Colorectal cancer remains the third most common cancer and second most common cause of cancer deaths, often from metastatic disease.1-6 While liver metastases are most common, other sites of metastases include lung, peritoneum, ovary, and brain.1-6 We report the presentation of cutaneous skin metastases in a patient with history of recent renal transplant.
Clinical Scenario
A 68-year-old man who had undergone kidney transplant two years prior presented to clinic with weeks of constipation, decreased flatus, and malaise. Ongoing abdominal pain and bloating led to poor oral intake and a 15-pound weight loss over three months. On physical exam, his abdomen was distended and tender on the right side. He was noted to have multiple firm, nontender, pink papules in the right lower quadrant (Figure 1). The patient reported that the papules had been present for several months. He was admitted to the hospital and underwent a noncontrasted CT of his chest, abdomen, and pelvis. This scan demonstrated pulmonary nodules, retroperitoneal lymphadenopathy, dilated small bowel, and narrowing of the ascending colon with decompressed distal colon (Figure 2). Carcinoembryonic antigen (CEA) was 398 ng/ml (normal = 0-5.4 ng/ml). No masses in the liver were identified.
A presumptive diagnosis of obstructing colon cancer was made, and the abdominal skin nodules were biopsied. Histopathologic examination showed an adenocarcinoma consistent with metastasis from a colonic primary (Figure 3). Due to pain, obstruction, and concern for potential perforation in the setting of malnutrition, he underwent a palliative resection with end ileostomy. Pathology for this tumor revealed poorly differentiated, mucinous adenocarcinoma with multiple positive lymph nodes. Final stage was pT4b pN2a pM1a. The tumor was found to be MLH1/PMS2 deficient by immunohistochemistry and molecular testing revealed a BRAF V600E mutation. The patient decided to focus on comfort driven measures and did not receive adjuvant chemotherapy and immunotherapy. He succumbed to the disease four months after diagnosis.
Clinical Pearls
Prior to being listed for kidney transplant, patients undergo extensive medical evaluation to ensure fitness for the operation and immunosuppression.7 These include cancer screening tests, such as colonoscopy and dermatological skin exam.7 This patient had undergone colonoscopy at a referring institution four years prior to this presentation, two years before his transplant. Findings at his colonoscopy included five polyps, measuring 0.3-1 cm, from his ascending, transverse, and descending colon. Pathology of each polyp was consistent with tubular adenoma. At the time, it was recommended to repeat screening colonoscopy in three years, but that was never completed.
This case highlights the increased rates of cancer in transplant patients due to immunosuppression, the varied metastatic patterns of colon cancer, and the importance of timely screening and surveillance colonoscopies as well as their false negative rate.
Immunosuppression prevents transplanted organ rejection but also increases risk of malignancy in the transplant recipient.7 The two major ways this occurs is by decreasing immune surveillance and increasing susceptibility to viruses such as BK polyomavirus, cytomegalovirus (CMV), human papillomavirus (HPV) and Epstein Barr virus (EBV) which are associated with cancer development.7 Cell lines including T-lymphocytes, naïve B-lymphocytes and natural killer cells (NK cells) are reduced which in turn reduces the recognition of dysregulated cellular replication and viral reproductions.7 While the rate of cancer rises with age, the risk elevation is not proportional to age. Younger transplant patients have a three to five times greater relative risk of developing a malignancy than older transplants since they are immunosuppressed; this contributes to their increased risk of cancer compared to the general population.7 Regardless, colorectal cancer rates are still elevated by 1.5-to-3-fold.7 Therefore, there needs to be a high index of suspicion for cancer in transplant recipients, and screening guidelines must reflect that.
Colonoscopy remains the gold standard for colorectal cancer. However, around 1% of colorectal cancers occur within the interval between colonoscopies.1 Currently, the most cited reason for post-colonoscopy colorectal cancer is a missed lesion, representing up to 57% of cases.1 It is suggested that a quarter of colonoscopies have missed adenomas or precancerous lesions.1 Wallace et al. demonstrated this in their evaluation of artificial intelligence (AI) enhanced screening colonoscopies followed by a short interval repeat colonoscopy (frequently same day) with 15-32% adenoma miss rate in AI and non-AI screening colonoscopies.1
Around 20-35% of patients with colorectal cancer present with metastatic disease at diagnosis.4,5 Cutaneous metastases in CRC are uncommon, occurring in 4-5% of cases.2,3 They are often associated with BRAF V600E mutations.3 Cutaneous metastases are an independent predictor of poor survival, with around two-thirds of patients dying within six months of diagnosis.2,3
Immunotherapy has shifted the treatment paradigm of high microsatellite instability (MSI-H) colorectal cancers and has significantly improved progression-free survival.5 MSI-H, found in up to 20% of colon cancers, is due to a deficiency in mismatch repair (MMR) proteins and subsequent unrepaired alterations in DNA sequences.5 While this patient had an MLH1/PMS2 deficiency that may have responded to immunotherapy, he was not offered it due to his renal transplant. In transplant patients, immunotherapy risks triggering graft rejection. Furthermore, its efficacy in the setting of maintenance immunosuppression may be reduced.8 As this patient did not wish to risk allograft rejection and need for hemodialysis, he transitioned to hospice care.
