriasis

Up to 73% of patients with PBC report having one or more extrahepatic autoimmune diseases. Liver function abnormalities observed during treatment of extrahepatic autoimmune disease should prompt consideration of comorbid PBC.44 Many papers have demonstrated an association between PBC and autoimmune conditions with characteristic dermatologic findings.45–49 Up to 25% of systemic sclerosis patients are positive for PBC-specific antimitochondrial antibodies, 13% of psoriasis patients have concurrent PBC, and up to 73% of patients with Sjögren’s syndrome develop comorbid PBC.46,50,51 Systemic sclerosis can manifest with numerous cutaneous findings including sclerodactyly (thickening and tightness of the skin of the digits) [Figure 12], microstomia, or digital calcinosis. Patients should be referred to dermatology for management. Cutaneous manifestations of Sjögren’s syndrome include xerosis, hypohidrosis, and small vessel/urticarial vasculitis of the lower extremities. Dermatologic treatment is limited to soap and detergent avoidance, with emollients and humectants for xerosis. Plaque psoriasis involves symmetrically distributed, pink-red plaques with silvery scale and well-defined borders, typically on extensor surfaces [Figure 13]. Treatment may include topical corticosteroids, phototherapy, or biologic agents. Biologic agents can be particularly effective in cases of severe disease; etanercept may actually reduce AST:ALT, improve insulin sensitivity, and reduce hepatic fibrosis risk. Adalimumab and ustekinumab are also safe for use, however, infliximab should be used with caution in patients with liver failure. 

Primary Sclerosing Cholangitis 

Inflammatory bowel disease overlap: erythema nodosum, pyoderma gangrenosum

Primary sclerosing cholangitis (PSC) has a strong association with inflammatory bowel disease (IBD), with approximately 60%-80% of patients having coexisting ulcerative colitis (UC).52 Conversely, PSC is diagnosed in 2-14% of patients with IBD. The two most common cutaneous manifestations of IBD, also seen in PSC patients, are erythema nodosum and pyoderma gangrenosum. Erythema nodosum presents as tender, erythematous nodules, 1-5cm in diameter, on the bilateral anterior tibia [Figure 14]. Pathogenesis is considered to involve a form of hypersensitivity reaction. Most lesions resolve within 8 weeks, though treatment of underlying IBD may lead to accelerated improvement. Pain management with colchicine, NSAIDs (with caution in patients with IBD, as they may trigger disease flare-up), and venous compression therapy may be helpful. Additionally, oral potassium iodide can be given to reduce lesion inflammation. Pyoderma gangrenosum is the second-most common cutaneous manifestation of IBD. See the section on “Autoimmune Hepatitis” above for specifics regarding clinical features and management of pyoderma lesions [Figure 2].53

Metabolic Dysfunction-Associated Steatotic Liver Disease 

Psoriasis

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) affects 20-30% of the general population, but has been reported to affect up to 50% of patients with psoriasis.54 Notably, higher PASI scores (indicating greater extent and severity of psoriasis) have been associated with a greater likelihood of comorbid MASLD. This association has been hypothesized to relate to a “hepato-dermal axis” wherein hepatic inflammatory cytokines stimulate keratinocyte hyperproliferation in the skin and/or pro-inflammatory cytokine release from skin lymphocytes leads to insulin resistance and subsequent lipid accumulation in the liver. See the section on “Primary Biliary Cholangitis” above for specifics regarding clinical features and management of plaque psoriasis [Figure 13].55–57

Acanthosis nigricans

The presence of acanthosis nigricans (AN), particularly in diabetic patients, may also predict hepatic steatosis and fibrosis. AN presents with symmetric, velvety, dark brown patches and plaques most commonly in intertriginous regions such as the axillae, groin, and folds of the neck [Figure 15]. These lesions are papillomatous overgrowths of the epidermis, often associated with insulin resistance. Notably, insulin resistance is also widely accepted as an underlying cause of MASLD. A study of 114 patients with type 2 diabetes mellitus (T2DM) found that, of the 78 patients with AN, 41 (53%) had MASLD.58 A 2024 case-control study found evidence of an independent association between AN and the presence of both hepatic steatosis and fibrosis, indicating that AN may have some utility as a clinical marker for MASLD.59 Another study of 3012 patients found that AN was present more frequently in those with MASLD compared to healthy male (37.9% vs. 4.8%, p < 0.001) and female patients (39.8% vs. 5.8%, p < 0.001), with a specificity of ~95%.60 Regarding treatment, focus should remain on management of the underlying disease. Treatment for cosmetic reasons may include topical retinoids, calcipotriol, fish oil, podophyllin, keratolytic agents such as salicylic acid, glycolic acid, or trichloroacetic acid, or procedural modalities such as dermabrasion or alexandrite laser.61

Conclusion

Dermatologic findings often represent the very earliest extrahepatic signs of chronic liver disease. A consideration of cutaneous findings in conjunction with other signs and symptoms can be helpful in identification of underlying hepatic dysfunction. In order to properly recognize the cutaneous manifestations of chronic liver disease, providers should be aware of the general principles of lesion identification and description. Recognition of dermatologic findings is invaluable, as it can contribute to the diagnostic picture, aid in more rapid diagnosis, and hasten time to treatment for patients. 

References

1. Asrani SK, Devarbhavi H, Eaton J, Kamath PS. Burden of liver diseases in the world. J Hepatol. 2019;70(1):151-171. doi:10.1016/j.jhep.2018.09.014

2. Kochanek KD. Mortality in the United States, 2022. 2024;(492).

3. Mattiuzzi C, Lippi G. Leading Causes of US Deaths in the 2022. J Clin Med. 2024;13(23):7088. doi:10.3390/jcm13237088

4. Ma C, Qian AS, Nguyen NH, et al. Trends in the Economic Burden of Chronic Liver Diseases and Cirrhosis in the United States: 1996–2016. Am J Gastroenterol. 2021;116(10):2060-2067. doi:10.14309/ajg.0000000000001292

5. Nath P, Anand AC. Extrahepatic Manifestations in Alcoholic Liver Disease. Journal of Clinical and Experimental Hepatology. 2022;12(5):1371-1383. doi:10.1016/j.jceh.2022.02.004

6. Bhandari A, Mahajan R. Skin Changes in Cirrhosis. Journal of Clinical and Experimental Hepatology. 2022;12(4):1215-1224. doi:10.1016/j.jceh.2021.12.013

7. Mack CL, Adams D, Assis DN, et al. Diagnosis and Management of Autoimmune Hepatitis in Adults and Children: 2019 Practice Guidance and Guidelines From the American Association for the Study of Liver Diseases. Hepatology. 2020;72(2):671-722. doi:10.1002/hep.31065

8. Muratori P, Fabbri A, Lalanne C, Lenzi M, Muratori L. Autoimmune liver disease and concomitant extrahepatic autoimmune disease: European Journal of Gastroenterology & Hepatology. 2015;27(10):1175-1179. doi:10.1097/MEG.0000000000000424

9. Gill L, Zarbo A, Isedeh P, Jacobsen G, Lim HW, Hamzavi I. Comorbid autoimmune diseases in patients with vitiligo: A cross-sectional study. Journal of the American Academy of Dermatology. 2016;74(2):295-302. doi:10.1016/j.jaad.2015.08.063

10. Sacher M, Blümel P, Thaler H, Manns M. Chronic active hepatitis associated with vitiligo, nail dystrophy, alopecia and a new variant of LKM antibodies. Journal of Hepatology. 1990;10(3):364-369. doi:10.1016/0168-8278(90)90148-K

11. Terziroli Beretta-Piccoli B, Invernizzi P, Gershwin ME, Mainetti C. Skin Manifestations Associated with Autoimmune Liver Diseases: a Systematic Review. Clinic Rev Allerg Immunol. 2017;53(3):394-412. doi:10.1007/s12016-017-8649-9

12. Teufel A, Weinmann A, Kahaly GJ, et al. Concurrent Autoimmune Diseases in Patients With Autoimmune Hepatitis. Journal of Clinical Gastroenterology. 2010;44(3):208-213. doi:10.1097/MCG.0b013e3181c74e0d

13. Seneschal J, Boniface K. Vitiligo: Current Therapies and Future Treatments. Dermatol Pract Concept. 2023;13(4S2):e2023313S. doi:10.5826/dpc.1304S2a313S

14. Oka M, Berking C, Nesbit M, et al. Interleukin-8 overexpression is present in pyoderma gangrenosum ulcers and leads to ulcer formation in human skin xenografts. Lab Invest. 2000;80(4):595-604. doi:10.1038/labinvest.3780064

15. Dantas SG, Quintella LP, Fernandes NC. Exuberant pyoderma gangrenosum in a patient with autoimmune hepatitis. An Bras Dermatol. 2017;92(1):114-117. doi:10.1590/abd1806-4841.20174871

16. Goldenberg G, Jorizzo JL. Use of etanercept in treatment of pyoderma gangrenosum in a patient with autoimmune hepatitis. Journal of Dermatological Treatment. 2005;16(5-6):347-349. doi:10.1080/09546630500424722

17. Wat H, Haber RM. Trends in the Association between Pyoderma Gangrenosum and Autoimmune Hepatitis: Case Report and Review of the Literature. J Cutan Med Surg. 2014;18(5):345-352. doi:10.2310/7750.2013.13177

18. Androutsakos T, Stamopoulos P, Aroni K, Hatzis G. A case report of successful treatment of pyoderma gangrenosum in a patient with autoimmune hepatitis, and review of the literature. BMC Gastroenterol. 2015;15(1):149. doi:10.1186/s12876-015-0376-1

19. George C, Deroide F, Rustin M. Pyoderma gangrenosum – a guide to diagnosis and management. Clin Med (Lond). 2019;19(3):224-228. doi:10.7861/clinmedicine.19-3-224

20. Zakko L, Finch J, Rothe MJ, Grant-Kels JM. Hemochromatosis: Dermatological Features. In: Wu GY, Selsky N, Grant-Kels JM, eds. Atlas of Dermatological Manifestations of Gastrointestinal Disease. Springer New York; 2013:189-190. doi:10.1007/978-1-4614-6191-3_72

21. Akbarialiabad H, Jamshidi P, Callen JP, Murrell DF. Dermatologic manifestations of hereditary hemochromatosis: A systematic review. Acad Dermatol Venereol. Published online May 16, 2024:jdv.20098. doi:10.1111/jdv.20098

22. Chevrant-Breton J, Simon M, Bourel M, Ferrand B. Cutaneous manifestations of idiopathic hemochromatosis. Study of 100 cases. Arch Dermatol. 1977;113(2):161-165.

23. Leung. Iron Screening in Alopecia Areata Patients May Catch Hereditary Hemochromatosis Early. Cutis. 2022;110(4). doi:10.12788/cutis.0650

24. Arora N, Nguyen K, Hudson A, Bicknell L. Ichthyosis Skin Changes in a Patient With Hereditary Hemochromatosis. Cureus. 2024;16(1):e52823. doi:10.7759/cureus.52823

25. Vella J. Cutaneous Markers of Systemic Disease in the Lower Extremity. Clinics in Podiatric Medicine and Surgery. 2016;33(3):423-440. doi:10.1016/j.cpm.2016.02.009

26. K. J. K, Bavanandam S, Dheivamani N, Reddy VC, K. M. Spectrum of cutaneous manifestations in Wilson’s disease in children in a tertiary care center in South India: a prospective study. Int J Contemp Pediatr. 2017;4(6):2060. doi:10.18203/2349-3291.ijcp20174731

27. Seyhan M, Erdem T, Selimoğlu MA, Ertekin V. Dermatological signs in Wilson’s disease. Pediatr Int. 2009;51(3):395-398. doi:10.1111/j.1442-200X.2008.02766.x

28. Nandi M, Sarkar S, Mondal R. Generalized hyperpigmentation in Wilson’s disease: An unusual association. J Neurosci Rural Pract. 2013;4(1):70-72. doi:10.4103/0976-3147.105621

29. Leu ML. Skin Pigmentation in Wilson’s Disease. JAMA. 1970;211(9):1542. doi:10.1001/jama.1970.03170090058016

30. Bem RS de, Muzzillo DA, Deguti MM, Barbosa ER, Werneck LC, Teive HAG. Wilson’s disease in southern Brazil: a 40-year follow-up study. Clinics (Sao Paulo). 2011;66(3):411-416. doi:10.1590/s1807-59322011000300008

31. Tiwari L, Fadila  null, Ghorui A. Hyperpigmented patch: an uncommon but early marker of Wilson’s disease. BMJ Case Rep. 2022;15(2):e246075. doi:10.1136/bcr-2021-246075

32. Beam AG. AZURE LUNULAE: AN UNUSUAL CHANGE IN THE FINGERNAILS IN TWO PATIENTS WITH HEPATOLENTICULAR DEGENERATION (WILSON’S DISEASE). JAMA. 1958;166(8):904. doi:10.1001/jama.1958.62990080001010

33. Zakko L, Finch J, Rothe MJ, Grant-Kels JM. Wilson’s Disease (Hepatolenticular Degeneration): Dermatological Features. In: Wu GY, Selsky N, Grant-Kels JM, eds. Atlas of Dermatological Manifestations of Gastrointestinal Disease. Springer New York; 2013:185-186. doi:10.1007/978-1-4614-6191-3_70

34. Hori H, Kudo Y, Kuroiwa Y, Tanaka F. Azure Lunulae and Leukoencephalopathy in Wilson Disease. Intern Med. 2021;60(9):1479. doi:10.2169/internalmedicine.5417-20

35. Franciosi AN, Ralph J, O’Farrell NJ, et al. Alpha-1 antitrypsin deficiency–associated panniculitis. Journal of the American Academy of Dermatology. 2022;87(4):825-832. doi:10.1016/j.jaad.2021.01.074

36. O’Riordan K, Blei A, Rao MS, Abecassis M. alpha 1-antitrypsin deficiency-associated panniculitis: resolution with intravenous alpha 1-antitrypsin administration and liver transplantation. Transplantation. 1997;63(3):480-482. doi:10.1097/00007890-199702150-00028

37. de Oliveira P, Paz-Melgar L, Takahashi MDF, et al. Alpha-1-antitrypsin deficiency associated with panniculitis treated with plasma exchange therapy. Int J Dermatol. 2004;43(9):693-697. doi:10.1111/j.1365-4632.2004.02054.x

38. American Thoracic Society, European Respiratory Society. American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 2003;168(7):818-900. doi:10.1164/rccm.168.7.818

39. Düll MM, Kremer AE. Evaluation and Management of Pruritus in Primary Biliary Cholangitis. Clinics in Liver Disease. 2022;26(4):727-745. doi:10.1016/j.cld.2022.06.009

40. Verma SB. Revisiting the Origin, Evolution and Morphological Nuances of the “Butterfly sign.” Indian Dermatol Online J. 2021;12(3):475-476. doi:10.4103/idoj.IDOJ_552_20

41. Naik P. Getting to the Core of Contemporary Therapies for Post-Inflammatory Hyperpigmentation. J Drugs Dermatol. 2022;21(3):276-283. doi:10.36849/JDD.6485

42. Harris J, Cao S, Hile G, Eshaq M. Diffuse xanthomas in a patient with primary biliary cholangitis and lipoprotein X. JAAD Case Rep. 2021;7:30-32. doi:10.1016/j.jdcr.2020.10.029

43. Petrie E, Hoppmann NA, Wilcox CM, Al Diffalha S, Gray ME. Gastric Xanthomatosis Secondary to Lipoprotein X in Primary Biliary Cholangitis. Journal of Investigative Medicine High Impact Case Reports. 2022;10:23247096221089488. doi:10.1177/23247096221089488

44. Ma G, Yang J, Wang X, et al. Dissecting causal relationships between primary biliary cholangitis and extrahepatic autoimmune diseases based on Mendelian randomization. Sci Rep. 2024;14(1):11528. doi:10.1038/s41598-024-62509-x

