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.
References
1. Asrani SK, Devarbhavi H, Eaton J, Kamath PS. Burden of liver diseases in the world. J Hepatol. 2019;70(1):151-171. doi:10.1016/j.jhep.2018.09.014
2. Kochanek KD. Mortality in the United States, 2022. 2024;(492).
3. Mattiuzzi C, Lippi G. Leading Causes of US Deaths in the 2022. J Clin Med. 2024;13(23):7088. doi:10.3390/jcm13237088
4. Ma C, Qian AS, Nguyen NH, et al. Trends in the Economic Burden of Chronic Liver Diseases and Cirrhosis in the United States: 1996–2016. Am J Gastroenterol. 2021;116(10):2060-2067. doi:10.14309/ajg.0000000000001292
5. Nath P, Anand AC. Extrahepatic Manifestations in Alcoholic Liver Disease. Journal of Clinical and Experimental Hepatology. 2022;12(5):1371-1383. doi:10.1016/j.jceh.2022.02.004
6. Bhandari A, Mahajan R. Skin Changes in Cirrhosis. Journal of Clinical and Experimental Hepatology. 2022;12(4):1215-1224. doi:10.1016/j.jceh.2021.12.013
7. Li CP, Lee FY, Hwang SJ, et al. Spider angiomas in patients with liver cirrhosis: role of alcoholism and impaired liver function. Scand J Gastroenterol. 1999;34(5):520-523. doi:10.1080/003655299750026272
8. Li CP, Lee FY, Hwang SJ, et al. Spider angiomas in patients with liver cirrhosis: role of vascular endothelial growth factor and basic fibroblast growth factor. World J Gastroenterol. 2003;9(12):2832-2835. doi:10.3748/wjg.v9.i12.2832
9. Silvério A de O, Guimarães DC, Elias LFQ, Milanez EO, Naves S. Are the spider angiomas skin markers of hepatopulmonary syndrome? Arq Gastroenterol. 2013;50(3):175-179. doi:10.1590/S0004-28032013000200031
10. Liu Y, Zhao Y, Gao X, et al. Recognizing skin conditions in patients with cirrhosis: a narrative review. Ann Med. 2022;54(1):3017-3029. doi:10.1080/07853890.2022.2138961
11. Satoh T, Yokozeki H, Nishioka K. Vascular spiders and paper money skin improved by hemodialysis. Dermatology. 2002;205(1):73-74. doi:10.1159/000063136
12. Serrao R, Zirwas M, English JC. Palmar erythema. Am J Clin Dermatol. 2007;8(6):347-356. doi:10.2165/00128071-200708060-00004
13. Matsumoto M, Ohki K, Nagai I, Oshibuchi T. Lung traction causes an increase in plasma prostacyclin concentration and decrease in mean arterial blood pressure. Anesth Analg. 1992;75(5):773-776. doi:10.1213/00000539-199211000-00021
14. Waqar MU, Cohen PR, Fratila S. Disseminated Superficial Actinic Porokeratosis (DSAP): A Case Report Highlighting the Clinical, Dermatoscopic, and Pathology Features of the Condition. Cureus. 2022;14(7):e26923. doi:10.7759/cureus.26923
15. Santa Lucia G, Snyder A, Lateef A, et al. Safety and Efficacy of Topical Lovastatin Plus Cholesterol Cream vs Topical Lovastatin Cream Alone for the Treatment of Disseminated Superficial Actinic Porokeratosis: A Randomized Clinical Trial. JAMA Dermatol. 2023;159(5):488. doi:10.1001/jamadermatol.2023.0205
16. Philips CA, Arora A, Shetty R, Kasana V. A Comprehensive Review of Portosystemic Collaterals in Cirrhosis: Historical Aspects, Anatomy, and Classifications. Int J Hepatol. 2016;2016:6170243. doi:10.1155/2016/6170243
17. Chen PT, Tzeng HL, Wang HP, Liu KL. Caput Medusae Bleeding. Am J Gastroenterol. 2020;115(10):1570-1570. doi:10.14309/ajg.0000000000000542
18. Peyrot I, Boulinguez S, Sparsa A, Le Meur Y, Bonnetblanc JM, Bedane C. Bier’s white spots associated with scleroderma renal crisis. Clin Exp Dermatol. 2007;32(2):165-167. doi:10.1111/j.1365-2230.2006.02298.x
19. Terry R. White nails in hepatic cirrhosis. Lancet. 1954;266(6815):757-759. doi:10.1016/s0140-6736(54)92717-8
20. Nelson N, Hayfron K, Diaz A, et al. Terry’s Nails: Clinical Correlations in Adult Outpatients. J Gen Intern Med. 2018;33(7):1018-1019. doi:10.1007/s11606-018-4441-7
21. Neumann HA, Berretty PJ, Folmer SC, Cormane RH. Hepatitis B surface antigen deposition in the blood vessel walls of urticarial lesions in acute hepatitis B. Br J Dermatol. 1981;104(4):383-388. doi:10.1111/j.1365-2133.1981.tb15307.x
22. Gupta R, Fakunle I, Samji V, Hale EB. Serum Sickness-Like Reaction Associated With Acute Hepatitis B in a Previously Vaccinated Adult Male. Cureus. 2021;13(4):e14742. doi:10.7759/cureus.14742
23. Cozzani E, Herzum A, Burlando M, Parodi A. Cutaneous manifestations of HAV, HBV, HCV. Ital J Dermatol Venereol. 2021;156(1). doi:10.23736/S2784-8671.19.06488-5
24. Clark BM, Kotti GH, Shah AD, Conger NG. Severe serum sickness reaction to oral and intramuscular penicillin. Pharmacotherapy. 2006;26(5):705-708. doi:10.1592/phco.26.5.705
25. Trepo C, Guillevin L. Polyarteritis nodosa and extrahepatic manifestations of HBV infection: the case against autoimmune intervention in pathogenesis. J Autoimmun. 2001;16(3):269-274. doi:10.1006/jaut.2000.0502
26. Guillevin L, Mahr A, Callard P, et al. Hepatitis B virus-associated polyarteritis nodosa: clinical characteristics, outcome, and impact of treatment in 115 patients. Medicine (Baltimore). 2005;84(5):313-322. doi:10.1097/01.md.0000180792.80212.5e
27. Dikici B, Uzun H, Konca C, Kocamaz H, Yel S. A case of Gianotti Crosti syndrome with HBV infection. Adv Med Sci. 2008;53(2):338-340. doi:10.2478/v10039-008-0013-0
28. Fergin P. Gianotti-Crosti syndrome. Non-parenterally acquired hepatitis B with a distinctive exanthem. Med J Aust. 1983;1(4):175-176. doi:10.5694/j.1326-5377.1983.tb104350.x
29. Lee S, Kim KY, Hahn CS, Lee MG, Cho CK. Gianotti-Crosti syndrome associated with hepatitis B surface antigen (subtype adr). Journal of the American Academy of Dermatology. 1985;12(4):629-633. doi:10.1016/S0190-9622(85)70085-0
30. To-Figueras J. Association between hepatitis C virus and porphyria cutanea tarda. Mol Genet Metab. 2019;128(3):282-287. doi:10.1016/j.ymgme.2019.05.003
31. Asaad T, Samdani AJ. Association of lichen planus with hepatitis C virus infection. Ann Saudi Med. 2005;25(3):243-246. doi:10.5144p/0256-4947.2005.243
32. Gandolfo S, Richiardi L, Carrozzo M, et al. Risk of oral squamous cell carcinoma in 402 patients with oral lichen planus: a follow-up study in an Italian population. Oral Oncol. 2004;40(1):77-83. doi:10.1016/s1368-8375(03)00139-8
33. Gheorghe C, Mihai L, Parlatescu I, Tovaru S. Association of oral lichen planus with chronic C hepatitis. Review of the data in literature. Maedica (Bucur). 2014;9(1):98-103.
34. Pelet Del Toro N, Strunk A, Garg A, Han G. Prevalence and treatment patterns of lichen planus. J Am Acad Dermatol. Published online November 22, 2024:S0190-9622(24)03236-5. doi:10.1016/j.jaad.2024.09.081
35. Lauletta G, Russi S, Conteduca V, Sansonno L. Hepatitis C virus infection and mixed cryoglobulinemia. Clin Dev Immunol. 2012;2012:502156. doi:10.1155/2012/502156
36. Lunel F, Musset L, Cacoub P, et al. Cryoglobulinemia in chronic liver diseases: role of hepatitis C virus and liver damage. Gastroenterology. 1994;106(5):1291-1300. doi:10.1016/0016-5085(94)90022-1
37. Schamberg NJ, Lake-Bakaar GV. Hepatitis C Virus-related Mixed Cryoglobulinemia: Pathogenesis, Clinica Manifestations, and New Therapies. Gastroenterol Hepatol (N Y). 2007;3(9):695-703.
38. Yokoyama K, Kino T, Nagata T, et al. Hepatitis C Virus-associated Cryoglobulinemic Livedo Reticularis Improved with Direct-acting Antivirals. Intern Med. 2023;62(24):3631-3636. doi:10.2169/internalmedicine.1671-23
39. Abdallah MA, Ghozzi MY, Monib HA, et al. Necrolytic acral erythema: a cutaneous sign of hepatitis C virus infection. J Am Acad Dermatol. 2005;53(2):247-251. doi:10.1016/j.jaad.2005.04.049
40. Khanna VJ, Shieh S, Benjamin J, et al. Necrolytic acral erythema associated with hepatitis C: effective treatment with interferon alfa and zinc. Arch Dermatol. 2000;136(6):755-757. doi:10.1001/archderm.136.6.755
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.
Endoscopic retrograde cholangiopancreaticography (ERCP) is a commonly used therapeutic procedure for diagnostic and therapeutic purposes for various pancreatic-biliary pathologies. Endoscopic sphincterotomy (ES) is a requirement for many biliary interventions. ES can serve as the initial step in the treatment of biliary pathologies, such as the extraction of stones or to allow cholangioscopy or some forms of biliary duct stenting. The outcomes after ES are dependent on the interplay between several factors, including pre-sphincterotomy ductal cannulation, the technique and instrumentation used for sphincterotomy, the post-sphincterotomy therapeutic intervention performed, and finally, the experience and expertise of the endoscopist.1
Approximately 4 to 5% of ES are associated with some degree of adverse event.2 Bleeding is one of the most common adverse events associated with sphincterotomy.3 The bleeding can range from minimal oozing to life-threatening hemorrhage requiring multiple blood transfusions and emergent endoscopic/radiologic/surgical intervention to achieve hemostasis. Understanding the type of sphincterotomy-related bleeding, recognizing high-risk scenarios, and implementing prompt and appropriate hemostatic strategies are key for improving patient outcomes. This article aims to provide a comprehensive overview of the incidence, risk factors, classification, current management strategies, and advanced interventions for refractory cases of endoscopic sphincterotomy-related bleeding.