References
References
1. Wallace MB, Sharma P, Bhandari P, et al. Impact of Artificial Intelligence on Miss Rate of Colorectal Neoplasia. Gastroenterology. Jul 2022;163(1):295-304 e5. doi:10.1053/j.gastro.2022.03.007
2. Bittencourt MJS, Imbiriba AA, Oliveira OA, Santos J. Cutaneous metastasis of colorectal cancer. An Bras Dermatol. Nov/Dec 2018;93(6):884-886. doi:10.1590/abd1806-4841.20187610
3. Zhou S, Tang W, Wang Q, et al. A Case Report: Cutaneous Metastasis of Advanced Rectal Cancer with BRAF Mutation. Onco Targets Ther. 2021;14:989-993. doi:10.2147/OTT.S287064
4. Xia W, Geng Y, Hu W. Peritoneal Metastasis: A Dilemma and Challenge in the Treatment of Metastatic Colorectal Cancer. Cancers (Basel). Nov 29 2023;15(23)doi:10.3390/cancers15235641
5. Hou W, Yi C, Zhu H. Predictive biomarkers of colon cancer immunotherapy: Present and future. Front Immunol. 2022;13:1032314. doi:10.3389/fimmu.2022.1032314
6. Aakif M, Balfe P, Elfaedy O, et al. Study on colorectal cancer presentation, treatment and follow-up. Int J Colorectal Dis. Jul 2016;31(7):1361-3. doi:10.1007/s00384-015-2479-0
7. Au E, Wong G, Chapman JR. Cancer in kidney transplant recipients. Nat Rev Nephrol. Aug 2018;14(8):508-520. doi:10.1038/s41581-018-0022-6
8. Padala SA, Patel SK, Vakiti A, et al. Pembrolizumab-induced severe rejection and graft intolerance syndrome resulting in renal allograft nephrectomy. J Oncol Pharm Pract. Mar 2021;27(2):470-476. doi:10.1177/1078155220934160
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:
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 PDS
Other Symptoms of EPS
Postprandial epigastric pain or burning
Pain may be induced by ingestion of a meal, relieved by ingestion of a meal, or may occur while fasting
Postprandial epigastric bloating
Epigastric bloating
Postprandial belching
Excessive 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.
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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
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.
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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.
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
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
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
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
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
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 (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 (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.
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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
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
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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
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, CHES3,41Acute 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 Nomenclature
Criteria
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
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
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 Group
Recommended Intake
Vegetables
≥ 2 servings/meal
Fruits
1–2 servings/meal
Whole grains
As primary carbohydrate source
Legumes
≥ 2 servings/week
Nuts and seeds
1 serving/day
Extra virgin olive oil (EVOO)
Main source of MUFAs; 4–6 tablespoons/day
Fish and seafood
≥ 2 servings/week
Poultry and eggs
Moderate consumption
Red and processed meats
Limited; < 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
encourages 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 Barrier
Proposed Solution
Limited access to fresh produce
Encourage use of frozen or canned vegetables (low-sodium) Promote participation in local food banks or produce voucher programs
High cost of fish and seafood
Suggest affordable alternatives such as canned tuna/salmon (in water) Recommend plant-based omega-3 sources (e.g., flaxseed, chia)
Cost of olive oil and nuts
Promote moderation in use to stretch supply Recommend alternative healthy fats (e.g., canola oil) when necessary
Provide 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
Step
Clinical 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 Principles
Encourage 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-Up
Monitor liver enzymes, weight, and diet adherence Celebrate small wins Use motivational interviewing to maintain momentum
5. Utilize Resources
Recommend apps, cookbooks, or community programs Involve family for support Share visuals or handouts to reinforce learning
6. Refer When Appropriate
Dietitian 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
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8. Ganakumar V, Halebidu T, Goroshi M, Ghatnatti V.
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9. Al-Dayyat HM, Rayyan YM, Tayyem RF. Non-alcoholic
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10. Habib S. Metabolic dysfunction-associated steatotic
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11. Shi Y, Wang Q, Sun Y, et al. The Prevalence of Lean/
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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.
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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
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15. Xing J, Guan X, Zhang Q, Chen S, Wu S, Sun X.
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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.
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
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.
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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.
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