45. Zhao D, Zhao Q, Xu F, Zhang F, Bai W. Primary biliary cirrhosis and psoriasis: a two-sample Mendelian randomization study. Front Immunol. 2024;14:1264554. doi:10.3389/fimmu.2023.1264554

46. Rigamonti C, Bogdanos DP, Mytilinaiou MG, Smyk DS, Rigopoulou EI, Burroughs AK. Primary biliary cirrhosis associated with systemic sclerosis: diagnostic and clinical challenges. Int J Rheumatol. 2011;2011:976427. doi:10.1155/2011/976427

47. Marasini B, Gagetta M, Rossi V, Ferrari P. Rheumatic disorders and primary biliary cirrhosis: an appraisal of 170 Italian patients. Ann Rheum Dis. 2001;60(11):1046-1049. doi:10.1136/ard.60.11.1046

48. Selmi C, Meroni PL, Gershwin ME. Primary biliary cirrhosis and Sjögren’s syndrome: autoimmune epithelitis. J Autoimmun. 2012;39(1-2):34-42. doi:10.1016/j.jaut.2011.11.005

49. Liu Y, Han K, Liu C, Duan F, Cheng J, Yang S. Clinical Characteristics and Prognosis of Concomitant Primary Biliary Cholangitis and Autoimmune Diseases: A Retrospective Study. Can J Gastroenterol Hepatol. 2021;2021:5557814. doi:10.1155/2021/5557814

50. Deng X, Li J, Hou S, Ci B, Liu B, Xu K. Prevalence and impact of Sjögren’s syndrome in primary biliary cholangitis: a systematic review and meta-analysis. Annals of Hepatology. 2022;27(6):100746. doi:10.1016/j.aohep.2022.100746

51. Fiore M, Leone S, Maraolo AE, Berti E, Damiani G. Liver Illness and Psoriatic Patients. Biomed Res Int. 2018;2018:3140983. doi:10.1155/2018/3140983

52. Gidwaney NG, Pawa S, Das KM. Pathogenesis and clinical spectrum of primary sclerosing cholangitis. World J Gastroenterol. 2017;23(14):2459-2469. doi:10.3748/wjg.v23.i14.2459

53. He R, Zhao S, Cui M, et al. Cutaneous manifestations of inflammatory bowel disease: basic characteristics, therapy, and potential pathophysiological associations. Front Immunol. 2023;14:1234535. doi:10.3389/fimmu.2023.1234535

54. Mikolasevic I, Milic S, Turk Wensveen T, et al. Nonalcoholic fatty liver disease – A multisystem disease? WJG. 2016;22(43):9488. doi:10.3748/wjg.v22.i43.9488

55. Gau SY, Huang KH, Lee CH, Kuan YH, Tsai TH, Lee CY. Bidirectional Association Between Psoriasis and Nonalcoholic Fatty Liver Disease: Real-World Evidence From Two Longitudinal Cohort Studies. Front Immunol. 2022;13:840106. doi:10.3389/fimmu.2022.840106

56. Ruan Z, Lu T, Chen Y, et al. Association Between Psoriasis and Nonalcoholic Fatty Liver Disease Among Outpatient US Adults. JAMA Dermatol. 2022;158(7):745. doi:10.1001/jamadermatol.2022.1609

57. Prussick R, Prussick L, Nussbaum D. Nonalcoholic Fatty liver disease and psoriasis: what a dermatologist needs to know. J Clin Aesthet Dermatol. 2015;8(3):43-45.

58. Prabhakar A, N. R. A, Kartha T. D. U, B. R. Prevalence of non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus and its correlation with coronary artery disease (CAD). Int J Res Med Sci. 2017;5(12):5175. doi:10.18203/2320-6012.ijrms20175079

59. Dutta K, Bhatt SP, Madan S, et al. Acanthosis nigricans independently predicts hepatic fibrosis in people with type 2 diabetes in North India. Prim Care Diabetes. 2024;18(2):224-229. doi:10.1016/j.pcd.2024.01.003

60. Niriella MA, Dassanayake AS, Kalubovila KVU, et al. 1013 IS ACANTHOSIS NIGRICANS A USEFUL CLINICAL SCREENING TEST FOR NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IN RESOURCE POOR SETTINGS? Journal of Hepatology. 2009;50:S367. doi:10.1016/S0168-8278(09)61015-1

61. Patel NU, Roach C, Alinia H, Huang W, Feldman S. Current treatment options for acanthosis nigricans. CCID. 2018;Volume 11:407-413. doi:10.2147/CCID.S137527

Download Tables, Images & References

Frontiers in Endoscopy, Series #100

Pancreaticobiliary Endoscopic Ultrasound: How We Do It

November 2025 • Volume XLIX, Issue 11
Jennifer L. Maranki,Douglas G. Adler

Read Article

Introduction

Endoscopic ultrasound (EUS) has evolved into an indispensable tool in the evaluation and management of pancreaticobiliary diseases. Over 40 years ago, EUS was developed as a radial scanner, providing circumferential views of the gastrointestinal mucosa and surrounding structures. Comprehension of this type of imaging was akin to axial views of computed tomography (CT) scans and was widely accepted. In the 1990s, linear array echoendoscopes were developed, which provided the ability to obtain biopsies and perform other interventions. While conceptually more difficult to learn, linear EUS has become the main modality for pancreaticobiliary assessment, particularly when an intervention such as biopsy or drainage is required. It is crucial for the trainee endoscopist to have a sound understanding of abdominal anatomy, probe handling, and interpretive skills.

This review provides a practical framework for performing pancreaticobiliary EUS from the perspective of an interventional endoscopist, focusing on scope manipulation to achieve optimization of the image, anatomical landmarks, and identification of pathology.

Intubation of the Esophagus

The tip of the echoendoscope is rigid, nonbending, and relatively long with the ultrasound transducer positioned in front of the optical lens on radial and linear devices. The large knob of the scope is used to deflect the scope tip past the base of the tongue and into the hypopharynx where subsequent straightening eases passage. Inflating the balloon of the echoendoscope, if one is utilized, provides some cushioning as it penetrates the cricopharyngeus, and this can be done before advancing the scope into the mouth if needed. Similar to passing a duodenoscope, the endoscopic view is limited. However, a rule of thumb is that if the vocal cords are seen on the screen, the tip of the echoendoscope is in line with the esophagus and may be advanced. Slight rotation of the probe allows the echoendoscope to enter the proximal esophagus. It is essential to avoid pushing against fixed resistance to reduce the risk of a perforation.

A Station Approach to the Examination

Gastroesophageal Junction (GEJ)

With the echoendoscope positioned just distal to the squamocolumnar junction, the abdominal aorta is readily identified by applying clockwise torque to the shaft of the scope. With the linear echoendoscope, the aorta appears as a long, anechoic structure, often with hyperechoic walls, sloping down from right to left across the monitor with the pleura of the left lung clearly seen below the vessel wall. The diaphragmatic crura are seen, and when the echoendoscope is advanced further, the celiac artery is identified as it is the first vessel branching off the abdominal aorta. The superior mesenteric artery is located just below it, and the inferior mesenteric artery is also easily seen below that. (Figure 1) The echoendoscope should be gently torqued clockwise and counterclockwise to visualize these structures.

The celiac artery can be followed until it branches into the splenic artery and the common hepatic artery. (Figure 2) At that point, advancing the echoendoscope another 1 to 2 cm and deflecting the scope tip down (thumb up, dial moves “away”), the pancreas and confluence of the portal vein should come into view. If this is not achieved because of a hiatal hernia or other anatomic variant, another approach is to advance the echoendoscope into the body of the stomach, to about 50 cm from the incisors. Gentle withdrawal of the echoendoscope with simultaneous clockwise torque will often allow the body of the pancreas to come into view.

The body of the pancreas is identified by its characteristic “salt and pepper” appearance, as well as the presence of the splenic artery and vein. (Figure 3) The splenic artery and vein can be confirmed by pulse wave doppler based on flow patterns, and in general the splenic artery is narrower than the vein and follows a more tortuous course. In the body of the pancreas, the splenic artery and vein are seen as two anechoic circles, and the main pancreatic duct is positioned to the left of these on the monitor. (Figure 4) From that position, the echoendoscope may be gently torqued clockwise and withdrawn to keep the pancreatic duct in view and to scan the body and tail of the pancreas. During this maneuver, the left kidney is identified and acts as a guide to the demarcation of the junction between the body and tail. (Figure 5) The splenic artery and vein may be traced with further withdrawal to the splenic hilum and spleen. With minor counterclockwise torque, the left adrenal gland is also identified as a sprawling “longhorn steer-shaped” structure. (Figure 6) 

From the body of the pancreas, with the splenic artery and vein in view, the rest of the body of the pancreas and genu may be visualized by counterclockwise torque and gentle advancement of the scope. In children or in very thin adults, the pancreatic head can often be seen from the stomach but this is not typical for normal sized adults. The pancreatic duct may be traced across the portal confluence as it dives down into the head.

Generally, the next step in the station-based evaluation is to advance the echoendoscope to the duodenal bulb. However, another option for evaluating the common bile duct and head of the pancreas from the GEJ involves executing an “alpha maneuver.”1 Starting at the GEJ and the scope in the anticlockwise position, the left lobe of the liver is identified and the scope is rotated clockwise 90 degrees. The inferior vena cava, hepatic veins, and potentially the liver hilum are brought into view. By pushing the scope inferiorly 2 cm, the portal vein, hepatic artery, and common hepatic duct (CHD) are seen. The gallbladder and cystic duct may also be seen inferior to the CHD. The portal vein and common bile duct (CBD) may be traced with a downward and gentle clockwise-counter-clockwise rotation until the head of the pancreas and portal confluence is identified. The rest of the pancreatic head and CBD are identified with further clockwise rotation and tip deflection.1 This is an important technique, particularly in the setting of gastric outlet obstruction or altered anatomy, when the duodenum is not accessible for the station approach to pancreaticobiliary imaging.

Duodenal Bulb

The echoendoscope is advanced to the antrum of the stomach and through the pylorus. It may be helpful to insufflate the balloon of the scope with a small amount of water to provide a cushion for the stiff scope tip as it enters the duodenal bulb. The tip of the linear echoendoscope is approximated to the apex of the duodenal bulb, with the scope tip deflected upward (thumb down). This is often referred to as “wedging” the echoendoscope in the duodenal bulb. Gentle counter-clockwise rotation will reveal the head of the pancreas. A main landmark is the portal vein, confirmed by the use of color Doppler. Between the transducer and the PV, the CBD is identified along with the PV. The CBD will be closer to the transducer than the PD. (Figure 7) The CBD can be traced into the liver with counter-clockwise torque, and through the head of the pancreas to the ampulla with clockwise rotation. The main pancreatic duct is also identified in the head of the pancreas, and it can also be traced to the ampulla with rightward torque. This position is the most common site for sampling masses in the head of the pancreas and is also the most critical for assessing biliary stone disease in the CBD or CHD.

Ampulla

The echoendoscope is advanced to the second portion of the duodenum and reduced, similar to an ERCP scope. During withdrawal, the major papilla is identified endoscopically. 

Once identified endoscopically, the tip of the scope is deflected upward such that the transducer is nestled perpendicular to the papilla. The transducer is gently rotated clockwise, and the ampulla with common bile duct and pancreatic duct in a linear orientation come into view. Anticlockwise rotation will allow the operator to look up towards the proximal biliary tree. The ampulla appears as a thickened, hypoechoic, homogeneous structure within the duodenal wall but projecting outward towards the lumen, with the bile duct appearing more superficial or close to the transducer (given the intraduodenal nature of the distal common bile duct), and the pancreatic duct deeper.  (Figures 8a and 8b) The pancreatic duct and common bile duct may form a common channel is they enter the major papilla, or they may arrive with distinct orifices, each surrounded completely by sphincter tissue. The echoendoscope is slowly withdrawn and rotated clockwise and counterclockwise until the portal confluence is identified. 

In the setting of pancreas divisum, the ventral pancreatic duct will be seen entering the ampulla, but it will appear short and truncated. The dorsal pancreatic duct will be unable to be identified merging into the main pancreatic duct and may be identified merging into the duodenal wall at the minor papilla. 

Second and Third Portion of the Duodenum

For imaging the uncinate process of the pancreas, the echoendoscope is advanced just distal to the major papilla. With rotation of the scope clockwise and counterclockwise, the aorta is identified, often running vertically along the left-hand side of the EUS image, with the IVC appearing parallel to it. Upon identification of the aorta, the shaft of the scope is generally rotated clockwise and slowly withdrawn. The uncinate identified, and with further gentle scope withdrawal and torquing, the examination of the pancreas is completed. The dorsal anlage of the pancreas comprises the anterior and superior portions of the head and extends into the neck, body, and tail. It is typically more homogeneous and hyperechoic compared with the ventral anlage. The ventral anlage, derived from the ventral pancreatic bud, is located in the posteroinferior aspect of the pancreatic head and uncinate process, and appears more heterogeneous than the dorsal anlage. It is usually more hypoechoic and lobular. It is important to recognize these normal embryologic differences so that the ventral anlage is not mistaken for changes of chronic pancreatitis or neoplasm.

Identification of Pathology

Among the most common indications for pancreaticobiliary EUS are suspected choledocholithiasis and solid or cystic lesions of the pancreas. The best location to identify stones in the bile duct is with the echoendoscope in the duodenal bulb. From this viewpoint, the portal vein and common bile duct are identified and can be traced cephalad to the liver and down to the ampulla. The view from the ampulla may also identify distal stones. Stones in the bile duct appear as round, oval, or triangular hyperechoic structures that typically have post acoustic shadowing. (Figure 9) Shadowing represents a disruption in the sound waves by a dense structure, causing a dark, echo-free image beyond the structure. Occasionally, soft stones or sludge will not create a shadow, but must be accurately identified regardless.

The appearance of pancreatic lesions is dependent on the nature of the mass. Cystic lesions may appear as anechoic structures that may or may not have a wall and/or septations. Side-branch intraductal papillary mucinous neoplasms (IPMN) may sometimes be identified as communicating with the main pancreatic duct. Main duct IPMNs appear as either diffuse or focal dilation of the main pancreatic duct. Serous cystadenomas are typically multiseptated, with a sponge-like appearance, with a “central scar,” which appears as a bright structure within the cyst. (Figure 10) Mucinous cystic neoplasms are often unilocular and appear most commonly in the body and tail of the pancreas. Solid pseudopapillary tumors typically appear as well-defined, mixed solid and cystic lesions that are hypoechoic and often with a hyperechoic rim. Pancreatic pseudocysts are generally located adjacent to the pancreas, are often left of the midline, and may become very large, compressing adjacent organs and vessels, and they may (rarely) have septations. They often appear anechoic, but in the setting of infection or necrosis, may appear more hypoechoic as opposed to anechoic. Organized necrosis within the pseudocyst appears hyperechoic.

Solid masses include neuroendocrine tumors, pancreatic ductal adenocarcinoma, and metastatic lesions. Neuroendocrine tumors may be solid, mixed, or cystic, thereby complicating diagnosis. If solid, they are generally well-defined, hypoechoic, homogeneous lesions. Pancreatic adenocarcinoma is identified as a hypoechoic area, sometimes poorly defined, often with shadowing due to the density of the tissue or the presence of calcifications. Metastatic lesions are either isoechoic or hypoechoic and well-defined.