Incidence
The American Gastroenterological Association (AGA) recognized sphincterotomy as the most important risk factor for bleeding during ERCP as the bleeding from ERCP.3 The incidence of bleeding associated with sphincterotomy can range from 0.5% to 12%.4-8 It is important to note that reporting of the incidence of bleeding varies and is highly dependent on the definition used by the investigators and authors across studies. Some studies define bleeding as a clinical diagnosis (melena or hematemesis) with laboratory evidence of a drop in hemoglobin while others include any bleeding at all, even mild, self-limited oozing. For example, the MESH study by Freeman et al. reported an incidence of bleeding post-ES of 2%.6 Others consider bleeding as endoscopic evidence after performing sphincterotomy. For example, Kim et al. and Leung et al. defined post-sphincterotomy bleeding as an adverse event if the bleeding did not subside after two to three minutes following sphincterotomy.7,8 Hence, the reported incidence was greater, 12.1% and 10.4%, respectively. Nonetheless, the incidence of bleeding as an adverse event post-sphincterotomy has decreased over time. From 10-12% in the 1990s, the current guidelines by the American Society for Gastrointestinal Endoscopy and the AGA cite an expected rate of sphincterotomy-associated bleeding as approximately 1 to 2%, likely representing advanced in sphincterotomy generator waveforms.9
Risk Factors
The risk factors for post-ES bleed include liver cirrhosis, end-stage renal disease, difficult cannulation, precut sphincterotomy and lower ERCP case volumes.9,10,11 The AGA identifies coagulopathy, anticoagulant therapy within three days of procedure, cholangitis, low endoscopist case volume (less than 1 per week), and additional therapeutic maneuvers including ampullectomy as risk factors for bleeding with ES.3 The risks specific for ES can be grouped depending on patient and procedure. A retrospective study by Lin et al. reported significantly increased incidence of post-sphincterotomy bleeding in patients with cirrhosis (OR 3.1), end stage renal disease (OR 3.55), antiplatelet use within three days before or after the procedure (OR 4.95), CBD dilation (OR 1.24) and history of duodenal ulcers (OR 2.06).10 Similarly, the endoscopist experience and the number of sphincterotomies/ERCPs performed also play an important role. For example, mean case volume of ≤ 1/week was associated with 74% significantly higher odds of bleed compared to operators with a high case volume.6
Kim et al. in their prospective analysis found statistically higher bleeding rates with a needle-knife sphincterotome compared to a traditional pull-type sphincterotome (79.4% vs 20.6%, p < 0.025). Moreover, bleeding was significantly more with zipper cuts (3.7% vs 1.2%, p 0.049%).7 However, it is important to note that with recent advancements in the field of advanced endoscopy and newer devices, zipper cuts are extremely rare. Bae et al. showed that the length of ES as an independent risk factor for bleeding.12 Full length (papillary orifice up to the superior margin of the sphincter opening, OR 68.27) was associated with the highest risk followed by medium length (papillary orifice to the midpoint between the proximal hooding fold and the superior margin of sphincter opening, OR 10.97) and then minimal length (papillary orifice to the proximal hooding fold, OR 1). It should be noted that, in general, a complete sphincterotomy is best for the patient. Evidence of extension of previous ES is mixed. While some studies state that it does not affect the risk of bleeding, Leung et al. reported significantly increased risk.3 Prabhu et al. in their review paper explained how sphincterotomy extension was safe without significant risk of adverse events.13
The type of device used for ES also plays an important role. Perini et al. in their study showed that the ValleyLab generator, which is no longer in clinical use, was associated with increased endoscopically evident bleeding (OR 4.02) compared to the microprocessor- controlled generator (ICC 200; ERBE). The ValleyLab generator was associated with increased occurrence of moderate or severe bleeding with increased requirement of urgent endoscopic intervention. It has since been replaced by modern electrosurgical generators.
Classification of Sphincterotomy-Associated Bleeding
Bleeding can be broadly classified as clinically significant or insignificant. Clinically important bleeding can be defined as any bleed that requires intervention (endoscopic hemostasis, transfusion, etc.) and is visible not only through endoscopy but also in the form of melena/hematemesis/hematochezia with a significant drop in hemoglobin.
Cotton et al. proposed a grading system to classify bleeding based on its severity.14 Bleeding can be classified into mild, moderate, and severe. Mild bleeding is defined as clinically apparent bleeding with a hemoglobin drop of less than 3 g/dL that does not require transfusion. Moderate bleeding refers to bleeding that necessitates transfusion of up to four units of blood, without the need for angiographic or surgical intervention. Severe bleeding involves the transfusion of five or more units and/or requires angiographic or surgical management. A clinically insignificant bleed would broadly include all the bleeds that do not fit the above criteria. However, in essence, the distinction between clinically significant and insignificant bleeding after a sphincterotomy is made via clinical judgment and observation and hinges on the impact on the patient’s health and the level of medical intervention required to control the bleeding.
Freeman et al. reported a rate of 2% clinically significant bleeds, out of which 0.6% were mild (not requiring transfusion), 0.9% were moderate (requiring up to 4 units of blood), and 0.5% had severe bleeds (5 or more units of blood, surgery, or angiography).6 Similarly, other studies mostly report mild to moderate bleeding as the most common bleeding severity after sphincterotomy. Leung et al. in their study reported mild, moderate, and severe bleeds as 92.4%, 6.7% and 0.9%, respectively.8
Clinically evident bleeds can become life-threatening emergencies requiring massive blood transfusions, endoscopic interventions, and/or interventional radiology (IR) intervention for embolization. Freeman et al. reported 43.75% post-sphincterotomy patients requiring endoscopic intervention for hemostasis, and 4.2% patients required surgical intervention.6 Death occurred in 4.2% of cases despite aggressive intervention.
Bleeding can also be classified as immediate or delayed based on the timing/onset of bleeding. Immediate bleeding usually occurs during the procedure and is evident by oozing or spurting of blood and is directly observed with the duodenoscope.6,8 However, this may not be clinically significant and in the majority of instances it is self-limiting and managed conservatively.6,8,15
Delayed bleeding refers to a clinically significant bleed occurring after the sphincterotomy, with usually biochemical evidence of hemoglobin drop.8,9 Freeman et al. reported delayed bleeding 1-10 days post-sphincterotomy in 52% cases.6 Lin et al. in their study reported 69.2% immediate and 30.8% delayed bleeds.10 Beyond that, 20% of these severe bleeds were more severe than those with immediate bleeding. Reported delayed bleeding rates were lower in the study by Leung et al., at 4.2% with all cases requiring blood transfusions and repeat endoscopic intervention.8 This indicates that delayed bleeding, although less frequent, can be more fatal compared to immediate bleeding.
Management of Sphincterotomy Induced Bleeding
The cornerstones of managing post-sphincterotomy bleeding are rapid recognition, risk stratification, and immediate availability of appropriate endoscopic tools and expertise. Immediate bleeding, typically identified during ERCP, is addressed using a stepwise endoscopic approach based on bleeding severity and visibility. It should be noted that mild bleeding often stops spontaneously and, if not interfering with visualization, may not require treatment per se.
If treatment is desired, balloon tamponade is usually the first method applied for mild bleeds and this technique can be supplemented with other treatment interventions if adequate hemostasis is not achieved in short order. Injection of epinephrine, hemostatic clips, stents, and thermal coagulation are commonly used endoscopic interventions for hemostasis.4 Topical agents can be used as adjuvants. Delayed bleeding is managed with supportive care and resuscitation with blood products, followed by repeat endoscopy for definitive control if bleeding does not stop spontaneously. In cases with severe bleeding, referral to interventional radiology for angiography with embolization or, rarely, surgical intervention may be necessary. The choice of intervention is often governed by whether the bleed is immediate or delayed, intermittent or ongoing, mild or severe, and the patient’s overall stability. In the following sections, we will discuss the various treatment interventions in detail that can be used to achieve hemostasis in post-sphincterotomy bleeding.
Tamponade
Balloon tamponade is frequently used to control sphincterotomy bleeding and ensure adequate visualization of the bleeding site. (Figure 1) The balloon exerting direct pressure on the bleeding vessel promotes clot formation and hemostasis. This tamponade is most commonly provided using a standard stone extraction balloon or, less frequently, a dilation balloon.16 One advantage of this approach is that the bleeding site can often be directly visualized through the clear plastic of the balloon itself, allowing for interrogation and direct confirmation of ongoing bleeding or cessation of bleeding.
Balloon tamponade is an effective strategy especially for immediate onset bleeding after sphincterotomy. A recent study by Askora et al. showed that balloon tamponade was successful in achieving hemostasis in 10 of 18 subjects (55.6%), and an additional 4 subjects (22.2%) achieved hemostasis after 5 minutes of tamponade.17 Hence, it can be easily used by the endoscopist in cases of immediate post-ES bleed and often the first line of intervention.18 Staritz, et al. used balloon catheters in two cases of severe hemorrhage from the papillary orifice and reported cessation of bleeding after ten minutes.19
Despite the advantages and ease of use of balloon tamponade, it is not free of the risk of adverse events. It can lead to mucosal ischemia through increased pressure application to the mucosal surface during tamponade, although such events are rare. Other adverse events associated with balloon tamponade include bile duct injury, perforation, pancreatitis and cholangitis, and these risks are likely higher with dilation balloons than with retrieval balloons.10,20 Edema or spasm of the pancreatic duct or the biliary duct due to pressure application from the tamponade can contribute to these adverse events. Hence, the endoscopist should be careful in selecting a balloon of appropriate size, ensuring adequate but not undue inflation pressure, and just enough duration of balloon application to avoid adverse events. Despite that, balloon tamponade is a minimally invasive and highly effective intervention for initial use. It is also a cost-effective intervention option compared to more invasive procedures.
Local Injections
Local injection therapy, most commonly with epinephrine, remains a commonly employed technique for controlling post-sphincterotomy bleeding. Injection with diluted epinephrine (1:10000 to 1:20000) is mostly effective in achieving hemostasis by two methods: vasoconstriction and mechanical tamponade by volume of fluid injected into submucosal space surrounding the vessel which compresses it and facilitates thrombosis.15 It should be noted that not all available injection catheters work through a duodenoscope, and simple plastic catheters may be deformed by the elevator mechanism of the duodenoscope and thus fail. Tsou et al. reported epinephrine injection alone was as effective as combination treatment with epinephrine injection and thermotherapy (96.2% vs 100%, p 0.44).22 Apart from epinephrine, hypertonic saline-epinephrine, dextrose-epinephrine, and polidocanol have also been utilized. Sakai et al. reported 100% successful hemostasis with hypertonic-epinephrine injection.23 Hence, local injections can be effectively used as first line agents to achieve hemostasis for mild bleeding and can be used as an adjunctive initial method which can then be followed immediately by a definitive treatment with clipping or thermal coagulation. Recently, fibrin glue has also been reported as an alternative to refractory post-ES bleeding. It contains fibrinogen and thrombin and promotes thrombogenesis to achieve hemostasis. Orlandini et al. reported 91.4% clinical success rate with one injection of fibrin glue in refractory post-ES bleeds.24 Out of the remaining 8.6%, half responded to a second injection of fibrin glue.