EUS is also used to diagnose chronic pancreatitis using a variety of changes related to the parenchyma and ducts. Parenchymal changes include calcifications, lobularity, hyperechoic strands and foci, cysts, and honeycombing. Ductal changes include calcifications within the duct, ductal dilation and ectasia, visible side branches, and hyperechoic duct margins. Objective grading systems such as the Rosemont Criteria are often applied when considering a diagnosis of chronic pancreatitis.2

EUS-Guided Tissue Sampling of Solid Pancreatic Lesions

The ability to biopsy solid lesions in the pancreas and surrounding areas is one of the key skills of linear-based endosonography. Additionally, EUS-guided sampling of pancreatic parenchyma may be helpful in diagnosing autoimmune pancreatitis. Previously, fine-needle aspiration (FNA) needles were used in conjunction with rapid on-site evaluation (ROSE) for sampling of solid lesions, particularly in the pancreas. With the advent of newer, fine-needle biopsy (FNB) needles, the need for ROSE has significantly diminished.3 Current society statements recommend the use of end-cutting FNB needles over reverse-bevel FNB or FNA needles. 4,5,6Additionally, the routine use of ROSE for solid pancreatic masses is not recommended.5

 The fanning technique, whereby the needle is moved in multiple directions within the lesion during each pass using deflection of the large (up-down) wheel, is recommended by some authors as it improves diagnostic accuracy and adequacy of tissue sampling.7 Additionally, 19- and 22-gauge needles are often suggested over 25-gauge needles, as they may result in higher-quality specimens that are more likely to be adequate for personalized medicine and ancillary molecular testing.5,8 However, in cases where the endoscope is severely torqued and there is limited maneuverability, or when the 22-gauge needle does not penetrate the lesion, the 25-gauge needle is an acceptable option. 

Conclusion

The approach to pancreaticobiliary linear EUS anatomy outlined here helps learners establish a framework for completing their exams using a systematic approach. As experience is gained, each endosonographer will develop their own modifications of these methods to achieve optimal imaging and assessment of the pancreaticobiliary anatomy. 

References

References

1. Dhir V, Adler DG, Pausawasdi N, Maydeo A, Ho KY. Feasibility of a complete pancreatobiliary linear endoscopic ultrasound examination from the stomach. Endoscopy. Jan 2018;50(1):22-32. doi:10.1055/s-0043-118592

2. Catalano MF, Sahai A, Levy M, et al. EUS-based criteria for the diagnosis of chronic pancreatitis: the Rosemont classification. Gastrointest Endosc. Jun 2009;69(7):1251-61. doi:10.1016/j.gie.2008.07.043

3. Dbouk M, Davis BG, Peller M, et al. EUS-guided fine-needle biopsy sampling of solid pancreatic masses with and without rapid onsite evaluation for commercial next-generation genomic profiling. Gastrointest Endosc. Mar 21 2025;doi:10.1016/j.gie.2025.03.1208

4. Facciorusso A, Arvanitakis M, Crinò SF, et al. Endoscopic ultrasound-guided tissue sampling: European Society of Gastrointestinal Endoscopy (ESGE) Technical and Technology Review. Endoscopy. Apr 2025;57(4):390-418. doi:10.1055/a-2524-2596

5. Machicado JD, Sheth SG, Chalhoub JM, et al. American Society for Gastrointestinal Endoscopy guideline on the role of endoscopy in the diagnosis and management of solid pancreatic masses: summary and recommendations. Gastrointest Endosc. Nov 2024;100(5):786-796. doi:10.1016/j.gie.2024.06.002

6. Gkolfakis P, Crinò SF, Tziatzios G, et al. Comparative diagnostic performance of end-cutting fine-needle biopsy needles for EUS tissue sampling of solid pancreatic masses: a network meta-analysis. Gastrointest Endosc. Jun 2022;95(6):1067-1077.e15. doi:10.1016/j.gie.2022.01.019

7. Lee JM, Lee HS, Hyun JJ, et al. Slow-Pull Using a Fanning Technique Is More Useful Than the Standard Suction Technique in EUS-Guided Fine Needle Aspiration in Pancreatic Masses. Gut Liver. May 15 2018;12(3):360-366. doi:10.5009/gnl17140

8. Tomoda T, Kato H, Fujii Y, et al. Randomized trial comparing the 25G and 22G Franseen needles in endoscopic ultrasound-guided tissue acquisition from solid pancreatic masses for adequate histological assessment. Dig Endosc. Mar 2022;34(3):596-603. doi:10.1111/den.14079

Download Tables, Images & References

Nutrition Reviews in Gastroenterology, SERIES #28

The Role of the Mediterranean Diet Pattern in Treatment and Management of Metabolic Dysfunction-Associated Steatotic Liver Disease 

November 2025 • Volume XLIX, Issue 11
Alexander W. Worix,Jennifer C. Lai,Neha D. Shah

Read Article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is defined by excessive hepatic fat accumulation in individuals without significant alcohol intake. Previously termed non-alcoholic fatty liver disease (NAFLD), this condition included nonalcoholic fatty liver and nonalcoholic steatohepatitis. The Mediterranean diet, characterized by limiting saturated fats, red meat, and refined sugars with increased consumption of fiber, polyunsaturated, and monounsaturated fats, has shown efficacy in improving hepatic steatosis and metabolic parameters in NAFLD. However, as diagnostic criteria have evolved, further research is needed to assess the diet’s impact specifically on MASLD outcomes. This review will discuss the prevalence and diagnosis of MASLD, its associated metabolic and lifestyle risk factors, and evaluate existing evidence on the Mediterranean diet as a therapeutic approach, underscoring its close association with the earlier NAFLD classification.

Alexander W. Worix, MD1 Jennifer C. Lai, MD, MBA2 Neha D. Shah MPH, RD, CNSC, CHES3,4 1Acute and Chronic Liver Disease Fellow, Division of Gastroenterology, University of California, San Francisco, CA 2Professor of Medicine in Residence, Endowed Professor in Liver Health and Transplantation, Division of Gastroenterology, University of California, San Francisco, CA 3Clinical Nutrition Department, University of California, San Francisco, CA 4Neha Shah Nutrition LLC, San Francisco, CA

Introduction 

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a disorder characterized by the accumulation of excess fat within the liver, known as hepatic steatosis (HS).1 MASLD is classified into two phenotypes: metabolic dysfunction-associated steatotic liver (MASL) and metabolic dysfunction-associated steatohepatitis (MASH). MASLD, formerly referred to as non-alcoholic fatty liver disease (NAFLD), encompasses a spectrum of liver diseases that occur in the absence of significant alcohol consumption. Previously, NAFLD was also classified into two main phenotypes: nonalcoholic fatty liver (NAFL), defined by the presence of at least 5% hepatic steatosis without evidence of hepatocyte ballooning, and nonalcoholic steatohepatitis (NASH), which is distinguished by hepatic steatosis accompanied by inflammation and hepatocyte injury, with or without fibrosis. MASLD, with its two phenotypes, representing the current terminology, is congruent with the same definitions as NAFLD and its two phenotypes. 

In 2023, multiple professional liver societies developed a Delphi consensus statement to update both the diagnostic criteria and terminology.2 This process involved input from 236 panelists who participated in surveys and meetings. The terms “non-alcoholic” and “fatty” were considered stigmatizing by a majority of participants—61% and 66%, respectively.2 The prior terminology was also exclusionary for a diagnosis (the “non” portion of the diagnosis), while also using terminology of NAFLD that did not highlight the disease drivers, hence one of the big highlights of the use of MASLD, where metabolic dysfunction also shines light onto the drivers of the underlying disease state. As a result, steatotic liver disease (SLD) was adopted as an overarching term, and NAFLD was renamed MASLD. Under the new criteria, in addition to hepatic steatosis, at least one of five cardiometabolic risk factors must now be present to establish a diagnosis of MASLD.2 

Table 1. Updates for Steatotic Liver Disease Nomenclature 

Prior NomenclatureCriteria 
Non-Alcoholic Fatty Liver Disease
(NAFLD)		Presence of hepatic steatosis confirmed by imaging
or by histology Lack of significant alcohol consumption
Non-Alcoholic Steatohepatitis
(NASH)		Presence of 5% hepatic steatosis Inflammation and hepatocyte injury (+/- fibrosis)
New Nomenclature Criteria
Steatotic Liver Disease
(SLD)		Overarching term to encompass the various causes of steatosis 
Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) Presence of hepatic steatosis  Lack of significant alcohol consumption At least one of five cardiometabolic risk factors
Metabolic Dysfunction-Associated Alcoholic Liver Disease (MetALD)Meets MASLD Criteria Individuals who consume more than 140 g/week of alcohol for women and 210 g/week for men
Alcoholic-Associated Liver Disease
(ALD)		Clinical-histologic spectrum including fatty liver, alcohol hepatitis, and cirrhosis with its complications Documentation on chronic heavy alcohol use  Exclusion of other causes of liver disease 
Specific Etiology Steatotic Liver Disease
(Specific Etiology SLD)		Fatty liver conditions with a known cause, distinct from metabolic dysfunction-associated steatotic liver disease or alcohol-related liver disease 
Cryptogenic Steatotic Liver Disease
(Cryptogenic SLD)		Not meeting criteria for MASLD or a specific alternative etiology Patients may be reclassified in the future as more data emerge 

Modification of diet through the Mediterranean diet (MedDiet) with reducing intake of animal-based protein, saturated fats, and concentrated sweets and increasing intake of dietary fiber, polyunsaturated fatty acids (PUFAs), and monounsaturated fatty acids (MUFAs) has been previously shown to reduce NAFLD.3 Ongoing studies will continue to evaluate its impact on the metabolic and hepatic parameters now used to define MASLD. 

This review will discuss the prevalence and diagnostic criteria for MASLD, explore metabolic and lifestyle risk factors, and examine current evidence on the MedDiet for its treatment and management, demonstrating a strong association with the prior nomenclature of NAFLD. Studies included in the review that evaluated MASLD using current diagnostic criteria will use the MASLD nomenclature, whereas earlier NAFLD studies will retain NAFLD nomenclature.

Prevalence 

A prior meta-analysis published before the change in nomenclature has estimated that the global prevalence of NAFLD was 25.24%. Africa has the lowest prevalence whereas South America and the Middle East have the highest prevalence. Upon analysis of the regions, the prevalence of NAFLD was 13% for Europe, 12.89% for North America and 9.26% for Asia.4 

Despite evolving nomenclature, there remains a high concordance between NAFLD and MASLD, with nearly identical clinical outcomes. Notably, approximately 5% of individuals previously classified as having NAFLD would not meet the updated MASLD criteria.5 Similar to NAFLD, the highest regional prevalence of MASLD is observed in Latin America (44.4%), while the lowest is found in Western Europe (25.1%). Projections indicate that global MASLD prevalence may rise to 55.4% by 2040.5 Of particular concern, countries in the Middle East and North Africa (MENA) region, along with much of Asia, are experiencing significant increases in obesity and type 2 diabetes-key metabolic drivers of MASLD.

Diagnosis 

MASLD is diagnosed based on the presence of hepatic steatosis in combination with at least one cardiometabolic risk factor, after excluding significant alcohol use and other chronic liver diseases. MASLD encompasses a spectrum of hepatic disorders, including isolated liver steatosis (referred to as metabolic dysfunction-associated steatotic liver, or MASL), steatohepatitis (MASH), and advanced fibrosis or cirrhosis.6 See Table 1. Historically, differentiation between MASL and MASH required liver biopsy for histologic identification of steatohepatitis; however, clinical practice has shifted toward noninvasive methods for staging disease severity. Biomarkers and imaging techniques such as vibration-controlled transient elastography (VCTE) and fibrosis-4 (FIB-4) index are now commonly used to stratify fibrosis risk, with diagnostic performance comparable to that seen in NAFLD populations.7 

Food GroupRecommended Intake
Vegetables≥ 2 servings/meal
Fruits1–2 servings/meal
Whole grainsAs primary carbohydrate source
Legumes≥ 2 servings/week
Nuts and seeds1 serving/day
Extra virgin olive oil (EVOO)Main source of MUFAs; 4–6 tablespoons/day
Fish and seafood≥ 2 servings/week
Poultry and eggsModerate consumption
Red and processed meatsLimited; < 1 serving/week
Dairy (preferably low-fat)Moderate consumption
Alcohol (optional)Moderate wine with meals
(if culturally appropriate)

Importantly, imaging with abdominal ultrasound is not mandatory for diagnosis in patients at high risk of MASLD. In such cases, clinicians may proceed directly to fibrosis risk stratification following exclusion of secondary causes of hepatic steatosis, regardless of transaminase levels.8 The diagnostic criteria for MASLD require the presence of hepatic steatosis along with at least one of the following cardiometabolic risk factors:8,9

Body mass index (BMI) >25 kg/m2 (or >23 kg/m2 for Asian individuals) or waist circumference (WC) >94 cm (men), >80 cm (women), or ethnicity-adjusted equivalents. 

Fasting serum glucose ³5.6 mmol/L (³100 mg/dL), 2-hour post-load glucose ³7.8 mmol/L (³140 mg/dL), HbA1c ³5.7% (³39 mmol/L), diagnosis of type 2 diabetes, or treatment for diabetes. 

Blood pressure ³130/85 mmHg or use of antihypertensive medication. 

Fasting plasma triglycerides (TG) ³1.70 mmol/L (³150 mg/dL) or use of lipid-lowering therapy.

Plasma HDL-cholesterol ≤1.0 mmol/L (≤40 mg/dL) in men or ≤1.3 mmol/L (≤50 mg/dL) in women, or use of lipid lowering therapy.

Table 3. Mediterranean Diet Pattern and Clinical Impact in Patients with MASLD

Component of Mediterranean Diet PatternMechanism of ActionClinical Impact in Patients with MASLD
Monounsaturated Fatty Acids (e.g., olive oil)improve lipid profiles enhance insulin sensitivity reduce hepatic fat accumulation⎠ intrahepatic triglycerides ⎠ insulin resistance
Dietary Fiber
(e.g., fruits, vegetables, legumes, whole grains)		slows glucose absorption supports gut microbiota reduces inflammation↑ insulin sensitivity ⎠ systemic and hepatic inflammation
Polyphenols
(e.g., fruits, red wine, nuts)		antioxidant and anti-inflammatory properties⎠ oxidative stress ⎠ liver injury
High-Quality Protein
(e.g., fish, moderate dairy)		provides essential amino acids reduces intake of saturated fat⎠ hepatic fat accumulation    supports lean body mass
Low Red/Processed Meat
and Sugar Intake		reduces caloric excess and saturated fat/sugar burden⎠ obesity ⎠ insulin resistance ⎠ hepatic inflammation
Overall Dietary Patternencourages satiety, nutrient density, and sustainable metabolic balance⎠ risk of steatohepatitis and fibrosis
   progression

Risk Factors 

Metabolic Risk Factors

A primary risk factor for the development of MASLD is excess adiposity—particularly obesity and overweight status. The principal underlying driver is dysfunctional visceral adipose tissue, which contributes to insulin resistance and chronic metabolic inflammation. The global burden of MASLD has increased in tandem with rising rates of type 2 diabetes mellitus (DM) and obesity.10 Shi et al., in a comprehensive meta-analysis of 151 studies originally conducted under NAFLD criteria, including over 101,000 patients who underwent liver biopsy, reported prevalence estimates of 69.9% among individuals with overweight and 75.3% among those with obesity.11 Although these studies used NAFLD criteria, they provide relevant insight into populations at high risk for MASLD. 

Beyond obesity, MASLD is strongly associated with insulin resistance, dyslipidemia, and DM.8 MASLD has been observed across multiple forms of DM, including type 2, type 1, ketone-prone diabetes, and maturity-onset diabetes of the young (MODY). Prevalence for NAFLD in type 2 DM, reported in earlier studies, ranges from 55% to 76%, while type 1 DM shows a slower but notable prevalence, generally 4%–20%, with most studies reporting rates near 20%.12

Dyslipidemia prevalence in this population ranges widely from 20% to 80%, depending on the study population and diagnostic criteria.13 Patients with hypertriglyceridemia have a significantly higher likelihood of developing NAFLD compared to those with normal TG levels.14 In a large population-based study, elevated BMI and high TG levels were both identified as independent risk factors for NAFLD incidence. Among individuals with a BMI >24, elevated TG levels alone accounted for approximately 25% of NAFLD cases.15

Lifestyle Risk Factors

Lifestyle risk factors for MASLD include poor diet quality and inadequate amounts of physical activity, which play an important factor in achieving sustainable weight loss, which is linked to significant improvements in insulin resistance and metabolic parameters associated with steatotic liver disease. In earlier NAFLD studies, patients were shown to have a higher intake of saturated fat, cholesterol, and a lower intake of PUFAs and fiber. The dietary habits seen here have the potential to directly influence hepatic steatosis.16 In earlier NAFLD studies, patients were found to consume higher amounts of fructose-containing products compared to healthy controls. High fructose intake may also contribute to MASLD development by promoting hepatic lipogenesis, decreasing insulin sensitivity, and increasing the severity of liver fibrosis.17

Emerging evidence highlights the significant role of dietary patterns, particularly the widespread consumption of ultra-processed foods (UPFs)—in the development and progression of MASLD. UPFs are industrially manufactured food products typically high in added sugars, saturated fats, sodium, and various additives, while lacking essential nutrients and dietary fiber. Their consumption has been closely linked to obesity, insulin resistance, and hepatic inflammation—key drivers in the pathogenesis of MASLD.18 

Recent studies have shown that the high intake of UPFs during childhood and adolescence is associated with an increased risk of MASLD and related metabolic disturbances. Similarly, adult and elderly populations consuming diets rich in UPFs are at elevated risk for hepatic steatosis and its long-term complications.18 These findings underscore the importance of nutritional quality across the lifespan.

Table 4. Solutions for Socioeconomic Barriers to Implementing the Mediterranean Diet Pattern

Socioeconomic BarrierProposed Solution
Limited access to fresh produceEncourage use of frozen or canned vegetables (low-sodium) Promote participation in local food banks or produce voucher programs
High cost of fish and seafoodSuggest affordable alternatives such as canned tuna/salmon (in water) Recommend plant-based omega-3 sources (e.g., flaxseed, chia)
Cost of olive oil and nutsPromote moderation in use to stretch supply Recommend alternative healthy fats (e.g., canola oil) when necessary
Lack of culturally relevant
food options		Adapt Mediterranean diet principles using culturally familiar foods
(e.g., beans, whole grains, seasonal vegetables)
Limited nutrition knowledgeProvide basic education through handouts and/or group classes
Partner with registered dietitians and/or community health educators
Lack of cooking facilities
or time		Suggest minimal-prep meals (e.g., salads, grain bowls) Provide microwave-friendly recipes
Food deserts or limited
grocery access		Connect patients with mobile markets, farmers’ markets Home delivery services where available
Risk of caloric excess from
energy-dense Mediterranean foods		Educate on portion control, especially with olive oil and nuts Offer practical visual cues and meal planning tools

Garcia et al. reported that reducing UPF intake can lead to improvements in clinical and biochemical parameters associated with MASLD.19 In particular, dietary modifications such as decreased consumption of red meat, sweets, and pastries, along with greater adherence to the Mediterranean diet, have been effective in reducing UPF intake.19 UPFs are energy-dense and nutrient-poor, which promotes excess caloric intake while impairing metabolic regulation and promoting systemic inflammation and oxidative stress—factors that further contribute to MASLD pathophysiology.19

Mediterranean Diet 

The MedDiet comprises the food patterns of individuals residing alongside the Mediterranean Sea. The diet is mostly plant-based foods of fruits, vegetables, whole grains, legumes, nuts, pulses, fish, seafood, and extra virgin olive oil that are included daily, at the majority of meals.20 Due to abundance in plant-based foods, the diet is rich in fiber and phytonutrients, which both serve as anti-inflammatory nutrients. The diet is also rich in MUFAs through its frequent inclusion of fish, nuts, seeds, and olive oil. Fish is the main source of animal protein in the diet, whereas consumption of other sources of animal protein, including meat, poultry, and dairy is not daily.20 Olive oil is included at each meal as a source of polyphenols and monounsaturated fats. The diet also includes guidelines for how often foods are to be consumed daily or weekly. See Table 2.

An expanding body of evidence supports the therapeutic potential of the MedDiet in managing MASLD. This dietary pattern favorably modulates key metabolic and inflammatory pathways.20 Collectively, these components reduce intrahepatic triglyceride accumulation, enhance insulin sensitivity, regulate gene expression related to adipogenesis and adipocyte proliferation, and attenuate pro-inflammatory responses associated with visceral adiposity.20

Multiple independent studies have demonstrated that adherence to the MedDiet is associated with significant reductions in hepatic steatosis among patients with MASLD. One of the pioneer investigations reported reductions in intrahepatic fat content along with a decreased incidence of progression to steatohepatitis.21 A six-month earlier NAFLD study by Marin-Alejandre et al. involving 98 patients highlighted the central role of MUFAs—abundant in the MedDiet—in improving lipid profiles, carbohydrate metabolism, and insulin resistance.22 These changes were associated with improved blood pressure and decreased hepatic fat content, collectively contributing to a more favorable clinical course.22 See Table 3.

Table 5. Practical Guidelines: Promoting the Mediterranean Diet Pattern for Patients with MASLD

StepClinical Action
1.
Assess Readiness and Personalize		Use open-ended questions to explore current eating habits Identify barriers (cost, time, cultural factors) Emphasize clinical benefits
2. Teach Core MedDiet PrinciplesEncourage substitutions:  Use olive oil instead of butter Choose fish/legumes for protein over red meats Snack on whole fruit and nuts Favor whole grains versus refined grains
(e.g., whole wheat versus refined wheat)
3.
Recommend Gradual Implementation		Start with 1 MedDiet-style meal per day Encourage cooking with olive oil and seasonal produce Share simple, culturally relevant recipes
4. Reinforce at Follow-UpMonitor liver enzymes, weight, and diet adherence Celebrate small wins Use motivational interviewing to maintain momentum
5. Utilize ResourcesRecommend apps, cookbooks, or community programs Involve family for support Share visuals or handouts to reinforce learning
6. Refer When AppropriateDietitian referral for patients with comorbidities
or complex dietary needs Tailor support to individual and cultural contexts
7.
Key Messages for Patient Counseling
“This isn’t a restrictive diet. It’s a sustainable and flavorful eating pattern.” “Even small steps can help improve your liver and heart health.” “Focus on consistency, not perfection. Build healthy habits gradually.”

Further research including intervention studies among Western, non-Mediterranean populations have confirmed these benefits.23 Clinical trials lasting between 6 to 24 weeks have consistently demonstrated reductions in intrahepatic fat and improvements in insulin sensitivity and cardiovascular risk markers among individuals with MASLD.23 In a 6-week randomized crossover NAFLD trial in Australia, Ryan et al. observed a 39% reduction in intrahepatic lipid content in patients
following the MedDiet, compared to only 7% with a low-fat diet.24

Participants in the MedDiet group also showed insulin sensitivity and lower circulating insulin levels, as well as greater reductions in systolic blood pressure and serum triglycerides.24 Similarly, a 12-week isocaloric trial involving 48 adults with hepatic steatosis found comparable reductions in intrahepatic fat content with both the MedDiet (25%) and a low-fat diet (32%).25 These findings suggest that dietary quality—regardless of macronutrient composition—plays a crucial role in overall management of hepatic steatosis.25 

Similar outcomes are seen in Eastern populations. A retrospective study by Lee et al. examined MedDiet adherence in a Korean population and found that individuals with high adherence had significantly lower rates of MASLD.26 This group also exhibited reduced triglyceride levels and lower triglyceride-glucose indices, reinforcing the diet’s potential to prevent MASLD and its complications.26 Overall, these studies underscore the clinical benefits of the MedDiet and those with MASLD should attempt to transition to this dietary pattern. 

Practical Applications

While the MedDiet has demonstrated clear benefits in managing MASLD, one of the key challenges in its implementation is the adaptability of the dietary pattern to individual patient needs. Socioeconomic barriers—such as limited access to fresh produce, fish, and other core components—can pose significant obstacles to adherence, particularly in underserved populations. To address these barriers, clinicians can emphasize cost-effective and culturally relevant alternatives—such as canned or frozen vegetables and legumes, affordable sources of healthy fats like canola oil, and community-based resources like food pantries or subsidized farmers markets. Additionally, incorporating nutrition education and connecting patients with registered dietitians and/or community health educators can empower individuals to make sustainable dietary choices within their means. See Table 4.

Moreover, while the MedDiet is often perceived as inherently healthy, it is not immune to caloric excess.20 Patients with hepatic steatosis should consider portion control, as the liberal use of energy-dense foods such as olive oil and nuts can inadvertently lead to a hypercaloric diet. Individualized nutritional counseling should emphasize both the quality and quantity of food intake, balancing the beneficial components of the MedDiet with appropriate caloric targets to support weight management and reduce hepatic fat accumulation.20 See Table 5. 

References

1. Rinella ME, Neuschwander-Tetri BA, Siddiqui MS, et
al. AASLD Practice Guidance on the clinical assessment
and management of nonalcoholic fatty liver disease.
Hepatology. 2023;77(5):1797-1835.
2. Rinella ME, Lazarus JV, Ratziu V, et al. A multisociety
Delphi consensus statement on new fatty liver disease
nomenclature. Ann Hepatol. 2024;29(1):101133.
3. Perumpail BJ, Cholankeril R, Yoo ER, Kim D, Ahmed A.
An Overview of Dietary Interventions and Strategies to
Optimize the Management of Non-Alcoholic Fatty Liver
Disease. Diseases. 2017;5(4):23.
4. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry
L, Wymer M. Global epidemiology of nonalcoholic fatty
liver disease-Meta-analytic assessment of prevalence,
incidence, and outcomes. Hepatology. 2016;64(1):73-84.
5. Younossi ZM, Kalligeros M, Henry L. Epidemiology
of metabolic dysfunction-associated steatotic liver disease.
Clin Mol Hepatol. 2025;31(Suppl):S32-S50.
6. European Association for the Study of the Liver (EASL);
European Association for the Study of Diabetes (EASD);
European Association for the Study of Obesity (EASO).
EASL-EASD-EASO Clinical Practice Guidelines on the
management of metabolic dysfunction-associated steatotic
liver disease (MASLD). J Hepatol. 2024;81(3):492-
542.
7. Kanwal F, Neuschwander-Tetri BA, Loomba R, Rinella
ME. Metabolic dysfunction-associated steatotic liver
disease: Update and impact of new nomenclature on the
American Association for the Study of Liver Diseases
practice guidance on nonalcoholic fatty liver disease.
Hepatology. 2024;79(5):1212-1219.
8. Ganakumar V, Halebidu T, Goroshi M, Ghatnatti V.
Diagnosis and management of MASLD: a metabolic
perspective of a multisystem disease. Int J Clin Metab
Diabetes. 2025;1(1):45-57.
9. Al-Dayyat HM, Rayyan YM, Tayyem RF. Non-alcoholic
fatty liver disease and associated dietary and lifestyle risk
factors. Diabetes Metab Syndr. 2018;12(4):569-575.
10. Habib S. Metabolic dysfunction-associated steatotic
liver disease heterogeneity: Need of subtyping. World J
Gastrointest Pathophysiol. 2024;15(2):92791.
11. Shi Y, Wang Q, Sun Y, et al. The Prevalence of Lean/
Nonobese Nonalcoholic Fatty Liver Disease: A Systematic
Review and Meta-Analysis. J Clin Gastroenterol.
2020;54(4):378-387.
12. Rojano-Toimil A, Rivera-Esteban J, Manzano-Nuñez
R, et al. When Sugar Reaches the Liver: Phenotypes
of Patients with Diabetes and NAFLD. J Clin Med.
2022;11(12):3286.
13. Pirillo A, Casula M, Olmastroni E, Norata GD, Catapano
AL. Global epidemiology of dyslipidaemias. Nat Rev
Cardiol. 2021;18(10):689-700.
14. Tomizawa M, Kawanabe Y, Shinozaki F, et al. Triglyceride
is strongly associated with nonalcoholic fatty liver disease
among markers of hyperlipidemia and diabetes. Biomed
Rep. 2014;2(5):633-636.
15. Xing J, Guan X, Zhang Q, Chen S, Wu S, Sun X.
Triglycerides Mediate Body Mass Index and Nonalcoholic
Fatty Liver Disease: A Population-Based Study. Obes
Facts. 2021;14(2):190-196.
16. Musso G, Gambino R, De Michieli F, et al. Dietary habits
and their relations to insulin resistance and postprandial
lipemia in nonalcoholic steatohepatitis. Hepatology.
2003;37(4):909-916.
17. Alwahsh SM, Gebhardt R. Dietary fructose as a risk factor
for non-alcoholic fatty liver disease (NAFLD). Arch
Toxicol. 2017;91(4):1545-1563.
18. Calcaterra V, Cena H, Rossi V, Santero S, Bianchi A,
Zuccotti G. Ultra-Processed Food, Reward System and
Childhood Obesity. Children (Basel). 2023;10(5):804.
19. García S, Monserrat-Mesquida M, Ugarriza L,
et al. Ultra-Processed Food Consumption and
Metabolic-Dysfunction-Associated Steatotic Liver
Disease (MASLD): A Longitudinal and Sustainable
Analysis. Nutrients. 2025;17(3):472.
20. Cordain L, Eaton SB, Sebastian A, et al. Origins and evolution
of the Western diet: health implications for the 21st
century. Am J Clin Nutr. 2005;81(2):341-354.
21. Rajewski P, Cieściński J, Rajewski P, Suwała S, Rajewska
A, Potasz M. Dietary Interventions and Physical Activity
as Crucial Factors in the Prevention and Treatment
of Metabolic Dysfunction-Associated Steatotic Liver
Disease. Biomedicines. 2025;13(1):217.
22. Marin-Alejandre BA, Abete I, Cantero I, et al. The
Metabolic and Hepatic Impact of Two Personalized
Dietary Strategies in Subjects with Obesity and
Nonalcoholic Fatty Liver Disease: The Fatty Liver in
Obesity (FLiO) Randomized Controlled Trial. Nutrients.
2019;11(10):2543.
23. Sualeheen A, Tan SY, Georgousopoulou E, et al.
Mediterranean diet for the management of metabolic
dysfunction-associated steatotic liver disease in non-
Mediterranean, Western countries: What’s known and
what’s needed? Nutr Bull. 2024;49(4):444-462.
24. Ryan MC, Itsiopoulos C, Thodis T, et al. The
Mediterranean diet improves hepatic steatosis and insulin
sensitivity in individuals with non-alcoholic fatty liver
disease. J Hepatol. 2013;59(1):138-143.
25. Properzi C, O’Sullivan TA, Sherriff JL, et al. Ad Libitum
Mediterranean and Low-Fat Diets Both Significantly
Reduce Hepatic Steatosis: A Randomized Controlled
Trial. Hepatology. 2018;68(5):1741-1754.
26. Lee JY, Kim S, Lee Y, Kwon YJ, Lee JW. Higher
Adherence to the Mediterranean Diet Is Associated with a
Lower Risk of Steatotic, Alcohol-Related, and Metabolic
Dysfunction-Associated Steatotic Liver Disease: A
Retrospective Analysis. Nutrients. 2024;16(20):3551.