Thermal Coagulation
Thermal coagulation plays a significant role in achieving hemostasis when local injection has failed to provide adequate hemostasis. Thermal therapies include monopolar or bipolar electrocautery, heater probes and argon plasma coagulation. (Figure 2) Controlled thermal energy delivered through these techniques cauterizes the bleeding site and can often result in durable hemostasis.25 It should be noted that the cutting wire of the sphincterotome itself can be used to provide monopolar electrocautery to the bleeding site. Katsinelos et al. reported monopolar cautery was 100% successful in controlling post-ES bleeding which was not controlled with epinephrine injection alone.26 Similarly, Sherman et al. reported an 89% hemostasis rate with bipolar cautery in post-ES bleeds.27 A key advantage of thermal methods over injection alone is the creation of a more durable seal with the possibility of coaptation (thus compressing and cauterizing the bleeding vessel at the same time) leading to significantly lower rates of rebleeding. Combination therapies consisting of epinephrine injections and thermal coagulation have also been widely used. Tsou et al. reported 100% success rate in achieving hemostasis across all 37 patients who were treated with combination therapy.22
Clipping
For refractory bleeding not controlled by tamponade or hemostatic topical agents, endoscopic clips can be used. Application of clip is technically challenging with a side viewing endoscope as the small mechanical parts of through-the-scope (TTS) clips can become damaged by the elevator mechanism of the duodenoscope, but some TTS clips work despite this challenge. Cap-assisted end-viewing endoscopes can potentially overcome this problem. Clips can be deployed directly onto the bleeding site, and they can be effective for both active bleeding and for prophylactic prevention. TTS clip application through end-viewing endoscope can achieve successful hemostasis in 90% cases.28 Kim et al. retrospectively evaluated the efficacy of clips for post-ES induced bleeding that was not controlled with epinephrine injection or tamponade. They reported a 100% success rate with no delayed bleeding or complications in all 45 patients treated with clips.29
A propensity score matched analysis conducted by Jinpei et al. in 2024 compared prophylactic hemostatic clip placement after ES with 232 patients in the hemostatic clip group and 161 in the control arm. They reported significantly lower odds of delayed bleeding in the hemostatic clip group arm (OR 0.134, 95% CI 0.025 – 0.719).30 Similarly, Chon et al. reported 100% success rates in all 57 subjects who were managed with endoclip for controlling post-ES bleed.31 Care must be taken to avoid inadvertent closure of the bile or pancreatic duct while placing the clip. However, such adverse events are very rare. Moreover, no significant adverse events have been reported associated with the clips. Clips are a good alternative for refractory post-ES bleeding uncontrolled by injections/ tamponade, which is easier to perform and has low chance of adverse events.
Stenting
Stents are another treatment alternative for post-ES bleeds uncontrolled with topical agents/ tamponade, and in general covered metal stents are used to treat sphincterotomy bleeding. Itoi et al. suggested 10 mm as an ideal diameter size of the stent.32 Fully covered self-expandable metal stents (FC-SEMS) have been shown to provide excellent tamponade. (Figure 3) Cochrane et al. reported FC-SEMS had significantly lower rate of bleeding at 72 hours compared to traditional endoscopic interventions (tamponade/epinephrine injection).33
In a retrospective study by Bilal et al. including 97 patients, FC-SEMS had a 100% technical success rate in achieving immediate hemostasis and 94% success in achieving durable clinical success for delayed hemostasis. Rebleeding was noted in 6.2% cases which were managed with repeat EGD/ERCP, embolization and surgery.34 The adverse events reported post FC-SEMS included pancreatitis in 4.1% cases and stent migration in 4.1% cases. Even though FC-SEMS have good success rates, due to the higher costs and adverse events associated they are considered as treatment alternatives after conventional endoscopic interventions like tamponate, topical agents or cauterization have failed to control bleeding. FC-SEMS are generally removed several weeks after placement when used to treat sphincterotomy bleeding.
Topical Agents
Topical agents represent a significant advancement in the treatment of GI bleeding, offering a non-mechanical method of hemostasis ideally suited for achieving hemostasis for diffuse hemorrhage or anatomically difficult locations which cannot be controlled by local injections, tamponade or clips. Hemospray (Cook Endoscopy, Winston-Salem NC) acts as a mechanical barrier between the bleeding vessel and the lumen. When applied to the bleeding surface, it absorbs water from the blood and tissue fluids, leading to concentration of clotting factors and platelets. This promotes formation of an adhesive plug that covers the mucosal defect and applies physical tamponade on the bleeding vessel promoting hemostasis.35 Purastat (3-D Matrix, Inc., Tokyo, Japan) is another topical agent used for post-ES bleeds. It is a synthetic hemostatic agent made of amino acids and forms a three-dimensional scaffold after coming in contact with blood.36 This scaffold mimics the human extracellular matrix causing an adhesive effect and promoting hemostasis at the bleeding site. Another agent used is Beriplast (CSL Behring, Marburg, Germany), a fibrin sealant, which mimics final steps of the coagulation cascade to achieve hemostasis.37
Studies have shown high rates of immediate hemostasis (>90%) with Hemospray in achieving hemostasis for gastrointestinal bleeds.38 However, studies evaluating the use of Hemospray for post-ES bleeds are limited. Lesmana et al. in their retrospective study compared Beriplast and Purastat with conventional hemostatic techniques (epinephrine / balloon tamponade) for post-ES bleeds. The study involved 100 patients with 60 patients in the study arm (Beriplast or Purastat) and 40 patients in the control arm (conventional hemostatic agents). They reported a 100% success rate in achieving immediate hemostasis in both the arms. However, two patients (5%) in the control arm had rebleed while none were reported in the study arm. Out of these two patients, one was managed with one out of the two hemostatic agents (Beriplast or Purastat) and the other was managed with argon plasma coagulation.39
A recent RCT was performed comparing the efficacy of a polysaccharide hemostatic powder (XunNing®; Lianbai Bochao Medical Equipment, Chongqing, China) to endoclips for post-ES non-pulsatile bleeding. The study included 104 subjects with 52 each in the study and control arm. Immediate hemostasis was achieved in 100% subjects with polysaccharide hemostatic powder (PHP) while it was 92.3% with endoclip use (p = 0.022). Overall treatment success, which was defined as immediate hemostasis with no delayed bleeding, was significantly more with the PHP use (100% vs 90.4%; P = 0.022). Moreover, hemostasis was achieved in a shorter time with PHP (50.77 vs. 62.81 sec, p = 0.011).40
With topical agents, the primary concern is rebleeding. Hemospray use for gastrointestinal bleeds have shown rebleed rates of as high as 10% to 30%.32 Moosavi et al. reported a case of transient biliary obstruction after application of hemospray for post-ES bleed.41 Despite promising results from Lesmana et al., prospective studies specifically evaluating topical agents for post-sphincterotomy bleeding are needed.39
IR/surgery for Profound Post-ES bleeding
With advancements in the endoscopic techniques, only a small subset of patients with post-sphincterotomy bleeding will require intervention beyond endoscopy. IR-guided embolization is the preferred next-step modality for hemodynamically unstable patients with ongoing bleeding that is refractory to endoscopic control or when endoscopic visualization is impossible. The IR approach involves angiographic localization of bleeding source, typically the posterior pancreaticoduodenal artery and/or one of the branches of the gastroduodenal artery followed by embolization with coils, particles or glue. Maleux et al. reported 97% successful embolization in post-ES bleeding that was refractory to medical and endoscopic treatment.42 If bleeding is from duodenal varices, IR approaches may have difficulty in fully stopping it. Recurrent bleeding occurred in 9% cases and 30-day mortality was 20.6%. The high mortality rates in this study were attributed to hemostatic disorders characterized by increased international normalized ratio (INR) and activated partial thromboplastin time (aPTT) with statistically significant correlation between the 30-day mortality and elevated levels of INR and aPTT (P value of 0.008 and 0.012, respectively).
Shenbagaraj et al., in their retrospective study, reported 100% success (n=4) with embolization in post-ES bleeds that were refractory to endoscopic intervention.43
Surgery remains the definitive treatment of last resort, reserved for cases who have failed embolization or when bleeding is too massive for endoscopic or angiographic control. The surgical options include open surgical vessel ligation or surgical repair of the duodenum and papilla. Most commonly performed surgery is duodenotomy with direct suture ligation of bleeding vessels at the sphincterotomy site.4 More extensive procedures such as pancreaticoduodenectomy are rarely required and carry significant morbidity and mortality.
The choice between IR guided intervention and surgery is multidisciplinary, dependent on patient clinical stability, anatomy and expertise available at the treatment center. However, the minimally invasive nature of angioembolization is considered as a bridge between failed endoscopy and high-risk surgery.
Conclusion
Post-ES bleeding is a well- reported adverse event which, in general, requires a structured approach for management. The cornerstone of treatment is endoscopic intervention. Epinephrine injection, balloon tamponade, thermal coagulation, and the use of endoscopic clips are foundational treatment modalities. For refractory cases, FC-SEMS and topical hemostatic agents offer valuable alternatives before considering angioembolization or surgery.
References
References
1. Neuhaus H. Biliary sphincterotomy. InERCP 2019 Jan 1 (pp. 137-147). Elsevier.
2. Perini RF, Sadurski R, Cotton PB, Patel RS, Hawes RH, Cunningham JT. Post-sphincterotomy bleeding after the introduction of microprocessor-controlled electrosurgery: does the new technology make the difference?. Gastrointestinal endoscopy. 2005 Jan 1;61(1):53-7.
3. Adler DG, Lieb JG, Cohen J, Pike IM, Park WG, Rizk MK, Sawhney MS, Scheiman JM, Shaheen NJ, Sherman S, Wani S. Quality indicators for ERCP. Official journal of the American College of Gastroenterology| ACG. 2015 Jan 1;110(1):91-101.
4. Ferreira LE, Baron TH. Post-sphincterotomy bleeding: who, what, when, and how. Official journal of the American College of Gastroenterology| ACG. 2007 Dec 1;102(12):2850-8.
5. Goodall RJ. Bleeding after endoscopic sphincterotomy. Annals of the Royal College of Surgeons of England. 1985 Mar;67(2):87.
6. Freeman ML, Nelson DB, Sherman S, Haber GB, Herman ME, Dorsher PJ, Moore JP, Fennerty MB, Ryan ME, Shaw MJ, Lande JD. Complications of endoscopic biliary sphincterotomy. New England Journal of Medicine. 1996 Sep 26;335(13):909-19.
7. Kim HJ, Kim MH, Kim DI, Lee HJ, Myung SJ, Yoo KS, Park ET, Lim BC, Seo DW, Lee SK, Min YI. Endoscopic hemostasis in sphincterotomy-induced hemorrhage: its efficacy and safety. Endoscopy. 1999 Aug;31(06):431-6.