Download Tables, Images & References

Special Article

Factors Predicting Patient Follow-Up in Clinic After Anorectal Manometry for Defecatory Disorders in a Community Hospital

October 2025 • Volume XLIX, Issue 10
Misha Gautam,Utkarsh Goel,Abbas Bader,Vinay Jahagirdar,Esmat Sadeddin,Hassan Ghoz

Read Article

Anorectal manometry (ARM) diagnoses anorectal sensorimotor disorders, and biofeedback therapy (BT) is an evidence-based treatment. We conducted a retrospective study at a community hospital to assess factors predicting patient follow-up and symptoms improvement after ARM. Analyzing 96 patients, we found those recommended both pharmacological treatments and Kegel exercises alongside biofeedback therapy (BT) showed better follow-up compared to BT alone (58.8% vs. 9.7%, p<0.01). A history of sexual abuse (14 vs. 25 weeks, p=0.04), co-existing urinary issues (27.8% vs. 56.6%, p=0.03) and anal hypo-contractility (23% vs. 55%, p=0.03), were significant predictors of longer follow-up duration and lesser symptom improvement respectively. Our study highlights that a multi-faceted approach to treatment ensures higher follow-up rates among patients undergoing ARM for anorectal disorders. Additionally, recognizing and accommodating patient-specific factors that influence outcomes is crucial for providing tailored multidisciplinary support and more intensive therapy. This study aims to explore the factors influencing patient follow-up rates and the timing of follow-up visits in a gastroenterology clinic after first ARM at a safety net hospital. Thereby, addressing a critical gap in literature affecting the effective management of these disorders. 

Download Tables, Images & References

Liver Disorders, SERIES #19

Beyond Jaundice Part 1: Identifying and Describing Cutaneous Manifestations of Hepatitis and Cirrhosis

October 2025 • Volume XLIX, Issue 10
Olivia Babich,Alexandra Savage,Tavankit Singh

Read Article

Dermatologic findings are common in liver disease, and may represent the very earliest or most prominent signs of an underlying disorder. While most practitioners recognize jaundice as a sign of hepatobiliary disease, there are numerous cutaneous signs which can point to concomitant liver dysfunction. Additional signs of liver disease may include findings like disseminated superficial actinic porokeratosis or Terry’s nails in cirrhosis, or porphyria cutanea tarda in hepatitis C. It is important for general practitioners and dermatologists alike to be able to recognize and describe such lesions, as identification of cutaneous manifestations of liver disease can lead to earlier diagnosis and treatment initiation for patients. In this article, we present the spectrum of typical associated cutaneous findings of hepatitis B, hepatitis C, and cirrhosis.

Introduction

Chronic liver disease is a preeminent cause of morbidity and mortality worldwide, accounting for nearly two million deaths annually.1 In the United States, 4.5 million adults aged eighteen or older have been diagnosed with liver disease, and the most recent CDC summary data lists chronic liver disease and cirrhosis as the 10th leading cause of death nationally.2,3 Total expenditures related to chronic liver disease exceeded $32.5 billion in 2016 and continue to rise, driven primarily by acute care spending.4 Extrahepatic manifestations of liver disease are numerous, and include effects on the gastrointestinal, nervous, endocrine, musculoskeletal, cardiovascular, and hematological systems as a result of the liver’s diverse functionality.5 However, the very earliest and most prominent presenting signs of underlying liver dysfunction often lie in the skin.6  Dermatologic manifestations of liver disease are common and may be readily identified in a non-invasive manner via the physical examination. In this review, we present the spectrum of specific and non-specific cutaneous findings in hepatitis B, hepatitis C, and cirrhosis. We discuss lesion description including pattern and morphology [Figure 1], lesion etiopathogenesis and significance, and briefly describe relevant steps for management of dermatologic lesions. 

Cirrhosis

Spider Angiomata

Spider angiomas are superficial groups of dilated blood vessels, blanchable with pressure, most often appearing on the face or upper trunk. A spider angioma can be described as a central red papule (arteriole) with fine, tortuous vessels extending radially outward in a stellate pattern [Figure 2]. These lesions are considered to occur in elevated estrogen states, such as cirrhosis, though recent studies have also examined the role of serum vascular growth factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF).7 Li et al. demonstrated that increased plasma levels of VEGF and bFGF were the most significant predictors for the presence of spider angiomas in a sample of 86 cirrhotic patients, indicating that neovascularization may play a key role in their pathogenesis.8 Multiple spider angiomas are characteristic of chronic liver disease with a specificity of 95% and, in patients with alcohol-associated liver disease, act as a predictor of increased risk for both esophageal varices and hepatopulmonary syndrome.6,9 Spider angiomas require no treatment, however fine-needle electrocautery, 585nm pulsed dye laser, 532nm KTP (potassium-titanyl-phosphate) laser, or electro-desiccation can be used to remove spider angiomata for cosmetic purposes. 

Paper money skin

Paper money skin, or “dollar paper markings”, is a common yet often overlooked finding in patients with cirrhosis. These lesions appear as diffusely scattered, threadlike, superficial capillaries which can look similar to spider angiomas and involve a similar pathogenetic process [Figure 3]. In contrast to spider angiomas, paper money skin lesions are described as short, randomly scattered telangiectatic vessels which occasionally coalesce into irregular annular patches.10 The finding of paper money skin is most often observed in cases of cirrhosis related to chronic alcohol use, with lesions typically appearing first on the upper trunk. No treatment is required for paper money skin, however case reports have noted a disappearance of these lesions in patients undergoing hemodialysis.11

Palmar Erythema

Of all patients with cirrhosis, approximately 23% will develop palmar erythema. Palmar erythema presents as a symmetrical, blanchable redness of the palms and fingertips, which may localize to the thenar and/or hypothenar eminence [Figure 4]. The degree of erythema is often related to the severity of the underlying condition, such that increasing redness indicates worsening disease. While the precise pathogenesis of this finding remains unknown, patients with cirrhosis likely develop palmar erythema secondary to local vasodilation from hyperestrogenemia. In addition, plasma prostacyclins and nitric oxide have also been posited to play a role.12,13 No treatment is indicated for palmar erythema, and management of underlying cirrhosis may or may not lead to improvement.

Disseminated superficial actinic porokeratosis

Disseminated superficial actinic porokeratosis (DSAP) is a keratinization disorder that causes discrete dry patches to form in clusters on sun-exposed areas of the lower arms and legs. Lesions are pink-brown annular or polycyclic macules and plaques with raised keratotic borders [Figure 5]. Patients with cirrhosis related to alcohol use are more prone to developing DSAP than the general population. DSAP has numerous documented triggers including sun exposure, phototherapy, and infection, though immunosuppression is widely considered a primary cause of onset.14 Given that cirrhosis is associated with several abnormalities of innate and adaptive immunity, it logically follows that porokeratosis could be triggered by immunosuppression due to liver cirrhosis. With regards to management, it is important to note that, while uncommon, squamous cell carcinoma can develop within DSAP lesions. For this reason, patients with DSAP should be referred to a dermatologist for examination and counseled regarding proper sun protection. Treatment for DSAP is varied and includes options such as topical 5-fluorouracil, cryotherapy, moisturizers to reduce dryness and irritation and, most promisingly, topical 2% lovastatin with or without topical cholesterol.15 

Caput medusae

Severe portal hypertension as a result of cirrhosis leads to portosystemic collateral formation in the form of esophageal, gastric, rectal, and abdominal varices.16 Paraumbilical abdominal wall varices are termed “caput medusae” or “head of Medusa”, referencing their likeness to the mythological Greek gorgon with snakes for hair. These collaterals form as a result of backflow from the left portal vein, through the paraumbilical veins, to the periumbilical systemic veins within the abdominal wall. Caput medusae are often described as blue-purple engorged, knotted, tortuous veins which radiate from the umbilicus across the anterior abdomen [Figure 6]. While typically asymptomatic, bleeding from caput medusae has been described in rare instances.10 In these situations, local wound care with suture hemostasis or use of pressure dressings can temporarily control bleeding, however, variceal hemorrhage will rapidly recur without relief of the underlying portal hypertension.17

Bier spots

Bier spots are another vascular phenomenon which can arise in association with liver disease, occurring secondary to venous stasis from damage to small blood vessels. These small lesions appear on the extremities as irregular, hypopigmented macules typically with a small surrounding halo of erythema [Figure 7]. Bier spots can be differentiated from true pigmentation disorders in that these spots are transient lesions which disappear with pressure or elevation of the affected limb. Bier spots are benign, asymptomatic, and self-limiting.18 

Terry’s nails

Terry’s nails were first described in 1954 by Dr. Richard Terry when he observed “white nails” in 82 of 100 consecutive patients with cirrhosis.19 This classic finding can be described as a diffuse ground glass opacity of the nail plate— powdery white at the proximal end with a thin 0.5-3.0mm band of reddening distally [Figure 8]. A recent prospective, cross-sectional observational study by Nelson et al. found Terry’s nails to be ten times more common among inpatients than outpatients, suggesting a positive correlation with disease severity. They also found the sign to be highly specific— up to 98%— for cirrhosis among outpatients, which is important to note for any physicians regularly seeing patients in the office setting.20 There is no specific treatment for Terry’s nails.

Hepatitis B 

Serum sickness-like reaction

A serum sickness-like reaction (SSLR) occurs in 10-20% of patients with acute hepatitis B (HBV) in the preicteric phase, making it the most common associated cutaneous manifestation. Symptoms of SSLR can include fever, malaise, synovitis and edema of joints, and dermatologic findings such as urticaria and maculopapular rash [Figure 9]. Urticarial lesions are intensely pruritic, well-circumscribed, raised, skin-colored wheals with or without surrounding erythema that may involve concurrent angioedema. Deposition of immune complexes is pathogenic in HBV, with histopathology revealing small vessel vasculitis with direct immunofluorescence positive for hepatitis B surface antigen (HBsAg), IgG, IgM, and C3.21 While SSLR has been associated with acute HBV infection, it has also been noted in rare cases following hepatitis B immunization.22,23 For mild to moderate rash and pruritis, symptomatic relief can be achieved with NSAIDs and/or antihistamines. For more severe symptoms, a 7 to 10-day course of systemic glucocorticoids can be helpful.24

Polyarteritis nodosa

It is estimated that 20% of patients with polyarteritis nodosa (PAN) are infected with hepatitis B, and approximately 7% of patients with acute hepatitis B infection go on to develop PAN. Cutaneous polyarteritis nodosa involves inflammation of small and medium-sized blood vessels, likely related to deposition of antigen-antibody complexes including hepatitis Be antigen (HBeAg) within vessel walls. Notably, HBV-associated PAN is not typically associated with anti-neutrophil cytoplasmic antibodies (ANCA), unlike other small vessel vasculidities.25 Lesions are most common on pressure points such as the lower legs, back of the foot, and knees. Lesions begin as small, tender nodules with overlying erythema and may progress to larger, ulcerating inflammatory plaques. PAN can also be associated with palpable purpura from small vessel vasculitis or ecchymoses and blood-filled vesicles due to cutaneous infarction [Figure 10]. Treatment for cutaneous PAN includes short-term oral corticosteroid therapy followed by antivirals and plasmapheresis.26

Papular acrodermatitis of childhood
(Gianotti-Crosti syndrome)

Gianotti-Crosti syndrome was first described in 1955 as a manifestation of acute HBV infection, occurring primarily in children up to 12 years of age and rarely in adults. Gianotti-Crosti syndrome is characterized by a symmetric, monomorphic rash consisting of flat-topped, pink-red papules which erupt over the thighs and buttocks and gradually spread to extensor surfaces of the arms and, eventually, the face [Figure 11].27 Patients may also develop vesicular lesions which eventually fade in 2-8 weeks with mild scaling. Post-inflammatory hyper/hypopigmentation may occur in darker skin types and persist for up to 6 months. While the rash is benign and self-limiting, a mild topical steroid, emollient, or oral antihistamine may be used for symptomatic relief of itching.28,29

Table 1.  Cirrhosis, Hepatitis, and Associated Dermatologic Manifestations

Liver DiseaseAssociated Dermatologic Findings
CirrhosisSpider angiomata Palmar erythema Paper money skin Disseminated Superficial Actinic Porokeratosis Caput medusae Bier spots Terry’s nails
Hepatitis BSerum sickness-like reaction Polyarteritis nodosa Papular acrodermatitis of childhood (Gianotti-Crosti syndrome)
Hepatitis CPorphyria cutanea tarda Lichen planus Mixed cryoglobulinemia Necrolytic acral erythema

Hepatitis C 

Porphyria cutanea tarda

Porphyria cutanea tarda (PCT) is caused by a deficiency of the hepatic enzyme uroporphyrin decarboxylase. As a consequence of this deficiency, excess heme precursors deposit in the skin resulting in cutaneous manifestations from acquired photosensitivity. Visible light activates precursors deposited in the skin, initiating a photochemical reaction which ultimately leads to characteristic skin blistering. Lesions are found on sun-exposed areas such as the face, scalp, and dorsal forearms and hands, and may appear vesicular, scleroderma-like, or manifest as crusted erosions following minor injuries [Figure 12]. Melasma-like hyperpigmentation and hypertrichosis may also be observed in the head and neck area. The sporadic form of PCT is significantly associated with hepatitis C virus (HCV) infection as well as chronic alcohol use.23 Management may include sun protection with titanium dioxide or zinc oxide-containing sunscreens, tanning cream containing dihydroxyacetone, and/or protective clothing. Areas of broken skin should be kept clean and any infection addressed promptly. Severe cases of PCT may be treated with iron removal via phlebotomy or antimalarial therapy such as hydroxycholorquine.30

Lichen planus 

Lichen planus is a chronic mucocutaneous inflammatory disease, most likely involving an immune-mediated reaction. Cutaneous lichen planus lesions can be described using the “Six Ps”: purple, polygonal, planar, pruritic papules and plaques. Lesions are most common around the flexor wrist and ankles, with hallmark signs being intense pruritis and Wickham’s striae: fine white reticulated lines overlying papules or plaques [Figure 13].31 Lichen planus can also affect the oral cavity, with possible involvement of the buccal mucosa, tongue, gums, and lips. Oral lichen planus may display either a white reticular, erosive, or plaque-like pattern. Treatment of lichen planus is primarily symptomatic and may not be required for mild disease. Options include topicals such as potent corticosteroids, tacrolimus ointment, and pimecrolimus cream. Notably, HCV patients with oral lichen planus may be at increased risk of developing squamous cell carcinoma (SCC). The current literature indicates a greater risk of malignant transformation in HCV patients with oral lichen planus than in those without HCV infection.32,33 Patients should be referred to dermatology for further management and symptom monitoring.34

Mixed cryoglobulinemia

Mixed cryoglobulinemia is the most commonly reported extrahepatic manifestation of HCV infection, with studies noting an incidence of HCV in 40-90% of patients with mixed cryoglobulinemia. In HCV patients, cryoglobulins may represent the product of virus-host interactions, as circulating virus acts as a continuous immune stimulus.35 Cutaneous manifestations of mixed cryoglobulinemia are diverse and can include palpable purpura of the lower extremities, Raynaud’s phenomenon (white coloration and numbness of the fingers upon exposure to cold), secondary acrocyanosis (asymmetric, persistent, blue discoloration of fingers or toes), and livedo reticularis (reticular cyanotic pattern with mottling, typically of the lower extremities) [Figure 14]. First-line therapy for HCV-associated cryoglobulinemia is direct-acting antivirals to treat HCV. Rituximab has also been reported to be effective. Finally, patients should be advised to avoid cold environments to prevent triggering precipitation of additional cryoglobulins.36–38

Necrolytic acral erythema

Necrolytic acral erythema (NAE) is a specific cutaneous feature of HCV infection. Notably, all instances of NAE have been documented in Asian or African patients. The etiopathogenesis of NAE appears to be multifactorial and may involve genetic factors and zinc deficiency as well as hypoalbuminemia and hypoglucagonemia as a result of chronic liver dysfunction. NAE presents as a symmetrical acral rash, typically on the dorsal feet, with well-circumscribed dusky discoloration and flaccid blistering which may progress to thick hyperpigmented plaques with adherent scale [Figure 15].39 Oral zinc supplementation and interferon-based regimens can aid in resolution of lesions. Topical treatments do not appear to be efficacious.40

Conclusion

Cirrhosis and hepatitis are associated with a number of extrahepatic manifestations, with dermatologic findings often being the earliest or most readily-identifiable. While most cutaneous findings are not necessarily specific for one condition, constellations of skin lesions with other symptoms can provide important clues to underlying disease processes. For this reason, it is important for general practitioners and dermatologists alike to be able to recognize and describe such lesions. Identification of typical cutaneous lesions in liver disease can lead to earlier diagnosis, reduction of unnecessary spending, and prompt treatment initiation. 

References

1. Asrani SK, Devarbhavi H, Eaton J, Kamath PS. Burden of liver diseases in the world. J Hepatol. 2019;70(1):151-171. doi:10.1016/j.jhep.2018.09.014

2. Kochanek KD. Mortality in the United States, 2022. 2024;(492).

3. Mattiuzzi C, Lippi G. Leading Causes of US Deaths in the 2022. J Clin Med. 2024;13(23):7088. doi:10.3390/jcm13237088

4. Ma C, Qian AS, Nguyen NH, et al. Trends in the Economic Burden of Chronic Liver Diseases and Cirrhosis in the United States: 1996–2016. Am J Gastroenterol. 2021;116(10):2060-2067. doi:10.14309/ajg.0000000000001292

5. Nath P, Anand AC. Extrahepatic Manifestations in Alcoholic Liver Disease. Journal of Clinical and Experimental Hepatology. 2022;12(5):1371-1383. doi:10.1016/j.jceh.2022.02.004

6. Bhandari A, Mahajan R. Skin Changes in Cirrhosis. Journal of Clinical and Experimental Hepatology. 2022;12(4):1215-1224. doi:10.1016/j.jceh.2021.12.013

7. Li CP, Lee FY, Hwang SJ, et al. Spider angiomas in patients with liver cirrhosis: role of alcoholism and impaired liver function. Scand J Gastroenterol. 1999;34(5):520-523. doi:10.1080/003655299750026272

8. Li CP, Lee FY, Hwang SJ, et al. Spider angiomas in patients with liver cirrhosis: role of vascular endothelial growth factor and basic fibroblast growth factor. World J Gastroenterol. 2003;9(12):2832-2835. doi:10.3748/wjg.v9.i12.2832

9. Silvério A de O, Guimarães DC, Elias LFQ, Milanez EO, Naves S. Are the spider angiomas skin markers of hepatopulmonary syndrome? Arq Gastroenterol. 2013;50(3):175-179. doi:10.1590/S0004-28032013000200031

10. Liu Y, Zhao Y, Gao X, et al. Recognizing skin conditions in patients with cirrhosis: a narrative review. Ann Med. 2022;54(1):3017-3029. doi:10.1080/07853890.2022.2138961

11. Satoh T, Yokozeki H, Nishioka K. Vascular spiders and paper money skin improved by hemodialysis. Dermatology. 2002;205(1):73-74. doi:10.1159/000063136

12. Serrao R, Zirwas M, English JC. Palmar erythema. Am J Clin Dermatol. 2007;8(6):347-356. doi:10.2165/00128071-200708060-00004

13. Matsumoto M, Ohki K, Nagai I, Oshibuchi T. Lung traction causes an increase in plasma prostacyclin concentration and decrease in mean arterial blood pressure. Anesth Analg. 1992;75(5):773-776. doi:10.1213/00000539-199211000-00021

14. Waqar MU, Cohen PR, Fratila S. Disseminated Superficial Actinic Porokeratosis (DSAP): A Case Report Highlighting the Clinical, Dermatoscopic, and Pathology Features of the Condition. Cureus. 2022;14(7):e26923. doi:10.7759/cureus.26923

15. Santa Lucia G, Snyder A, Lateef A, et al. Safety and Efficacy of Topical Lovastatin Plus Cholesterol Cream vs Topical Lovastatin Cream Alone for the Treatment of Disseminated Superficial Actinic Porokeratosis: A Randomized Clinical Trial. JAMA Dermatol. 2023;159(5):488. doi:10.1001/jamadermatol.2023.0205

16. Philips CA, Arora A, Shetty R, Kasana V. A Comprehensive Review of Portosystemic Collaterals in Cirrhosis: Historical Aspects, Anatomy, and Classifications. Int J Hepatol. 2016;2016:6170243. doi:10.1155/2016/6170243

17. Chen PT, Tzeng HL, Wang HP, Liu KL. Caput Medusae Bleeding. Am J Gastroenterol. 2020;115(10):1570-1570. doi:10.14309/ajg.0000000000000542

18. Peyrot I, Boulinguez S, Sparsa A, Le Meur Y, Bonnetblanc JM, Bedane C. Bier’s white spots associated with scleroderma renal crisis. Clin Exp Dermatol. 2007;32(2):165-167. doi:10.1111/j.1365-2230.2006.02298.x

19. Terry R. White nails in hepatic cirrhosis. Lancet. 1954;266(6815):757-759. doi:10.1016/s0140-6736(54)92717-8

20. Nelson N, Hayfron K, Diaz A, et al. Terry’s Nails: Clinical Correlations in Adult Outpatients. J Gen Intern Med. 2018;33(7):1018-1019. doi:10.1007/s11606-018-4441-7

21. Neumann HA, Berretty PJ, Folmer SC, Cormane RH. Hepatitis B surface antigen deposition in the blood vessel walls of urticarial lesions in acute hepatitis B. Br J Dermatol. 1981;104(4):383-388. doi:10.1111/j.1365-2133.1981.tb15307.x

22. Gupta R, Fakunle I, Samji V, Hale EB. Serum Sickness-Like Reaction Associated With Acute Hepatitis B in a Previously Vaccinated Adult Male. Cureus. 2021;13(4):e14742. doi:10.7759/cureus.14742

23. Cozzani E, Herzum A, Burlando M, Parodi A. Cutaneous manifestations of HAV, HBV, HCV. Ital J Dermatol Venereol. 2021;156(1). doi:10.23736/S2784-8671.19.06488-5

24. Clark BM, Kotti GH, Shah AD, Conger NG. Severe serum sickness reaction to oral and intramuscular penicillin. Pharmacotherapy. 2006;26(5):705-708. doi:10.1592/phco.26.5.705

25. Trepo C, Guillevin L. Polyarteritis nodosa and extrahepatic manifestations of HBV infection: the case against autoimmune intervention in pathogenesis. J Autoimmun. 2001;16(3):269-274. doi:10.1006/jaut.2000.0502

26. Guillevin L, Mahr A, Callard P, et al. Hepatitis B virus-associated polyarteritis nodosa: clinical characteristics, outcome, and impact of treatment in 115 patients. Medicine (Baltimore). 2005;84(5):313-322. doi:10.1097/01.md.0000180792.80212.5e

27. Dikici B, Uzun H, Konca C, Kocamaz H, Yel S. A case of Gianotti Crosti syndrome with HBV infection. Adv Med Sci. 2008;53(2):338-340. doi:10.2478/v10039-008-0013-0

28. Fergin P. Gianotti-Crosti syndrome. Non-parenterally acquired hepatitis B with a distinctive exanthem. Med J Aust. 1983;1(4):175-176. doi:10.5694/j.1326-5377.1983.tb104350.x

29. Lee S, Kim KY, Hahn CS, Lee MG, Cho CK. Gianotti-Crosti syndrome associated with hepatitis B surface antigen (subtype adr). Journal of the American Academy of Dermatology. 1985;12(4):629-633. doi:10.1016/S0190-9622(85)70085-0

30. To-Figueras J. Association between hepatitis C virus and porphyria cutanea tarda. Mol Genet Metab. 2019;128(3):282-287. doi:10.1016/j.ymgme.2019.05.003

31. Asaad T, Samdani AJ. Association of lichen planus with hepatitis C virus infection. Ann Saudi Med. 2005;25(3):243-246. doi:10.5144p/0256-4947.2005.243

32. Gandolfo S, Richiardi L, Carrozzo M, et al. Risk of oral squamous cell carcinoma in 402 patients with oral lichen planus: a follow-up study in an Italian population. Oral Oncol. 2004;40(1):77-83. doi:10.1016/s1368-8375(03)00139-8

33. Gheorghe C, Mihai L, Parlatescu I, Tovaru S. Association of oral lichen planus with chronic C hepatitis. Review of the data in literature. Maedica (Bucur). 2014;9(1):98-103.

34. Pelet Del Toro N, Strunk A, Garg A, Han G. Prevalence and treatment patterns of lichen planus. J Am Acad Dermatol. Published online November 22, 2024:S0190-9622(24)03236-5. doi:10.1016/j.jaad.2024.09.081

35. Lauletta G, Russi S, Conteduca V, Sansonno L. Hepatitis C virus infection and mixed cryoglobulinemia. Clin Dev Immunol. 2012;2012:502156. doi:10.1155/2012/502156

36. Lunel F, Musset L, Cacoub P, et al. Cryoglobulinemia in chronic liver diseases: role of hepatitis C virus and liver damage. Gastroenterology. 1994;106(5):1291-1300. doi:10.1016/0016-5085(94)90022-1

37. Schamberg NJ, Lake-Bakaar GV. Hepatitis C Virus-related Mixed Cryoglobulinemia: Pathogenesis, Clinica Manifestations, and New Therapies. Gastroenterol Hepatol (N Y). 2007;3(9):695-703.

38. Yokoyama K, Kino T, Nagata T, et al. Hepatitis C Virus-associated Cryoglobulinemic Livedo Reticularis Improved with Direct-acting Antivirals. Intern Med. 2023;62(24):3631-3636. doi:10.2169/internalmedicine.1671-23

39. Abdallah MA, Ghozzi MY, Monib HA, et al. Necrolytic acral erythema: a cutaneous sign of hepatitis C virus infection. J Am Acad Dermatol. 2005;53(2):247-251. doi:10.1016/j.jaad.2005.04.049

40. Khanna VJ, Shieh S, Benjamin J, et al. Necrolytic acral erythema associated with hepatitis C: effective treatment with interferon alfa and zinc. Arch Dermatol. 2000;136(6):755-757. doi:10.1001/archderm.136.6.755

Download Tables, Images & References

From the Pediatric Literature

Eosinophilic Esophagitis in Pediatric Patients Receiving Infliximab

October 2025 • Volume XLIX, Issue 10

Read Article

The treatment of pediatric inflammatory bowel disease (IBD) has improved markedly with the use of biologic therapy which includes such medications as infliximab. Although infliximab has been used for some time in the treatment of pediatric IBD, new potential side effects of this medication are sometimes noted. Eosinophilic esophagitis (EoE) is an immune reaction in which eosinophils infiltrate the esophagus and cause inflammation and potential fibrosis. Esophageal eosinophilia (EE), on the other hand, is present when eosinophils infiltrate the esophagus without associated inflammation. EE has an uncertain etiology but may lead to EoE.

The authors of this study retrospectively determined the number of EE cases in children with IBD after initiation of infliximab. Data for this study was collected over a 3-year period (2000-2003) from two tertiary hospitals which used the Partners Healthcare Research Practice Data Registry. Children with EE diagnosed before an IBD diagnosis, before use of infliximab, or after being switched from infliximab to another biologic therapy were excluded.

In total, 12 patients fit study criteria. All patients on infliximab had greater than 15 eosinophils per high power field in the setting of having normal esophageal biopsies prior to starting infliximab. One patient had ulcerative colitis, and the rest had Crohn’s disease. Inflammatory criteria were present in 82% of the patients with Crohn’s disease (B1 Montreal classification or non-stricturing, non-penetrating disease) with 27% of these patients having upper gastrointestinal tract IBD. Most patients were male, and all were white. The mean age at IBD diagnosis was 11.6 years, and the mean time from the diagnosis of IBD to starting infliximab was 4.9 years. The time duration from starting infliximab to being diagnosed with EE was 5.9 years. Atopy was present in 75% of patients with food allergies being the most common atopic diagnosis. Half of this patient group had a family history of IBD, and 75% of patients had a history of atopy. Most patients had a history of peripheral eosinophilia after starting infliximab and before / at the time of EE diagnosis. Five of these patients had dysphagia while another four patients had GERD or odynophagia symptoms. Three patients had no symptoms.  

The Index of Severity for Eosinophilic Esophagitis (I-SEE) of these patients ranged from 1 to 6, indicating no to mild symptoms. The Eosinophilic Esophagitis Endoscopic Reference Score (EREFS) of these patients ranged from 0 to 3 indicating that most patients had minimal endoscopic findings in association with EE / EoE. One patient with EE switched to vedolizumab during the study. Otherwise, therapies for EE in this patient group consisted of 3 patients undergoing observation alone, 6 patients starting proton pump inhibitor (PPI therapy), 1 patient starting PPI therapy with topical esophageal steroids, and 2 patients starting PPI therapy with topical esophageal steroids and food elimination. All patients who started the various therapies for EE had a clinical response.

This study provides potential evidence that EE may be a side effect in pediatric patients with IBD who use infliximab. There are some caveats to consider. The relatively small number of patients were recruited during a period in which first-line biologic therapy was not as prevalent as it is currently. Also, half of the patients had a family history of gastrointestinal inflammation (including IBD, celiac disease, and EoE) suggesting the importance of family history in this setting. Since children under the age of 6 years (early-onset IBD) appear to be one of the fastest growing groups of patients with IBD, more information is needed in this specific population to determine the potential risk for developing EE and subsequent EoE in the setting of IBD and infliximab use.

Wu M, Glickman J, Winter H.  Eosinophilic esophagitis associated with infliximab therapy in pediatric patients with inflammatory bowel disease.  Journal of Pediatric Gastroenterology and Nutrition 2025; 80:807-811.

Download Tables, Images & References

Frontiers in Endoscopy, Series #99

Post-Sphincterotomy Bleeding: Incidence, Risk Factors, and Management

October 2025 • Volume XLIX, Issue 10
Archit Garg,Douglas G. Adler

Read Article

Introduction

Endoscopic retrograde cholangiopancreaticography (ERCP) is a commonly used therapeutic procedure for diagnostic and therapeutic purposes for various pancreatic-biliary pathologies. Endoscopic sphincterotomy (ES) is a requirement for many biliary interventions. ES can serve as the initial step in the treatment of biliary pathologies, such as the extraction of stones or to allow cholangioscopy or some forms of biliary duct stenting. The outcomes after ES are dependent on the interplay between several factors, including pre-sphincterotomy ductal cannulation, the technique and instrumentation used for sphincterotomy, the post-sphincterotomy therapeutic intervention performed, and finally, the experience and expertise of the endoscopist.1

Approximately 4 to 5% of ES are associated with some degree of adverse event.2 Bleeding is one of the most common adverse events associated with sphincterotomy.3 The bleeding can range from minimal  oozing to life-threatening hemorrhage requiring multiple blood transfusions and emergent endoscopic/radiologic/surgical intervention to achieve hemostasis. Understanding the type of sphincterotomy-related bleeding, recognizing high-risk scenarios, and implementing prompt and appropriate hemostatic strategies are key for improving patient outcomes. This article aims to provide a comprehensive overview of the incidence, risk factors, classification, current management strategies, and advanced interventions for refractory cases of endoscopic sphincterotomy-related bleeding.