8. Leung JW, Chan FK, Sung JJ, Chung SS. Endoscopic sphincterotomy-induced hemorrhage: a study of risk factors and the role of epinephrine injection. Gastrointestinal endoscopy. 1995 Dec 1;42(6):550-4.
10. Lin WC, Lin HH, Hung CY, Shih SC, Chu CH. Clinical endoscopic management and outcome of post-endoscopic sphincterotomy bleeding. PloS one. 2017 May 17;12(5):e0177449.
11. Nelson DB, Freeman ML. Major hemorrhage from endoscopic sphincterotomy: risk factor analysis. Journal of clinical gastroenterology. 1994 Dec 1;19(4):283-7.
12. Bae SS, Lee DW, Han J, Kim HG. Risk factor of bleeding after endoscopic sphincterotomy in average risk patients. Surgical endoscopy. 2019 Oct 15;33(10):3334-40.
13. Parbhu S, Adler DG. Extension of a Prior Biliary or Pancreatic Sphincterotomy: Efficacy, Outcomes, and Adverse Events. PRACTICAL GASTROENTEROLOGY. 2016 Jan 1;40(1):21-32.
14. Cotton PB, Lehman G, Vennes J, Geenen JE, Russell RC, Meyers WC, Liguory C, Nickl N. Endoscopic sphincterotomy complications and their management: an attempt at consensus. Gastrointestinal endoscopy. 1991 May 1;37(3):383-93.
15. Wilcox CM, Canakis J, Mönkemüller KE, Bondora AW, Geels W. Patterns of bleeding after endoscopic sphincterotomy, the subsequent risk of bleeding, and the role of epinephrine injection. Official journal of the American College of Gastroenterology| ACG. 2004 Feb 1;99(2):244-8.
16. Rustagi T, Jamidar PA. Endoscopic retrograde cholangiopancreatography–related adverse events: general overview. Gastrointestinal Endoscopy Clinics. 2015 Jan 1;25(1):97-106.
17. Askora AA, Ibrahim AM, Elgohary M, Saad N, Abu Taleb MA. Efficacy and Safety of Balloon Tamponade in Control of Post Sphincterotomy Bleeding During Endoscopic Retrograde Cholangiopancreatography. Zagazig University Medical Journal. 2025 May 1;31(5):1911-27.
18. Ghoz HM, Dayyeh BK. Hemorrhagic complications following endoscopic retrograde cholangiopancreatography. Techniques in Gastrointestinal Endoscopy. 2014 Oct 1;16(4):175-82.
19. Staritz M, Ewe K, Goerg K, Meyer zum Büschenfelde KH. Endoscopic balloon tamponade for conservative management of severe hemorrhage following endoscopic sphincterotomy. Zeitschrift fur Gastroenterologie. 1984 Nov 1;22(11):644-6.
20. Mustafa FM, Ali HF. Endoscopic management of ERCP bleeding. The Egyptian Journal of Hospital Medicine. 2019 Apr 1;75(5):2888-93.
21. Matsushita M, Uchida K, Okazaki K. Effective injection site on endoscopic injection therapy for postsphincterotomy bleeding: apex or oral?. Official journal of the American College of Gastroenterology| ACG. 2008 Jun 1;103(6):1569-70.
22. Tsou YK, Lin CH, Liu NJ, Tang JH, Sung KF, Cheng CL, Lee CS. Treating delayed endoscopic sphincterotomy-induced bleeding: epinephrine injection with or without thermotherapy. World Journal of Gastroenterology: WJG. 2009 Oct 14;15(38):4823.
23. Sakai Y, Tsuyuguchi T, Sugiyama H, Nishikawa T, Kurosawa J, Saito M, Tawada K, Mikata R, Tada M, Ishihara T, Yokosuka O. Hypertonic saline-epinephrine local injection therapy for post-endoscopic sphincterotomy bleeding: removal of blood clots using pure ethanol local injection. Surgical Laparoscopy Endoscopy & Percutaneous Techniques. 2013 Aug 1;23(4):e156-9.
24. Orlandini B, Schepis T, Tringali A, Familiari P, Boškoski I, Borrelli de Andreis F, Perri V, Costamagna G. Fibrin glue injection: Rescue treatment for refractory post-sphincterotomy and post-papillectomy bleedings. Digestive Endoscopy. 2021 Jul;33(5):815-21.
25. Kuran S, Parlak E, Oguz D, Cicek B, Disibeyaz S, Sahin B. Endoscopic sphincterotomy–induced hemorrhage: treatment with heat probe. Gastrointestinal endoscopy. 2006 Mar 1;63(3):506-11.
26. Katsinelos P, Kountouras J, Chatzimavroudis G, Zavos C, Fasoulas K, Katsinelos T, Pilpilidis I, Paroutoglou G. Endoscopic hemostasis using monopolar coagulation for postendoscopic sphincterotomy bleeding refractory to injection treatment. Surgical Laparoscopy Endoscopy & Percutaneous Techniques. 2010 Apr 1;20(2):84-8.
27. Sherman S, Hawes RH, Nisi R, Lehman GA. Endoscopic sphincterotomy-induced hemorrhage: treatment with multipolar electrocoagulation. Gastrointestinal endoscopy. 1992 Mar 1;38(2):123-6.
28. Liu F, Wang GY, Li ZS. Cap-assisted hemoclip application with forward-viewing endoscope for hemorrhage induced by endoscopic sphincterotomy: a prospective case series study. BMC gastroenterology. 2015 Oct 15;15(1):135.
29. Kim TH, Sohn YW. Mo1428 Hemoclip Application Using CAP-Fitted Forward Endoscopy to Treat Post-Sphincterotomy Bleeding in Patients Undergoing ERCP. Gastrointestinal Endoscopy. 2015 May 1;81(5):AB416.
30. Dong J, Feng Q, Teng G, Niu H, Bian D. Application of a New Hemostatic Clip to Prevent Delayed Bleeding After Endoscopic Sphincterotomy: A Propensity Score–matched Analysis. Journal of Clinical Gastroenterology. 2024 Jul 1;58(6):614-8.
31. Chon HK, Kim TH. Endoclip therapy of post-sphincterotomy bleeding using a transparent cap-fitted forward-viewing gastroscope. Surgical Endoscopy. 2017 Jul;31(7):2783-8.
32. Itoi T, Yasuda I, Doi S, Mukai T, Kurihara T, Sofuni A. Endoscopic hemostasis using covered metallic stent placement for uncontrolled post-endoscopic sphincterotomy bleeding. Endoscopy. 2011 Apr;43(04):369-72.
33. Cochrane J, Schlepp G. Comparing endoscopic intervention against fully covered self-expanding metal stent placement for post-endoscopic sphincterotomy bleed (CEASE Study). Endoscopy International Open. 2016 Dec;4(12):E1261-4.
34. Bilal M, Chandnani M, McDonald NM, Miller CS, Saperia J, Wadhwa V, Singh S, Cohen JM, Berzin TM, Sawhney MS, Pleskow DK. Use of fully covered self-expanding metal biliary stents for managing endoscopic biliary sphincterotomy related bleeding. Endoscopy International Open. 2021 May;9(05):E667-73.
35. Holster IL, van Beusekom HM, Kuipers EJ, Leebeek FW, de Maat MP, Tjwa ET. Effects of a hemostatic powder hemospray on coagulation and clot formation. Endoscopy. 2015 Jul;47(07):638-45.
36. Subramaniam S, Kandiah K, Thayalasekaran S, Longcroft-Wheaton G, Bhandari P. Haemostasis and prevention of bleeding related to ER: The role of a novel self-assembling peptide. United European gastroenterology journal. 2019 Feb;7(1):155-62.
37. Eberhard U, Broder M, Witzke G. Stability of Beriplast® P fibrin sealant: Storage and reconstitution. International journal of pharmaceutics. 2006 Apr 26;313(1-2):1-4.
38. Chahal D, Sidhu H, Zhao B, Jogendran M, Dahiya M, Tandon P, Donnellan F. Efficacy of Hemospray (TC-325) in the treatment of gastrointestinal bleeding: an updated systematic review and meta-analysis. Journal of Clinical Gastroenterology. 2021 Jul 1;55(6):492-8.
39. Lesmana CR, Sandra S, Paramitha MS, Gani RA, Lesmana LA. Endoscopic Management Using Novel Haemostatic Agents for Immediate Bleeding during Endoscopic Retrograde Cholangio-Pancreatography. Canadian Journal of Gastroenterology and Hepatology. 2023;2023(1):5212580.
40. Li H, Zuo J, Wang W, Wu S, Zhao Y, Wei Y, Song J, Zhang Z, Yao W, Wang J, Liu C. Efficacy of Polysaccharide Hemostatic Powder on blood oozing among patients with Post-Endoscopic Sphincterotomy Bleeding: A Randomized Controlled Trial. Official journal of the American College of Gastroenterology| ACG. 2022 May 12:10-4309.
41. Moosavi S, Chen YI, Barkun AN. TC-325 application leading to transient obstruction of a post-sphincterotomy biliary orifice. Endoscopy. 2013 Dec;45(S 02):E130-.
42. Maleux G, Bielen J, Laenen A, Heye S, Vaninbroukx J, Laleman W, Verhamme P, Wilmer A, Van Steenbergen W. Embolization of post-biliary sphincterotomy bleeding refractory to medical and endoscopic therapy: technical results, clinical efficacy and predictors of outcome. European radiology. 2014 Nov;24(11):2779-86.
43. Shenbagaraj L, White J, Czajkowski M, Allison M. PTU-116 Delayed post sphincterotomy bleeding and management–4 year single centre experience.
The management of inflammatory bowel disease (IBD) during pregnancy presents unique challenges, requiring a balance between maternal health, disease control, and fetal well-being. A global consensus conference, led by a multidisciplinary team of gastroenterologists, content specialists, and patient advocates was held in May 2024 to standardize care across countries with evidence-based recommendations. In this article, key guidance is provided on preconception counseling, maintaining disease remission, and safe medication use throughout pregnancy and lactation. We also address fertility preservation, risk mitigation during delivery, and neonatal outcomes. Collaboration between gastroenterologists, obstetricians and colorectal surgeons (if needed) is essential to optimize outcomes. This article also provides recommendations for a foundation of consistent care and highlights areas for future research, particularly regarding novel therapies and long-term neonatal health.
Introduction
The management of inflammatory bowel disease (IBD) during pregnancy is a complex intersection of maternal health, fetal development, and disease management. This article synthesizes global consensus derived from the recent international meeting of leading gastroenterologists, maternal-fetal medicine experts, and patient advocates.1 The guidelines aim to standardize IBD care during pregnancy, emphasizing evidence-based practices while considering regional variations in resources. This summary highlights the key findings and actionable recommendations for gastroenterologists.