Incidence

The American Gastroenterological Association (AGA) recognized sphincterotomy as the most important risk factor for bleeding during ERCP as the bleeding from ERCP.3 The incidence of bleeding associated with sphincterotomy can range from 0.5% to 12%.4-8 It is important to note that reporting of the incidence of bleeding varies and is highly dependent on the definition used by the investigators and authors across studies. Some studies define bleeding as a clinical diagnosis (melena or hematemesis) with laboratory evidence of a drop in hemoglobin while others include any bleeding at all, even mild, self-limited oozing. For example, the MESH study by Freeman et al. reported an incidence of bleeding post-ES of 2%.6 Others consider bleeding as endoscopic evidence after performing sphincterotomy. For example, Kim et al. and Leung et al. defined post-sphincterotomy bleeding as an adverse event if the bleeding did not subside after two to three minutes following sphincterotomy.7,8 Hence, the reported incidence was greater, 12.1% and 10.4%, respectively. Nonetheless, the incidence of bleeding as an adverse event post-sphincterotomy has decreased over time. From 10-12% in the 1990s, the current guidelines by the American Society for Gastrointestinal Endoscopy and the AGA cite an expected rate of sphincterotomy-associated bleeding as approximately 1 to 2%, likely representing advanced in sphincterotomy generator waveforms.9

Risk Factors

The risk factors for post-ES bleed include liver cirrhosis, end-stage renal disease, difficult cannulation, precut sphincterotomy and lower ERCP case volumes.9,10,11 The AGA identifies coagulopathy, anticoagulant therapy within three days of procedure, cholangitis, low endoscopist case volume (less than 1 per week), and additional therapeutic maneuvers including ampullectomy as risk factors for bleeding with ES.3 The risks specific for ES can be grouped depending on patient and procedure. A retrospective study by Lin et al. reported significantly increased incidence of post-sphincterotomy bleeding in patients with cirrhosis (OR 3.1), end stage renal disease (OR 3.55), antiplatelet use within three days before or after the procedure (OR 4.95), CBD dilation (OR 1.24) and history of duodenal ulcers (OR 2.06).10 Similarly, the endoscopist experience and the number of sphincterotomies/ERCPs performed also play an important role. For example, mean case volume of ≤ 1/week was associated with 74% significantly higher odds of bleed compared to operators with a high case volume.6

Kim et al. in their prospective analysis found statistically higher bleeding rates with a needle-knife sphincterotome compared to a traditional pull-type sphincterotome (79.4% vs 20.6%, p < 0.025). Moreover, bleeding was significantly more with zipper cuts (3.7% vs 1.2%, p 0.049%).7 However, it is important to note that with recent advancements in the field of advanced endoscopy and newer devices, zipper cuts are extremely rare. Bae et al. showed that the length of ES as an independent risk factor for bleeding.12 Full length (papillary orifice up to the superior margin of the sphincter opening, OR 68.27) was associated with the highest risk followed by medium length (papillary orifice to the midpoint between the proximal hooding fold and the superior margin of sphincter opening, OR 10.97) and then minimal length (papillary orifice to the proximal hooding fold, OR 1). It should be noted that, in general, a complete sphincterotomy is best for the patient. Evidence of extension of previous ES is mixed. While some studies state that it does not affect the risk of bleeding, Leung et al. reported significantly increased risk.3 Prabhu et al. in their review paper explained how sphincterotomy extension was safe without significant risk of adverse events.13

The type of device used for ES also plays an important role. Perini et al. in their study showed that the ValleyLab generator, which is no longer in clinical use, was associated with increased endoscopically evident bleeding (OR 4.02) compared to the microprocessor- controlled generator (ICC 200; ERBE). The ValleyLab generator was associated with increased occurrence of moderate or severe bleeding with increased requirement of urgent endoscopic intervention. It has since been replaced by modern electrosurgical generators. 

Classification of Sphincterotomy-Associated Bleeding

Bleeding can be broadly classified as clinically significant or insignificant. Clinically important bleeding can be defined as any bleed that requires intervention (endoscopic hemostasis, transfusion, etc.) and is visible not only through endoscopy but also in the form of melena/hematemesis/hematochezia with a significant drop in hemoglobin. 

Cotton et al. proposed a grading system to classify bleeding based on its severity.14 Bleeding can be classified into mild, moderate, and severe. Mild bleeding is defined as clinically apparent bleeding with a hemoglobin drop of less than 3 g/dL that does not require transfusion. Moderate bleeding refers to bleeding that necessitates transfusion of up to four units of blood, without the need for angiographic or surgical intervention. Severe bleeding involves the transfusion of five or more units and/or requires angiographic or surgical management. A clinically insignificant bleed would broadly include all the bleeds that do not fit the above criteria. However, in essence, the distinction between clinically significant and insignificant bleeding after a sphincterotomy is made via clinical judgment and observation and hinges on the impact on the patient’s health and the level of medical intervention required to control the bleeding.  

Freeman et al. reported a rate of 2% clinically significant bleeds, out of which 0.6% were mild (not requiring transfusion), 0.9% were moderate (requiring up to 4 units of blood), and 0.5% had severe bleeds (5 or more units of blood, surgery, or angiography).6 Similarly, other studies mostly report mild to moderate bleeding as the most common bleeding severity after sphincterotomy. Leung et al. in their study reported mild, moderate, and severe bleeds as 92.4%, 6.7% and 0.9%, respectively.8

Clinically evident bleeds can become life-threatening emergencies requiring massive blood transfusions, endoscopic interventions, and/or interventional radiology (IR) intervention for embolization. Freeman et al. reported 43.75% post-sphincterotomy patients requiring endoscopic intervention for hemostasis, and 4.2% patients required surgical intervention.6 Death occurred in 4.2% of cases despite aggressive intervention. 

Bleeding can also be classified as immediate or delayed based on the timing/onset of bleeding. Immediate bleeding usually occurs during the procedure and is evident by oozing or spurting of blood and is directly observed with the duodenoscope.6,8 However, this may not be clinically significant and in the majority of instances it is self-limiting and managed conservatively.6,8,15

Delayed bleeding refers to a clinically significant bleed occurring after the sphincterotomy, with usually biochemical evidence of hemoglobin drop.8,9 Freeman et al. reported delayed bleeding 1-10 days post-sphincterotomy in 52% cases.6 Lin et al. in their study reported 69.2% immediate and 30.8% delayed bleeds.10 Beyond that, 20% of these severe bleeds were more severe than those with immediate bleeding. Reported delayed bleeding rates were lower in the study by Leung et al., at 4.2% with all cases requiring blood transfusions and repeat endoscopic intervention.8 This indicates that delayed bleeding, although less frequent, can be more fatal compared to immediate bleeding. 

Management of Sphincterotomy Induced Bleeding

The cornerstones of managing post-sphincterotomy bleeding are rapid recognition, risk stratification, and immediate availability of appropriate endoscopic tools and expertise. Immediate bleeding, typically identified during ERCP, is addressed using a stepwise endoscopic approach based on bleeding severity and visibility. It should be noted that mild bleeding often stops spontaneously and, if not interfering with visualization, may not require treatment per se. 

If treatment is desired, balloon tamponade is usually the first method applied for mild bleeds and this technique can be supplemented with other treatment interventions if adequate hemostasis is not achieved in short order. Injection of epinephrine, hemostatic clips, stents, and thermal coagulation are commonly used endoscopic interventions for hemostasis.4 Topical agents can be used as adjuvants. Delayed bleeding is managed with supportive care and resuscitation with blood products, followed by repeat endoscopy for definitive control if bleeding does not stop spontaneously. In cases with severe bleeding, referral to interventional radiology for angiography with embolization or, rarely, surgical intervention may be necessary. The choice of intervention is often governed by whether the bleed is immediate or delayed, intermittent or ongoing, mild or severe, and the patient’s overall stability. In the following sections, we will discuss the various treatment interventions in detail that can be used to achieve hemostasis in post-sphincterotomy bleeding.

Tamponade

Balloon tamponade is frequently used to control sphincterotomy bleeding and ensure adequate visualization of the bleeding site. (Figure 1) The balloon exerting direct pressure on the bleeding vessel promotes clot formation and hemostasis. This tamponade is most commonly provided using a standard stone extraction balloon or, less frequently, a dilation balloon.16 One advantage of this approach is that the bleeding site can often be directly visualized through the clear plastic of the balloon itself, allowing for interrogation and direct confirmation of ongoing bleeding or cessation of bleeding. 

Balloon tamponade is an effective strategy especially for immediate onset bleeding after sphincterotomy. A recent study by Askora et al. showed that balloon tamponade was successful in achieving hemostasis in 10 of 18 subjects (55.6%), and an additional 4 subjects (22.2%) achieved hemostasis after 5 minutes of tamponade.17 Hence, it can be easily used by the endoscopist in cases of immediate post-ES bleed and often the first line of intervention.18 Staritz, et al. used balloon catheters in two cases of severe hemorrhage from the papillary orifice and reported cessation of bleeding after ten minutes.19

Despite the advantages and ease of use of balloon tamponade, it is not free of the risk of adverse events. It can lead to mucosal ischemia through increased pressure application to the mucosal surface during tamponade, although such events are rare. Other adverse events associated with balloon tamponade include bile duct injury, perforation, pancreatitis and cholangitis, and these risks are likely higher with dilation balloons than with retrieval balloons.10,20 Edema or spasm of the pancreatic duct or the biliary duct due to pressure application from the tamponade can contribute to these adverse events. Hence, the endoscopist should be careful in selecting a balloon of appropriate size, ensuring adequate but not undue inflation pressure, and just enough duration of balloon application to avoid adverse events. Despite that, balloon tamponade is a minimally invasive and highly effective intervention for initial use. It is also a cost-effective intervention option compared to more invasive procedures.

Local Injections 

Local injection therapy, most commonly with epinephrine, remains a commonly employed technique for controlling post-sphincterotomy bleeding. Injection with diluted epinephrine (1:10000 to 1:20000) is mostly effective in achieving hemostasis by two methods: vasoconstriction and mechanical tamponade by volume of fluid injected into submucosal space surrounding the vessel which compresses it and facilitates thrombosis.15 It should be noted that not all available injection catheters work through a duodenoscope, and simple plastic catheters may be deformed by the elevator mechanism of the duodenoscope and thus fail. Tsou et al. reported epinephrine injection alone was as effective as combination treatment with epinephrine injection and thermotherapy (96.2% vs 100%, p 0.44).22 Apart from epinephrine, hypertonic saline-epinephrine, dextrose-epinephrine, and polidocanol have also been utilized. Sakai et al. reported 100% successful hemostasis with hypertonic-epinephrine injection.23 Hence, local injections can be effectively used as first line agents to achieve hemostasis for mild bleeding and can be used as an adjunctive initial method which can then be followed immediately by a definitive treatment with clipping or thermal coagulation. Recently, fibrin glue has also been reported as an alternative to refractory post-ES bleeding. It contains fibrinogen and thrombin and promotes thrombogenesis to achieve hemostasis. Orlandini et al. reported 91.4% clinical success rate with one injection of fibrin glue in refractory post-ES bleeds.24 Out of the remaining 8.6%, half responded to a second injection of fibrin glue.

Thermal Coagulation

Thermal coagulation plays a significant role in achieving hemostasis when local injection has failed to provide adequate hemostasis. Thermal therapies include monopolar or bipolar electrocautery, heater probes and argon plasma coagulation. (Figure 2) Controlled thermal energy delivered through these techniques cauterizes the bleeding site and can often result in durable hemostasis.25 It should be noted that the cutting wire of the sphincterotome itself can be used to provide monopolar electrocautery to the bleeding site. Katsinelos et al. reported monopolar cautery was 100% successful in controlling post-ES bleeding which was not controlled with epinephrine injection alone.26 Similarly, Sherman et al. reported an 89% hemostasis rate with bipolar cautery in post-ES bleeds.27 A key advantage of thermal methods over injection alone is the creation of a more durable seal with the possibility of coaptation (thus compressing and cauterizing the bleeding vessel at the same time) leading to significantly lower rates of rebleeding. Combination therapies consisting of epinephrine injections and thermal coagulation have also been widely used. Tsou et al. reported 100% success rate in achieving hemostasis across all 37 patients who were treated with combination therapy.22

Clipping 

For refractory bleeding not controlled by tamponade or hemostatic topical agents, endoscopic clips can be used. Application of clip is technically challenging with a side viewing endoscope as the small mechanical parts of through-the-scope (TTS) clips can become damaged by the elevator mechanism of the duodenoscope, but some TTS clips work despite this challenge. Cap-assisted end-viewing endoscopes can potentially overcome this problem. Clips can be deployed directly onto the bleeding site, and they can be effective for both active bleeding and for prophylactic prevention. TTS clip application through end-viewing endoscope can achieve successful hemostasis in 90% cases.28 Kim et al. retrospectively evaluated the efficacy of clips for post-ES induced bleeding that was not controlled with epinephrine injection or tamponade. They reported a 100% success rate with no delayed bleeding or complications in all 45 patients treated with clips.29

A propensity score matched analysis conducted by Jinpei et al. in 2024 compared prophylactic hemostatic clip placement after ES with 232 patients in the hemostatic clip group and 161 in the control arm. They reported significantly lower odds of delayed bleeding in the hemostatic clip group arm (OR 0.134, 95% CI 0.025 – 0.719).30 Similarly, Chon et al. reported 100% success rates in all 57 subjects who were managed with endoclip for controlling post-ES bleed.31 Care must be taken to avoid inadvertent closure of the bile or pancreatic duct while placing the clip. However, such adverse events are very rare. Moreover, no significant adverse events have been reported associated with the clips. Clips are a good alternative for refractory post-ES bleeding uncontrolled by injections/ tamponade, which is easier to perform and has low chance of adverse events.

Stenting

Stents are another treatment alternative for post-ES bleeds uncontrolled with topical agents/ tamponade, and in general covered metal stents are used to treat sphincterotomy bleeding. Itoi et al. suggested 10 mm as an ideal diameter size of the stent.32 Fully covered self-expandable metal stents (FC-SEMS) have been shown to provide excellent tamponade. (Figure 3) Cochrane et al. reported FC-SEMS had significantly lower rate of bleeding at 72 hours compared to traditional endoscopic interventions (tamponade/epinephrine injection).33

In a retrospective study by Bilal et al. including 97 patients, FC-SEMS had a 100% technical success rate in achieving immediate hemostasis and 94% success in achieving durable clinical success for delayed hemostasis. Rebleeding was noted in 6.2% cases which were managed with repeat EGD/ERCP, embolization and surgery.34 The adverse events reported post FC-SEMS included pancreatitis in 4.1% cases and stent migration in 4.1% cases. Even though FC-SEMS have good success rates, due to the higher costs and adverse events associated they are considered as treatment alternatives after conventional endoscopic interventions like tamponate, topical agents or cauterization have failed to control bleeding. FC-SEMS are generally removed several weeks after placement when used to treat sphincterotomy bleeding. 