Methodology
The GRADE (Grading of Recommendations Assessment, Development, and Evaluation) system provided a robust framework to assess the quality of evidence and the strength of recommendations. For questions that had inadequate data for GRADE, the RAND appropriateness method was used to vote on consensus recommendations.
Preconception Counseling and Optimization
Pregnancy represents a period of intense metabolic, hormonal, microbiome and immunological changes. The interaction between pregnancy and IBD is bi-directional, and it may increase the risk of maternal, fetal and obstetric complications.2,3 Proactive management before conception is critical to minimize risks for both mother and child.
Women with IBD are advised to achieve stable disease remission and optimize their nutritional status before conception to improve pregnancy outcomes. Preconception counseling is also recommended to enhance medication adherence, reduce the risk of disease flares during pregnancy, and minimize the likelihood of delivering low birth weight infants.
Fertility
Women with IBD may have reduced fertility compared to women without IBD due to reduced ovarian reserve.4 While there is a lack of data, based on the experience of the expert group, they may undergo oocyte retrieval without increased risk of flare. Additionally, women with IBD are suggested to have a higher risk of infertility when their disease is active compared to when it is in remission. In women with ulcerative colitis (UC), undergoing an ileal pouch anal anastomosis (IPAA) is associated with reduced fertility in comparison to UC patients who have not had this surgical procedure. However, women with IBD may have similar success rates with assisted reproductive technology (ART), including live birth outcomes, as women without IBD. Similarly, those who have undergone pelvic surgery for IBD show comparable effectiveness of in vitro fertilization (IVF) in terms of live birth rates to their non-IBD counterparts.
Table 1. Optimal Timing for IBD Therapy Discontinuation Prior to Conception
Drug
Recommended Time to Discontinue Before Conception*
Ozanimod
At least 3 months
Etrasimod
At least 1–2 weeks
Tofacitinib
At least 4 weeks
Upadacitinib
At least 4 weeks
Filgotinib
At least 4 weeks
Maternal Factors Impacting Pregnancy
The risk of developing UC and Crohn’s Disease (CD) among offspring of patients with IBD is 2-13 times higher than the risk in the general population.5 Furthermore, children born to a parent with CD may have higher risk of developing IBD than children born to a parent with UC.5 IBD disease activity is also positively associated with adverse pregnancy outcomes such as pre-term birth, low birth weight and small for gestation age.6,7 The placenta is an embryonic/fetal organ that expresses an equal complement of maternal and paternal genes without eliciting a maternal immune response and rejection of this organ. The placenta is a highly immunologic organ and may have a role in adverse outcomes among women with immune dysfunction.8 Additionally, maternal and fetal microbiome may be altered through prenatal antibiotic use and maternal diet, possibly leading to an increased risk of IBD in offspring.9,10
Disease Activity Management During Pregnancy
Maintaining disease remission throughout pregnancy is essential, as active disease correlates with adverse maternal and fetal outcomes. Pregnancy is marked by significant immunological changes, which may require medication adjustment and disease monitoring, with noninvasive tools, preferentially.
We recommend that IBD surgery during pregnancy be performed when it is required, without basing the decision solely on the trimester. Endoscopy should be considered only when it is likely to influence treatment decisions. In cases where cross-sectional imaging is needed during pregnancy, the use of intestinal ultrasound or MRI without gadolinium is preferred over a CT scan. Additionally, fecal calprotectin is suggested as a useful tool for monitoring disease activity throughout pregnancy.
Management of Pregnancy and Delivery
Pregnancies for women with IBD should be considered high risk. Aside from maintaining IBD remission, successful pregnancy and delivery in women with IBD require careful consideration of several nuanced factors. Women with IBD should be assessed early in pregnancy or preconception for nutritional status, weight gain and micronutrient deficiency. Pregnant women with IBD are also at an elevated risk for developing preeclampsia.11 The presence of an IPAA or perianal disease plays a critical role in determining the most appropriate mode of delivery. Disease activity monitoring and continuation/resumption of maintenance therapy in the postpartum period are vital.
We recommend that pregnant women with IBD begin taking low-dose aspirin with food between 12 and 16 weeks of gestation to reduce the risk of developing preterm preeclampsia, noting that there is no evidence of an increased risk of IBD flare with this practice12,13 and that stopping aspirin at week 36 may help reduce the risk of bleeding. Additionally, for those with Crohn’s disease and active perianal disease, we recommend opting for a cesarean section to prevent the worsening of perianal symptoms. Furthermore, we suggest that pregnant women with IBD who have previously undergone an IPAA consider cesarean section, as this may help reduce the risk of a decline in pouch function that can be associated with a complicated vaginal delivery.
Medication Use DuringPregnancy and Conception
IBD medications can generally be continued on schedule throughout pregnancy and lactation. This includes all biologics and biosimilars, mesalamine and thiopurines. The exceptions are methotrexate (teratogen – absolute contraindication) and janus kinase (JAK) inhibitors and sphingosine-1-phosphate (S1P) receptor modulators – which should be avoided unless essential for maternal health (Table 1). Disease activity at conception and during pregnancy, and de-escalation of biologics during pregnancy or after delivery are associated with postpartum disease activity and increased complications of labor and delivery in women with IBD. Continuing effective medication can mitigate this risk.14
Corticosteroid therapy may be used when clinically necessary with appropriate monitoring, as data do not demonstrate an increased risk of congenital malformation. However, the drug and/or underlying disease activity may lead to increased complications for infant and mother.
Table 2. Medical Therapy Recommendations During Pregnancy and Conception
Medication Category
Management
5-ASA
Continue for maintenance therapy
Sulfasalazine
Continue throughout pregnancy. Folic acid 2 mg daily
Corticosteroids
Use when clinically necessary, with appropriate monitoring
Should be discontinued one to three months before conception due to teratogenic risks
JAK Inhibitors (Tofacitinib, Upadacitinib)
Discontinue unless no other options for maternal health
S1P Receptor Modulators (Ozanimod, Etrasimod)
Discontinue unless no other options for maternal health
In women with IBD who continue thiopurines during pregnancy, precaution should be taken for intrahepatic cholestasis by measurement of liver enzymes, metabolite levels and consideration of split dosing.15 Women with IBD who are pregnant and have infections, fistula or pouchitis that require antibiotics may take an appropriate course of a low-risk antibiotic. Women with IBD may initiate or continue calcineurin inhibitors (cyclosporine and tacrolimus) during pregnancy with careful monitoring if there are no viable alternative treatment options available. Table 2 summarizes the medication management recommendations.
Table 3. Medical Therapy Recommendations During Breastfeeding
Anti-IL-12/23 and Anti-IL-23 Agents (Ustekinumab, Risankizumab, Mirikizumab, Guselkumab)
May breastfeed
Biosimilars
May breastfeed
S1P Receptor Modulators (Etrasimod, Ozanimod)
Should not breastfeed
JAK Inhibitors (Tofacitinib, Upadacitinib, Filgotinib)
Should not breastfeed
Lactation
Breastfeeding is strongly encouraged as it offers numerous benefits for the infant and does not exacerbate maternal IBD. For most drugs, a weight adjusted percentage of the maternal dosage (relative infant dose) of ≤ 10% is considered relatively safe.16,17 In infants exposed in utero to infliximab, adalimumab, vedolizumab or ustekinumab, maternal breastfeeding did not affect neonatal clearance of the drug.18,19,20 Due to limited human safety data including unknown effects on the immune system of the infant, breastfeeding should be avoided in case of treatment with JAK-inhibitor.21 Table 3 summarizes the medication management recommendations.
Maternal and Fetal Outcomes
The interaction between IBD and pregnancy outcomes is bidirectional, with active disease increasing the risk of complications. Controlling disease activity during pregnancy among women with IBD is critical to reduce maternal and fetal adverse outcomes.
We suggest that women with IBD face an increased risk of adverse pregnancy outcomes, including low birth weight and preterm delivery, compared to women without IBD. Moreover, those with moderate to severe disease activity are at a higher risk of spontaneous abortion than both women without IBD and those with milder forms of the disease. In addition, pregnant women with IBD are more likely to experience venous thromboembolism (VTE) during pregnancy and in the postpartum period compared to their counterparts without IBD and should be considered for prophylaxis, particularly after cesarean section.
Short and Long-term Neonatal Outcomes
Emerging evidence supports the safety of in utero exposure to most IBD medications.
We suggest that children born to women with IBD experience higher rates of neonatal ICU admissions and hospitalizations during their first year of life compared to those born to women without IBD. Additionally, children born to women with active IBD are more likely to be small for gestational age and have a low birth weight compared to those born to women with inactive IBD. We further suggest that treatment with biologics during pregnancy does not increase the risk of early childhood malignancy or developmental delays, and similarly, thiopurine therapy during pregnancy does not appear to elevate the risk of early childhood developmental delays.
Vaccinations
Inactive vaccines should be given on schedule to infants of women with IBD regardless of in utero IBD medication exposure. Children exposed to thiopurine monotherapy, JAK inhibitors or S1P receptor modulators in utero may receive appropriate live vaccines after 1 month of age and live vaccines can be given to infants of mothers breastfeeding while on biologics. Previously, guidelines recommended avoiding live vaccines for 6 months after in utero biologic exposure, however, evidence suggests that the rotavirus vaccine when administered to infants exposed to biologics in utero did not result in any serious adverse events.22,23 Bacillus Calmette-Guérin (BCG) vaccine, however, is greater risk. Infants exposed to in utero biologics should not receive BCG vaccine until after 6 months of age or until the time when infant serum concentrations of drug are undetectable.
Conclusion
The global consensus on IBD management in pregnancy provides a robust framework that underlines key strategies in the management of this vulnerable population, ensuring that gastroenterologists are well-equipped to facilitate effective decision-making and specialist collaboration. The pregnant patient with IBD requires multidisciplinary care from gastroenterologists, obstetricians and maternal-fetal medicine specialists as well as surgeons and nutritionists as appropriate. Key takeaways include prioritizing preconception counseling and ensuring that patients with IBD are in remission before conception to optimize both maternal and fetal outcomes. Educating patients about the safety of continuing most IBD therapies—including monoclonal antibodies—throughout pregnancy and lactation empowers them to make informed decisions. All IBD patients may be at risk for pre-term preeclampsia and should initiate low-dose aspirin between 12 to 16 weeks of gestation to mitigate this risk. Infants should receive all inactive vaccines on schedule regardless of in utero drug exposure. The live vaccine, rotavirus, can also be given on schedule, but BCG should only be given after 6 months if biologic exposure in utero.
Future research should aim to fill current knowledge gaps, particularly regarding newer oral therapies and long-term neonatal outcomes. By integrating these practices and focusing on maternal health, healthcare providers can play a pivotal role in safeguarding the well-being of both mother and child.
References
1. Global Consensus Statement on the management of pregnancy in inflammatory bowel disease. Mahadevan U, Seow CH, Barnes EL, Chaparro M, Flanagan E, Friedman S, Julsgaard M, Kane S, Ng S, Torres J, Watermeyer G, Yamamoto-Furusho J, Robinson C, Fisher S, Anderson P, Gearry R, Duricova D, Dubinsky M, Long M; Global Consensus Group for Pregnancy in IBD. Online ahead of print 1. Gut. 2025 Aug 28:gutjnl-2025-336402. doi: 10.1136/ gutjnl-2025-336402. PMID: 40876906 2. Clin Gastroenterol Hepatol. 2025 Aug 6:S1542-3565(25)00322-2. doi: 10.1016/j.cgh.2025.04.005. PMID: 40874901 3. Aliment Pharmacol Ther. 2025 Aug 28. doi: 10.1111/apt.70290. PMID: 40874657 4. Inflamm Bowel Dis. 2025 Aug 28:izaf171. doi: 10.1093/ibd/ izaf171. PMID: 40874613 5. Am J Gastroenterol. 2025 Aug 27. doi: 10.14309/ ajg.0000000000003651. PMID: 40862489 2. Fuhler GM. The immune system and microbiome in pregnancy. Best Pract Res Clin Gastroenterol. 2020;44-45:101671. doi:10.1016/j. bpg.2020.1016712 3. Förger F, Villiger PM. Immunological adaptations in pregnancy that modulate rheumatoid arthritis disease activity [published correction appears in Nat Rev Rheumatol. 2020 Mar;16(3):184. doi: 10.1038/ s41584-020-0394-4]. Nat Rev Rheumatol. 2020;16(2):113-122. doi:10.1038/s41584-019-0351-2 4. Sun H, Jiao J, Tian F, et al. Ovarian reserve and IVF outcomes in patients with inflammatory bowel disease: A systematic review and meta-analysis. EClinicalMedicine. 2022;50:101517. Published 2022 Jul 1. doi:10.1016/j.eclinm.2022.101517 5. Orholm M, Fonager K, Sørensen HT. Risk of ulcerative colitis and Crohn’s disease among offspring of patients with chronic inflammatory bowel disease. Am J Gastroenterol. 1999;94(11):3236-3238. doi:10.1111/j.1572-0241.1999.01526.x 6. Cornish J, Tan E, Teare J, Teoh TG, Rai R, Clark SK, Tekkis PP. A metaanalysis on the influence of inflammatory bowel disease on pregnancy. Gut. 2007;56:830–837. doi: 10.1136/gut.2006.108324 7. Mahadevan U, Sandborn WJ, Li DK, Hakimian S, Kane S, Corley DA. Pregnancy outcomes in women with inflammatory bowel disease: a large community-based study from Northern California. Gastroenterology. 2007;133:1106–1112. doi: 10.1053/j.gastro.2007.07.019 8. Taleban S, Gundogan F, Chien EK, Degli-Esposti S, Saha S. Placental inflammation is not increased in inflammatory bowel disease. Ann Gastroenterol. 2015;28(4):457-463 9. Örtqvist AK, Lundholm C, Halfvarson J, Ludvigsson JF, Almqvist C. Fetal and early life antibiotics exposure and very early onset inflammatory bowel disease: a population-based study. Gut. 2019;68(2):218-225. doi:10.1136/gutjnl-2017-314352 10. Torres J, Hu J, Seki A, et al. Infants born to mothers with IBD present with altered gut microbiome that transfers abnormalities of the adaptive immune system to germ-free mice. Gut. 2020;69(1):42-51. doi:10.1136/ gutjnl-2018-317855 11. Boyd HA, Basit S, Harpsøe MC, Wohlfahrt J, Jess T. Inflammatory Bowel Disease and Risk of Adverse Pregnancy Outcomes. PLoS One. 2015;10(6):e0129567. Published 2015 Jun 17. doi:10.1371/journal. pone.0129567 12. Rolnik DL, Wright D, Poon LC, et al. Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia. N Engl J Med. 2017;377(7):613-622. doi:10.1056/NEJMoa1704559 13. DeBolt CA, Gottlieb ZS, Rao MG, et al. Low-Dose Aspirin Use Does Not Increase Disease Activity in Pregnant Patients with Inflammatory Bowel Disease. Dig Dis Sci. 2024;69(5):1803-1807. doi:10.1007/ s10620-024-08364-2 14. Malhi G, Tandon P, Perlmutter JW, Nguyen G, Huang V. Risk Factors for Postpartum Disease Activity in Women with Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. Inflamm Bowel Dis. 2022;28(7):1090-1099. doi:10.1093/ibd/izab206 15. Prentice R, Flanagan E, Wright E, et al. Thiopurine Metabolite Shunting in Late Pregnancy Increases the Risk of Intrahepatic Cholestasis of Pregnancy in Women with Inflammatory Bowel Disease and Can be Managed with Split Dosing. J Crohns Colitis. 2024;18(7):1081-1090. doi:10.1093/ecco-jcc/jjae023 16. LaHue SC, Anderson A, Krysko KM, et al. Transfer of monoclonal antibodies into breastmilk in neurologic and non-neurologic diseases. Neurol Neuroimmunol Neuroinflamm. 2020;7(4):e769. Published 2020 May 27. doi:10.1212/NXI.0000000000000769 17. Sah BNP, Lueangsakulthai J, Hauser BR, et al. Purification of Antibodies from Human Milk and Infant Digestates for Viral Inhibition Assays. Front Nutr. 2020;7:136. Published 2020 Aug 25. doi:10.3389/fnut.2020.00136 18. Julsgaard M, Christensen LA, Gibson PR, et al. Concentrations of Adalimumab and Infliximab in Mothers and Newborns, and Effects on Infection. Gastroenterology. 2016;151(1):110-119. doi:10.1053/j. gastro.2016.04.002 19. Julsgaard M, Baumgart DC, Baunwall SMD, et al. Vedolizumab clearance in neonates, susceptibility to infections and developmental milestones: a prospective multicentre population-based cohort study. Aliment Pharmacol Ther. 2021;54(10):1320-1329. doi:10.1111/apt.16593 20. Julsgaard M, Wieringa JW, Baunwall SMD, et al. Infant Ustekinumab Clearance, Risk of Infection, and Development After Exposure During Pregnancy. Clin Gastroenterol Hepatol. 2025;23(1):134-143. doi:10.1016/j.cgh.2024.01.008 21. Julsgaard M, Mahadevan U, Vestergaard T, Mols R, Ferrante M, Augustijns P. Tofacitinib concentrations in plasma and breastmilk of a lactating woman with ulcerative colitis. Lancet Gastroenterol Hepatol. 2023;8(8):695-697. doi:10.1016/S2468-1253(23)00158-9 22. Fitzpatrick T, Alsager K, Sadarangani M, et al. Immunological effects and safety of live rotavirus vaccination after antenatal exposure to immunomodulatory biologic agents: a prospective cohort study from the Canadian Immunization Research Network. Lancet Child Adolesc Health. 2023;7(9):648-656. doi:10.1016/S2352-4642(23)00136-0 23. Ernest-Suarez K, Murguía-Favela LE, Constantinescu C, et al. Live Rotavirus Vaccination Appears Low-risk in Infants Born to Mothers with Inflammatory Bowel Disease on Biologics. Clin Gastroenterol Hepatol. Published online July 31, 2024. doi:10.1016/j.cgh.2024.07.007
As understanding of disease processes in medicine evolves, terminology must often evolve too. Terminology related to cirrhosis has been changing to better capture the spectrum of liver disease and patients’ progression along that spectrum that is not adequately captured by the terms “compensated cirrhosis” and “decompensated cirrhosis” alone. This article aims to review this newer terminology that has emerged over the past several years regarding portal hypertension and cirrhosis along the spectrum of compensated and decompensated disease. Appropriate use of terminology is important. It can help direct our conversations with patients in helping them to understand their disease and provide anticipatory guidance for what their future health may look like. It is also critically important in conveying how sick a patient may be when communicating with other providers and in conveying the complexity of medical decision making in our documentation.
Background
In medicine, there is constant advancement in the understanding of diseases, their pathophysiology, and subsequent management. Over time, these advances necessitate changes in the nomenclature related to diseases so that the terminology used best describes the disease process a patient has. Furthermore, these changes have the potential to communicate more nuanced information about the disease to convey severity and to globally portray prognosis and course. This can be seen in the divergence from eponyms to more disease descriptive terms and attempts to identify and change stigmatizing language. The field of hepatology has gone through a significant terminology revolution recently, notably with migration away from nonalcoholic steatohepatitis and nonalcoholic fatty liver disease to metabolic dysfunction-associated steatohepatitis (MASH) and metabolic dysfunction–associated steatotic liver disease (MASLD). This has been coupled with the addition of the term metabolic and alcohol related/associated liver disease (MET/ALD), which captures a patient population that likely has multifactorial steatosis that was not captured with the previous nomenclature.1 The field of hepatology has further experienced evolution in the nomenclature surrounding cirrhosis to better capture the spectrum of liver disease and patients’ progression along that spectrum that is not adequately captured by the terms “compensated cirrhosis” and “decompensated cirrhosis” alone (refer to Table 1). Addition of new terms, honing of definitions and adding new classification systems will hopefully capture more patients with liver disease and be able to better convey where a patient is along the liver disease spectrum. This article aims to review this newer terminology that has emerged over the past several years regarding portal hypertension and cirrhosis along the spectrum of compensated and decompensated disease. Appropriate use of terminology is important. It can help direct our conversations with patients in helping them to understand their disease and provide anticipatory guidance for what their future health may look like. It is also critically important in conveying how sick a patient may be when communicating with other providers and in conveying the complexity of medical decision making in our documentation.
Table 1.
As our understanding of cirrhosis has become more nuanced, so has our understanding of prognosis, and nomenclature has had to change to match this. Previously cirrhosis was viewed in 2 major stages, “compensated” and “decompensated”, with respective median survival being 10-12 years and 2-4 years.2-4 It has previously been acknowledged that generalized life expectancy estimations are difficult to apply to individual patients, since broadly stating decompensated cirrhosis has a certain mortality rate does not account for the differences in mortality that are seen with differing decompensating events such as development of ascites versus development of varices or differences with having one decompensating factor versus having two or more.2 Even in patients with compensated cirrhosis, generalized mortality statements do not account for possible differences related to compensated with varices versus compensated cirrhosis without varices.2 Though we do have scoring systems, like MELD3.0, that help to convey how sick our patients are, MELD3.0 was created to predict 3-month mortality without a liver transplant.5 When discussing longer term mortality and having informed discussions with patients, it is helpful to understand their global course and how certain events in the progression of cirrhosis affect survival.