Topical Agents 

Topical agents represent a significant advancement in the treatment of GI bleeding, offering a non-mechanical method of hemostasis ideally suited for achieving hemostasis for diffuse hemorrhage or anatomically difficult locations which cannot be controlled by local injections, tamponade or clips.  Hemospray (Cook Endoscopy, Winston-Salem NC) acts as a mechanical barrier between the bleeding vessel and the lumen. When applied to the bleeding surface, it absorbs water from the blood and tissue fluids, leading to concentration of clotting factors and platelets. This promotes formation of an adhesive plug that covers the mucosal defect and applies physical tamponade on the bleeding vessel promoting hemostasis.35 Purastat (3-D Matrix, Inc., Tokyo, Japan) is another topical agent used for post-ES bleeds. It is a synthetic hemostatic agent made of amino acids and forms a three-dimensional scaffold after coming in contact with blood.36 This scaffold mimics the human extracellular matrix causing an adhesive effect and promoting hemostasis at the bleeding site. Another agent used is Beriplast (CSL Behring, Marburg, Germany), a fibrin sealant, which mimics final steps of the coagulation cascade to achieve hemostasis.37

Studies have shown high rates of immediate hemostasis (>90%) with Hemospray in achieving hemostasis for gastrointestinal bleeds.38 However, studies evaluating the use of Hemospray for post-ES bleeds are limited. Lesmana et al. in their retrospective study compared Beriplast and Purastat with conventional hemostatic techniques (epinephrine / balloon tamponade) for post-ES bleeds. The study involved 100 patients with 60 patients in the study arm (Beriplast or Purastat) and 40 patients in the control arm (conventional hemostatic agents). They reported a 100% success rate in achieving immediate hemostasis in both the arms. However, two patients (5%) in the control arm had rebleed while none were reported in the study arm. Out of these two patients, one was managed with one out of the two hemostatic agents (Beriplast or Purastat) and the other was managed with argon plasma coagulation.39

A recent RCT was performed comparing the efficacy of a polysaccharide hemostatic powder (XunNing®; Lianbai Bochao Medical Equipment, Chongqing, China) to endoclips for post-ES non-pulsatile bleeding. The study included 104 subjects with 52 each in the study and control arm. Immediate hemostasis was achieved in 100% subjects with polysaccharide hemostatic powder (PHP) while it was 92.3% with endoclip use (p = 0.022). Overall treatment success, which was defined as immediate hemostasis with no delayed bleeding, was significantly more with the PHP use (100% vs 90.4%; P = 0.022). Moreover, hemostasis was achieved in a shorter time with PHP (50.77 vs. 62.81 sec, p = 0.011).40

With topical agents, the primary concern is rebleeding. Hemospray use for gastrointestinal bleeds have shown rebleed rates of as high as 10% to 30%.32 Moosavi et al. reported a case of transient biliary obstruction after application of hemospray for post-ES bleed.41 Despite promising results from Lesmana et al., prospective studies specifically evaluating topical agents for post-sphincterotomy bleeding are needed.39

IR/surgery for Profound Post-ES bleeding

With advancements in the endoscopic techniques, only a small subset of patients with post-sphincterotomy bleeding will require intervention beyond endoscopy. IR-guided embolization is the preferred next-step modality for hemodynamically unstable patients with ongoing bleeding that is refractory to endoscopic control or when endoscopic visualization is impossible. The IR approach involves angiographic localization of bleeding source, typically the posterior pancreaticoduodenal artery and/or one of the branches of the gastroduodenal artery followed by embolization with coils, particles or glue. Maleux et al. reported 97% successful embolization in post-ES bleeding that was refractory to medical and endoscopic treatment.42 If bleeding is from duodenal varices, IR approaches may have difficulty in fully stopping it. Recurrent bleeding occurred in 9% cases and 30-day mortality was 20.6%. The high mortality rates in this study were attributed to hemostatic disorders characterized by increased international normalized ratio (INR) and activated partial thromboplastin time (aPTT) with statistically significant correlation between the 30-day mortality and elevated levels of INR and aPTT (P value of 0.008 and 0.012, respectively).

Shenbagaraj et al., in their retrospective study, reported 100% success (n=4) with embolization in post-ES bleeds that were refractory to endoscopic intervention.43

Surgery remains the definitive treatment of last resort, reserved for cases who have failed embolization or when bleeding is too massive for endoscopic or angiographic control. The surgical options include open surgical vessel ligation or surgical repair of the duodenum and papilla. Most commonly performed surgery is duodenotomy with direct suture ligation of bleeding vessels at the sphincterotomy site.4 More extensive procedures such as pancreaticoduodenectomy are rarely required and carry significant morbidity and mortality.

The choice between IR guided intervention and surgery is multidisciplinary, dependent on patient clinical stability, anatomy and expertise available at the treatment center. However, the minimally invasive nature of angioembolization is considered as a bridge between failed endoscopy and high-risk surgery.

Conclusion

Post-ES bleeding is a well- reported adverse event which, in general, requires a structured approach for management. The cornerstone of treatment is endoscopic intervention. Epinephrine injection, balloon tamponade, thermal coagulation, and the use of endoscopic clips are foundational treatment modalities. For refractory cases, FC-SEMS and topical hemostatic agents offer valuable alternatives before considering angioembolization or surgery.  

References

References

1.  Neuhaus H. Biliary sphincterotomy. InERCP 2019 Jan 1 (pp. 137-147). Elsevier.

2.  Perini RF, Sadurski R, Cotton PB, Patel RS, Hawes RH, Cunningham JT. Post-sphincterotomy bleeding after the introduction of microprocessor-controlled electrosurgery: does the new technology make the difference?. Gastrointestinal endoscopy. 2005 Jan 1;61(1):53-7.

3.  Adler DG, Lieb JG, Cohen J, Pike IM, Park WG, Rizk MK, Sawhney MS, Scheiman JM, Shaheen NJ, Sherman S, Wani S. Quality indicators for ERCP. Official journal of the American College of Gastroenterology| ACG. 2015 Jan 1;110(1):91-101.

4. Ferreira LE, Baron TH. Post-sphincterotomy bleeding: who, what, when, and how. Official journal of the American College of Gastroenterology| ACG. 2007 Dec 1;102(12):2850-8.

5. Goodall RJ. Bleeding after endoscopic sphincterotomy. Annals of the Royal College of Surgeons of England. 1985 Mar;67(2):87.

6.  Freeman ML, Nelson DB, Sherman S, Haber GB, Herman ME, Dorsher PJ, Moore JP, Fennerty MB, Ryan ME, Shaw MJ, Lande JD. Complications of endoscopic biliary sphincterotomy. New England Journal of Medicine. 1996 Sep 26;335(13):909-19.

7.  Kim HJ, Kim MH, Kim DI, Lee HJ, Myung SJ, Yoo KS, Park ET, Lim BC, Seo DW, Lee SK, Min YI. Endoscopic hemostasis in sphincterotomy-induced hemorrhage: its efficacy and safety. Endoscopy. 1999 Aug;31(06):431-6.

8.  Leung JW, Chan FK, Sung JJ, Chung SS. Endoscopic sphincterotomy-induced hemorrhage: a study of risk factors and the role of epinephrine injection. Gastrointestinal endoscopy. 1995 Dec 1;42(6):550-4.

9.  Chandrasekhara V, Khashab MA, Muthusamy VR, Acosta RD, Agrawal D, Bruining DH, Eloubeidi MA, Fanelli RD, Faulx AL, Gurudu SR, Kothari S. Adverse events associated with ERCP. Gastrointestinal endoscopy. 2017 Jan 1;85(1):32-47.

10. Lin WC, Lin HH, Hung CY, Shih SC, Chu CH. Clinical endoscopic management and outcome of post-endoscopic sphincterotomy bleeding. PloS one. 2017 May 17;12(5):e0177449.

11. Nelson DB, Freeman ML. Major hemorrhage from endoscopic sphincterotomy: risk factor analysis. Journal of clinical gastroenterology. 1994 Dec 1;19(4):283-7.

12. Bae SS, Lee DW, Han J, Kim HG. Risk factor of bleeding after endoscopic sphincterotomy in average risk patients. Surgical endoscopy. 2019 Oct 15;33(10):3334-40.

13. Parbhu S, Adler DG. Extension of a Prior Biliary or Pancreatic Sphincterotomy: Efficacy, Outcomes, and Adverse Events. PRACTICAL GASTROENTEROLOGY. 2016 Jan 1;40(1):21-32.

14. Cotton PB, Lehman G, Vennes J, Geenen JE, Russell RC, Meyers WC, Liguory C, Nickl N. Endoscopic sphincterotomy complications and their management: an attempt at consensus. Gastrointestinal endoscopy. 1991 May 1;37(3):383-93.

15. Wilcox CM, Canakis J, Mönkemüller KE, Bondora AW, Geels W. Patterns of bleeding after endoscopic sphincterotomy, the subsequent risk of bleeding, and the role of epinephrine injection. Official journal of the American College of Gastroenterology| ACG. 2004 Feb 1;99(2):244-8.

16. Rustagi T, Jamidar PA. Endoscopic retrograde cholangiopancreatography–related adverse events: general overview. Gastrointestinal Endoscopy Clinics. 2015 Jan 1;25(1):97-106.

17. Askora AA, Ibrahim AM, Elgohary M, Saad N, Abu Taleb MA. Efficacy and Safety of Balloon Tamponade in Control of Post Sphincterotomy Bleeding During Endoscopic Retrograde Cholangiopancreatography. Zagazig University Medical Journal. 2025 May 1;31(5):1911-27.

18. Ghoz HM, Dayyeh BK. Hemorrhagic complications following endoscopic retrograde cholangiopancreatography. Techniques in Gastrointestinal Endoscopy. 2014 Oct 1;16(4):175-82.

19. Staritz M, Ewe K, Goerg K, Meyer zum Büschenfelde KH. Endoscopic balloon tamponade for conservative management of severe hemorrhage following endoscopic sphincterotomy. Zeitschrift fur Gastroenterologie. 1984 Nov 1;22(11):644-6.

20. Mustafa FM, Ali HF. Endoscopic management of ERCP bleeding. The Egyptian Journal of Hospital Medicine. 2019 Apr 1;75(5):2888-93.

21. Matsushita M, Uchida K, Okazaki K. Effective injection site on endoscopic injection therapy for postsphincterotomy bleeding: apex or oral?. Official journal of the American College of Gastroenterology| ACG. 2008 Jun 1;103(6):1569-70.

22. Tsou YK, Lin CH, Liu NJ, Tang JH, Sung KF, Cheng CL, Lee CS. Treating delayed endoscopic sphincterotomy-induced bleeding: epinephrine injection with or without thermotherapy. World Journal of Gastroenterology: WJG. 2009 Oct 14;15(38):4823.

23. Sakai Y, Tsuyuguchi T, Sugiyama H, Nishikawa T, Kurosawa J, Saito M, Tawada K, Mikata R, Tada M, Ishihara T, Yokosuka O. Hypertonic saline-epinephrine local injection therapy for post-endoscopic sphincterotomy bleeding: removal of blood clots using pure ethanol local injection. Surgical Laparoscopy Endoscopy & Percutaneous Techniques. 2013 Aug 1;23(4):e156-9.

24. Orlandini B, Schepis T, Tringali A, Familiari P, Boškoski I, Borrelli de Andreis F, Perri V, Costamagna G. Fibrin glue injection: Rescue treatment for refractory post-sphincterotomy and post-papillectomy bleedings. Digestive Endoscopy. 2021 Jul;33(5):815-21.

25. Kuran S, Parlak E, Oguz D, Cicek B, Disibeyaz S, Sahin B. Endoscopic sphincterotomy–induced hemorrhage: treatment with heat probe. Gastrointestinal endoscopy. 2006 Mar 1;63(3):506-11.

26. Katsinelos P, Kountouras J, Chatzimavroudis G, Zavos C, Fasoulas K, Katsinelos T, Pilpilidis I, Paroutoglou G. Endoscopic hemostasis using monopolar coagulation for postendoscopic sphincterotomy bleeding refractory to injection treatment. Surgical Laparoscopy Endoscopy & Percutaneous Techniques. 2010 Apr 1;20(2):84-8.

27. Sherman S, Hawes RH, Nisi R, Lehman GA. Endoscopic sphincterotomy-induced hemorrhage: treatment with multipolar electrocoagulation. Gastrointestinal endoscopy. 1992 Mar 1;38(2):123-6.

28. Liu F, Wang GY, Li ZS. Cap-assisted hemoclip application with forward-viewing endoscope for hemorrhage induced by endoscopic sphincterotomy: a prospective case series study. BMC gastroenterology. 2015 Oct 15;15(1):135.

29. Kim TH, Sohn YW. Mo1428 Hemoclip Application Using CAP-Fitted Forward Endoscopy to Treat Post-Sphincterotomy Bleeding in Patients Undergoing ERCP. Gastrointestinal Endoscopy. 2015 May 1;81(5):AB416.

30. Dong J, Feng Q, Teng G, Niu H, Bian D. Application of a New Hemostatic Clip to Prevent Delayed Bleeding After Endoscopic Sphincterotomy: A Propensity Score–matched Analysis. Journal of Clinical Gastroenterology. 2024 Jul 1;58(6):614-8.

31. Chon HK, Kim TH. Endoclip therapy of post-sphincterotomy bleeding using a transparent cap-fitted forward-viewing gastroscope. Surgical Endoscopy. 2017 Jul;31(7):2783-8.

32. Itoi T, Yasuda I, Doi S, Mukai T, Kurihara T, Sofuni A. Endoscopic hemostasis using covered metallic stent placement for uncontrolled post-endoscopic sphincterotomy bleeding. Endoscopy. 2011 Apr;43(04):369-72.

33. Cochrane J, Schlepp G. Comparing endoscopic intervention against fully covered self-expanding metal stent placement for post-endoscopic sphincterotomy bleed (CEASE Study). Endoscopy International Open. 2016 Dec;4(12):E1261-4.

34. Bilal M, Chandnani M, McDonald NM, Miller CS, Saperia J, Wadhwa V, Singh S, Cohen JM, Berzin TM, Sawhney MS, Pleskow DK. Use of fully covered self-expanding metal biliary stents for managing endoscopic biliary sphincterotomy related bleeding. Endoscopy International Open. 2021 May;9(05):E667-73.

35. Holster IL, van Beusekom HM, Kuipers EJ, Leebeek FW, de Maat MP, Tjwa ET. Effects of a hemostatic powder hemospray on coagulation and clot formation. Endoscopy. 2015 Jul;47(07):638-45.

36. Subramaniam S, Kandiah K, Thayalasekaran S, Longcroft-Wheaton G, Bhandari P. Haemostasis and prevention of bleeding related to ER: The role of a novel self-assembling peptide. United European gastroenterology journal. 2019 Feb;7(1):155-62.

37. Eberhard U, Broder M, Witzke G. Stability of Beriplast® P fibrin sealant: Storage and reconstitution. International journal of pharmaceutics. 2006 Apr 26;313(1-2):1-4.

38. Chahal D, Sidhu H, Zhao B, Jogendran M, Dahiya M, Tandon P, Donnellan F. Efficacy of Hemospray (TC-325) in the treatment of gastrointestinal bleeding: an updated systematic review and meta-analysis. Journal of Clinical Gastroenterology. 2021 Jul 1;55(6):492-8.

39. Lesmana CR, Sandra S, Paramitha MS, Gani RA, Lesmana LA. Endoscopic Management Using Novel Haemostatic Agents for Immediate Bleeding during Endoscopic Retrograde Cholangio-Pancreatography. Canadian Journal of Gastroenterology and Hepatology. 2023;2023(1):5212580.

40. Li H, Zuo J, Wang W, Wu S, Zhao Y, Wei Y, Song J, Zhang Z, Yao W, Wang J, Liu C. Efficacy of Polysaccharide Hemostatic Powder on blood oozing among patients with Post-Endoscopic Sphincterotomy Bleeding: A Randomized Controlled Trial. Official journal of the American College of Gastroenterology| ACG. 2022 May 12:10-4309.

41. Moosavi S, Chen YI, Barkun AN. TC-325 application leading to transient obstruction of a post-sphincterotomy biliary orifice. Endoscopy. 2013 Dec;45(S 02):E130-.

42. Maleux G, Bielen J, Laenen A, Heye S, Vaninbroukx J, Laleman W, Verhamme P, Wilmer A, Van Steenbergen W. Embolization of post-biliary sphincterotomy bleeding refractory to medical and endoscopic therapy: technical results, clinical efficacy and predictors of outcome. European radiology. 2014 Nov;24(11):2779-86.

43. Shenbagaraj L, White J, Czajkowski M, Allison M. PTU-116 Delayed post sphincterotomy bleeding and management–4 year single centre experience.

Download Tables, Images & References

Jojobet GirişmatbetcasibommeritkingcasibomcasibomcasibomGrandpashabetgrandpashabetcasibomGrandpashabetzirvebetjojobetcasibomGrandpashabetGrandpashabetGrandpashabetgrandpashabetcasibombetpasjojobet girişjojobet güncel girişUltrabetjojobetmatbetdeneme bonusu veren sitelerdeneme bonusu veren sitelermadridbetmadridbetMadridbetMadridbetgrandpashabetHoliganbet girişcasibomgrandpashabet girişJojobetcasibomgrandpashabetjojobetcasibomjojobetjojobetgrandpashabet girişcasibombetciograndpashabet girişcasibom girişgrandpashabet girişgrandpashabetgrandpashabetholiganbetBetpas