The term cirrhosis refers to a pathology-based diagnosis.6-8 With increasing availability of non-invasive tests and imaging, liver biopsy and hepatic venous pressure gradients (HVPG) are being obtained less frequently.9 Non-invasive testing (NIT) in patients that are otherwise compensated is often not able to account for the pathologic differences between advanced fibrosis and cirrhosis.6 Regardless of the pathologic stage, patients with increased liver stiffness levels on NIT still may have liver disease worth treating and or surveying long term. To account for the increasing number of patients falling into this category, the Baveno VI consensus applied the term compensated advanced chronic liver disease (cACLD), which encompassed patients with both advanced fibrosis (bridging fibrosis) and cirrhosis who did not have a liver biopsy.6,7 Using transient elastography (TE), cACLD may be termed “possible” for patients with liver stiffness measurements (LSM) over 10kPa and “certain” for patients with LSM over 15kPa.4,6 Patients may still have chronic liver disease with LSM under 10kPa. As with any of the more advanced stages of liver disease, the underlying etiology should be addressed but, for these patients, the 3-year risk of decompensation or liver related death is less than 1%.1 Patients with ongoing injury and LSM between 7-10kPa may need to be monitored for progression to cACLD.6
Compensated cirrhosis and cACLD can be further stratified into those with clinically significant portal hypertension and those without clinically significant portal hypertension.6,7 Clinically significant portal hypertension (CSPH) is defined as HVPG greater than or equal to 10mmHgand is the degree of elevation at which complications of portal hypertension can present.6,10 As a brief review of the pathophysiology of portal hypertension in cirrhosis, current understandings suggest that early in the disease process portal hypertension is driven by changes in the hepatic parenchyma and increase in intrahepatic vascular tone in response to various vasoactive mediators.10,11 Mild portal hypertension is defined as portal pressures between 5 and 10mmHg. As cirrhosis progresses though, changes in systemic circulation begin to contribute to portal hypertension including through increased cardiac output and increased intravascular volume.10 Patients with mild portal hypertension (5-10mmHg), may not yet have developed the hyperdynamic state that influences portal hypertension in patients with portal pressures over 10mmHg, which is thought to be the reason patients with mild portal hypertension do not respond as well to non-selective beta blocker therapies.10
For patients who have undergone NIT, there are parameters to identify who likely has CSPH and therefore do not require invasive measurement. Liver stiffness measurements (LSM) over 25kPa on TE regardless of platelet count, LSM of 20-25kPa with platelet count less than 150k/mm3 or LSM 15-20kPa with platelet count less than 110k/mm3 are consistent with CSPH. Other cutoff values exist for non-TE elastography methods.4 It should be kept in mind that these numbers are only validated in viral liver disease, alcohol-associated liver disease, and MASH.6 Imaging that shows recanalization of umbilical vein, periesophageal varices, splenorenal shunt, clinically apparent ascites or hepatofugal flow in the main portal vein on doppler ultrasound are also consistent with CSPH regardless of liver disease etiology.4
By stating that a patient has cACLD without clinically significant portal hypertension you are implying that the patient has liver disease but is not currently experiencing complications of their liver disease and is unlikely to experience a portal hypertensive complication in their current state. Management of patients in this subset should focus on identification and treatment of the underlying etiology of liver disease. When you state that a patient has compensated advanced chronic liver disease with clinically significant portal hypertension though, not only do they require etiologic identification and management, but they may also benefit from management of the hyperdynamic element of their portal hypertension with non-selective beta blocker therapy.4,6,11
Compensated cirrhosis is defined by the Baveno VII consensus statement as the absence of a present or past decompensating event (variceal bleeding, clinically apparent ascites and overt hepatic encephalopathy).6 This definition has not changed significantly over time, though it should be noted that while multiple studies have incorporated the presence of jaundice as a decompensating event, this has not been universally agreed upon as decompensation. At this time there is not enough data to allow for the classification of jaundice, minimal ascites only seen on imaging, minimal (“covert”) hepatic encephalopathy and occult bleeding from portal hypertensive gastropathy as decompensating events, so patients with these findings, at present, are still by current definitions compensated.6 In patients with compensated cirrhosis (or cACLD) and CSPH, non-selective beta blockers should be initiated with the goal of preventing decompensation.6 Compensated cirrhosis has historically been associated with median survival time of 12 years or more,2-4 but the presence or absence of varices has been shown to influence risk of death, with their absence being associated with 5-year risk of death of 1.5% and presence being associated with risk of death of 10%.18 Indeed, in patients with cACLD, progressive increase in LSM, regardless of etiology of liver disease, is associated with an increase in relative risk of decompensation and mortality.6
Decompensated cirrhosis, acute decompensation, further decompensation and acute on chronic liver failure
Decompensated cirrhosis refers to the development of complications of portal hypertension, specifically clinically apparent ascites, overt hepatic encephalopathy and variceal bleeding, and this has remained relatively unchanged over time.6 Of note, some research papers will include jaundice as a defining decompensating event12,13 and others bacterial infection14-17 but the Baveno VII consensus statement suggests that further research is required prior to the inclusion of jaundice in the definition of decompensation, and bacterial infections are considered a possible precipitant of decompensation, not a defining characteristic.6 After the first decompensating event occurs, median survival drops to 2-4 years.13Acute decompensation is the main cause of hospitalization in patients with cirrhosis.14 In the coming years we may see further stratification of decompensation based on the speed at which initial decompensating events occur. This may come with recommendations as to whether treatment for the decompensating event requires inpatient admission versus outpatient treatment with proposed addition of terminology to include non-acute decompensation, but more research is needed to determine the clinical significance of the more indolent presentations of decompensation.12
The development of a decompensating event is a key step in the natural history of cirrhosis that portends an increase in mortality with the different decompensating events having different associated mortality. Four percent of patients may die during their initial presentation with a decompensating event.19 Ascites is the most common initial decompensating event, reported to be seen in 36% of patients by itself and in combination with another decompensation event in 37% of patients.19 A prospective cohort study of 494 patients showed variceal bleeding as the first decompensating event in 10% of patients and hepatic encephalopathy in 5% of patients.18 The mortality associated with the development of ascites has been reported to be 20-58% at 1 year, 77% at 3 years, and 78% at 5 years.10,18,20-21 The combination of ascites with hepatic encephalopathy has been associated with median survival of just 1.1 years compared to median survival of 3.9 years with hepatic encephalopathy alone.21 Acute variceal hemorrhage is associated with significant short-term mortality of 10-15%19 although that is often not from the bleeding itself, but from complications that arise from the bleed, including worsening liver or renal failure.20 Estimated 5-year mortality is 20% for those presenting with bleeding alone and 88% for any combination of a bleeding event with a non-bleeding decompensation.19 Another important clinical event that is not considered a specific decompensating event is infection, which has been associated with 1 month mortality of 30% and an additional 30% at 1 year.20
It has been observed that when subsequent complications of portal hypertension follow an initial event, there is an even higher associated increase in mortality. This has been termed further decompensation. According to the Baveno VII consensus statement, further decompensation is defined as having a second portal hypertensive-mediated complication develop, such as the onset of ascites or hepatic encephalopathy in a patient who has had a previous variceal hemorrhage (with the caveat that it did not occur in the same time frame as the hemorrhagic event). Additional examples would be the development of recurrent variceal bleeding in a patient with previous bleeding, the requirement of more than 3 large volume paracenteses within 1 year, or recurrent hepatic encephalopathy; and although the following clinical scenarios are not defined as decompensation events, the development of jaundice, spontaneous bacterial peritonitis or hepatorenal syndrome acute kidney injury (HRS-AKI) can be defined as “further decompensation” in a patient with a prior traditional decompensation.6 Though this definition was included in the Baveno VII consensus statement, it was based on expert opinion, without significant evidence to support it. Part of the aim of a large multicenter cohort study published in 2024 was to evaluate whether risk of death increased with further decompensation as defined by the Baveno VII consensus statement. Based on their analysis, mortality was increased by approximately 2 times that of the associated first decompensating event, with a mean survival of 273 days (9 months) after further decompensation was reported.13
Acute on chronic liver failure (ACLF) is another term whose definition continues to be honed. It should be noted that there is no international consensus on the definition, with noted variability between European, North American and Asian societies.22 Despite the lack of a unifying definition of criteria, there is clear consensus that there is high short-term mortality with ACLF, and the European and North America definitions include the presence of extrahepatic organ failure.22,23 The specific definition used by the North American Consortium for the Study of End Stage Liver Disease (NACSELD) uses the presence of at least two different extrahepatic organ failures to define ACLF. These include shock, West Haven III/IV hepatic encephalopathy, need for renal replacement therapy, and mechanical ventilation.24 Another important concept to keep in mind with the definition used in North America is that ACLF can occur in patients with chronic liver disease even without the presence of cirrhosis.24 A large multicenter European cohort shows that in patients with acute decompensation that were diagnosed with ACLF, the 30- and 90-day mortality rates were 32.8% and 51.2% respectively, and 1.8% and 9.8% in those that did not have ACLF.14
Recompensation
It is important to remember that patients who have a history of ascites or hepatic encephalopathy, and whose disease is controlled with diuretics, TIPS, and/or hepatic encephalopathy-directed therapies, do not have compensated disease6,10 but rather decompensated disease controlled by medical and/or procedural therapies. There is, however, a subgroup of patients who have clinically meaningful response to treatment of their underlying etiology of liver disease, specifically those with hepatitis C viral infections who attain sustained viral response, hepatitis B infections with viral suppression, and sustained abstinence from alcohol. These patients, in the absence of other contributing liver disease (ex. MASH, alcohol use disorder), can experience improvement in their HVPG and consequent decrease in risk of decompensation. With sustained adequate improvement in LSM, those with cACLD can potentially stop long term liver stiffness monitoring regimens, and those with CSPH on beta blockers can potentially come off beta blockers if endoscopically proven to not have varices.6 Furthermore, patients who have previously had a decompensating event can potentially experience recompensation. Recompensation is a term that was introduced in the Baveno VII consensus statement. For recompensation to be present, all of the following must have occurred: removal, suppression or cure of the primary etiology of the liver disease, resolution of ascites and/or hepatic encephalopathy for more than 12 months off of decompensation-directed therapy, absence of variceal hemorrhage for at least 12 months and, finally, stable improvement of liver function testing.6
Conclusion
The continued refinement in the terminology we use in relation to liver disease is a crucial step in the history of our understanding of liver disease that will hopefully allow us to better categorize our patients into risk strata. This is important not just at the point of care to understand our patients’ individual risk, but also to ensure we can continue to advance research in the care for patients with chronic liver disease. There is currently a suggestion for application of new terminology related to the speed at which decompensation occurs (i.e., whether the first decompensating event comes on more slowly and is seen as an outpatient (“non-acute”) as opposed to an acute event that leads to hospitalization). Non-acute decompensation potentially accounts for 45% of decompensation.12 There is also a group of patients who have decompensated cirrhosis with symptoms that are adequately managed with medical therapy who should not be classified as recompensated as they likely do have a higher mortality than a patient who has never experienced decompensation or does not require medications anymore.
We should bear in mind that mortality prediction in cirrhosis is imperfect since the etiologies of cirrhosis are variable and the clinical outcomes of one etiology of cirrhosis do not necessarily align with those of other etiologies, but much of cirrhosis research to date has included heterogenous populations. In the future, we are likely to see further refinement of terminology in the staging of cirrhosis and chronic liver disease and continued refinement and individualization of care for patients based on that staging, their underlying etiology of liver disease and their portal pressures. As studies start to further analyze patients based on etiology of advanced chronic liver disease, we may also start to see differences in morbidity and mortality based on age and etiology of disease rather than simply type of decompensation as was shown in one population-based study evaluating mortality associated with hepatic encephalopathy.25 Indeed in 2012, the International Liver Pathology Study Group recommended discontinuation of the term cirrhosis altogether because of the implied problems that come with trying to classify many disease processes, with different patterns of scarring, regeneration and progression, with a “morphology-based unitary term”.10 While this has not come to bear in clinical practice, it is clearly of increasing importance for all providers who see these patients to understand the terminology here described, to ensure we understand the risk stratification of each of our patients and provide care commensurate to that risk.
References
References
1. D’Amico G. The clinical course of cirrhosis. Population based studies and the need of personalized medicine. Journal of Hepatology. 2014;60(2):241-242. doi:https://doi.org/10.1016/j.jhep.2013.10.023
2. Rinella ME, Lazarus JV, Vlad Ratziu, et al. A multi-society Delphi consensus statement on new fatty liver disease nomenclature. Hepatology. 2023;60(2). doi:https://doi.org/10.1097/hep.0000000000000520
3. D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. Journal of hepatology. 2006;44(1):217-231. doi:https://doi.org/10.1016/j.jhep.2005.10.013
4. Kaplan DE, Bosch J, Ripoll C, et al. AASLD practice guidance on risk stratification and management of portal hypertension and varices in cirrhosis. Hepatology. 2024;79(5):10.1097/HEP.0000000000000647. doi:https://doi.org/10.1097/HEP.0000000000000647
5. Kim WR, Mannalithara A, Heimbach JK, et al. MELD 3.0: The Model for End-Stage Liver Disease Updated for the Modern Era. Gastroenterology. 2021;161(6):1887-1895.e4. doi:https://doi.org/10.1053/j.gastro.2021.08.050
6. Roberto de Franchis, Bosch J, Garcia-Tsao G, et al. Corrigendum to “Baveno VII – Renewing consensus in portal hypertension” [J Hepatol (2022) 959-974]. Journal of hepatology. 2022;77(1):271-271. doi:https://doi.org/10.1016/j.jhep.2022.03.024
7. de Franchis R, Baveno VI Faculty. Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. Journal of hepatology. 2015;63(3):743-752. doi:https://doi.org/10.1016/j.jhep.2015.05.022
8. Hytiroglou P, Snover DC, Alves V, et al. Beyond “Cirrhosis.” American Journal of Clinical Pathology. 2012;137(1):5-9. doi:https://doi.org/10.1309/ajcp2t2ohtapbtmp
9. Sterling RK, Asrani SK, Levine D, et al. AASLD Practice Guideline on non-invasive liver disease assessments of portal hypertension. Hepatology. 2024;81(3). doi:https://doi.org/10.1097/hep.0000000000000844
10. Ripoll C, Bari K, Garcia-Tsao G. Serum albumin can identify patients with compensated cirrhosis with a good prognosis. Journal of clinical gastroenterology. 2015;49(7):613-619. doi:https://doi.org/10.1097/MCG.0000000000000207
12. Tonon M, D’Ambrosio R, Calvino V, et al. A new clinical and prognostic characterization of the patterns of decompensation of cirrhosis. Journal of hepatology. 2024;80(4):603-609. doi:https://doi.org/10.1016/j.jhep.2023.12.005
13. Gennaro D’Amico, Zipprich A, Villanueva C, et al. Further decompensation in cirrhosis. Results of a large multicenter cohort study supporting Baveno VII statements. Hepatology. 2023;79(4). doi:https://doi.org/10.1097/hep.0000000000000652
14. Moreau R, Jalan R, Gines P, et al. Acute-on-Chronic Liver Failure Is a Distinct Syndrome That Develops in Patients With Acute Decompensation of Cirrhosis. Gastroenterology. 2013;144(7):1426-1437.e9. doi:https://doi.org/10.1053/j.gastro.2013.02.042
15. Trebicka J, Fernandez J, Papp M, et al. The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology. Journal of Hepatology. 2020;73(4):842-854. doi:https://doi.org/10.1016/j.jhep.2020.06.013
16. Dilan Gülcicegi, Goeser T, Kasper P. Prognostic assessment of liver cirrhosis and its complications: current concepts and future perspectives. Frontiers in Medicine. 2023;10. doi:https://doi.org/10.3389/fmed.2023.1268102
17. Ferstl P, Trebicka J. Acute Decompensation and Acute-on-Chronic Liver Failure. Clinics in Liver Disease. 2021;25(2):419-430. doi:https://doi.org/10.1016/j.cld.2021.01.009
18. D’Amico G, Pasta L, Morabito A, et al. Competing risks and prognostic stages of cirrhosis: a 25-year inception cohort study of 494 patients. Alimentary Pharmacology & Therapeutics. 2014;39(10):1180-1193. doi:https://doi.org/10.1111/apt.12721
19. D’Amico G, Bernardi M, Angeli P. Towards a new definition of decompensated cirrhosis. Journal of Hepatology. 2022;76(1):202-207. doi:https://doi.org/10.1016/j.jhep.2021.06.018
20. Schiff ER, Maddrey WC, K Rajender Reddy. Schiff’s Diseases of the Liver. John Wiley & Sons Ltd; 2018.
21. Tapper EB, Aberasturi D, Zhao Z, Hsu CY, Parikh ND. Outcomes after hepatic encephalopathy in population-based cohorts of patients with cirrhosis. Alimentary Pharmacology & Therapeutics. 2020;51(12):1397-1405. doi:https://doi.org/10.1111/apt.15749
22. Arroyo V, Moreau R, Jalan R. Acute-on-Chronic Liver Failure. Longo DL, ed. New England Journal of Medicine. 2020;382(22):2137-2145. doi:https://doi.org/10.1056/nejmra1914900
23. Moreau R, Tonon M, Krag A, et al. EASL Clinical Practice Guidelines on acute-on-chronic liver failure. Journal of Hepatology. 2023;79(2):461-491. doi:https://doi.org/10.1016/j.jhep.2023.04.021
24. Constantine Karvellas, Bajaj JS, Kamath PS, et al. AASLD Practice guidance on Acute-on-chronic liver failure and the management of critically Ill patients with cirrhosis. Hepatology. 2023;79(6). doi:https://doi.org/10.1097/hep.0000000000000671
Irritable Bowel Syndrome (IBS) is a common gastrointestinal (GI) disorder marked by abdominal pain, bloating, and altered bowel habits. Dietary changes are key to managing symptoms, with the low-FODMAP diet being the most evidence-based approach. Its complexity and restrictiveness, however, can make adherence difficult without guidance from a registered dietitian (RD). Given rising concerns around food-related anxiety and disordered eating in IBS, a shift toward more flexible, individualized dietary strategies is emerging. More research is needed to confirm the long-term outcomes of these less restrictive approaches. This review aims to present the current state of scientific evidence on the use of the low-FODMAP diet for managing IBS, including its three-phase structure and possible application of less restrictive FODMAP diet versions. It also explores the key role of GI expert RDs in the practical implementation of diet therapy, including patient assessment for suitability.
Defining IBS: Symptoms, Prevalence, and Impact
Irritable bowel syndrome (IBS) is a multifactorial and commonly encountered GI disorder, classified as a disorder of gut-brain interaction (DGBI). The Rome IV criteria are used to diagnose IBS and includes presence of recurrent abdominal pain occurring at least once weekly in conjunction with disturbances in bowel habits, including changes in stool frequency and form for the past three months, in the absence of identifiable structural or known biomarkers. IBS occurs 2.5 times more in females than males and symptom onset must have occurred at least 6 months prior to diagnosis.1,2
Prevalence rates vary by country; a recent United States based survey study found that 6.1% met Rome IV IBS criteria,3 while higher rates have been found in low- and middle-income countries, ranging from 6-44%.4 The etiology of IBS has yet to be fully characterized but believed to involve GI motility changes, post-infectious reactivity, visceral hypersensitivity, altered gut-brain interactions, microbiota dysbiosis, small intestinal bacterial overgrowth, food sensitivity, carbohydrate malabsorption, and intestinal inflammation. An acute enteric infection can result in post-infectious IBS, and this represents the most direct risk factor for IBS.5,6
While interest and research are growing to better understand the pathophysiology of IBS to guide treatments, perceived efficacy of current therapies remain limited. Based on survey data, it is evident that many patients with IBS continue to face significant challenges. One survey study revealed that most patients would give up 25% of their remaining life (average 15 years) and 14% would risk a 1/1000 chance of death for a treatment that would relieve IBS symptoms.7 Another survey study revealed patients are willing to accept a 1% risk of sudden death in return for a 99% chance of cure of their symptoms from a medication.8 From a health-related quality of life (HRQOL) impact, patients with IBS had significantly worse HRQOL on selected SF-36 scales than patients with diabetes mellitus and end stage renal disease.9
Evolution of Diet as a Therapyin Irritable Bowel Syndrome
Dietary trials in IBS were limited until the early 2000s. Patients were often prescribed a high fiber diet which offered variable benefits. The term FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) emerged initially in the literature in 2005, speculating a potential link to diet induced small bowel ecology and colonic permeability, potentially predisposing one to inflammatory bowel disease.10 Many individuals living with IBS associate their symptoms to specific foods, which has spurred greater scientific research into the role of diet in managing this challenging and often debilitating disorder. A survey of nearly 200 individuals living with IBS found that 84% believed that eating any food could trigger their symptoms. The majority (70%) identified carbohydrates as triggers, particularly foods rich in fermentable carbohydrates such as dairy products (49%), beans/lentils (36%), apple (28%), flour (24%), and plum (23%).11 See Table 1 for FODMAP subtypes and food sources.The low-FODMAP diet approach evolved into a therapeutic strategy for IBS symptom management, starting initially as a broad elimination diet for IBS, to currently, a three-phase approach. See Figure 1.
Food intolerance (e.g., lactose intolerance) resulting from carbohydrate malabsorption can mimic symptoms of IBS, such as bloating, gas and alteration in bowel habits. The low-FODMAP elimination approach applied a more global restriction to commonly malabsorbed carbohydrates, restricting a wide range of poorly absorbed short-chain carbohydrates. Research trials revealed good efficacy rates, with a notable 50% to 80% of IBS noting clinically relevant symptom benefit.12,13 Efficacy data variability may be due to differences in the approach to diet implementation. In most studies, a dietitian provided guidance on dietary implementation, while participants prepared their own meals. While in the seminal study by Halmos et al., low- FODMAP meals were provided to the participants throughout the study period.14 Currently, there are numerous systematic reviews and meta-analyses supporting the diet’s benefits. A recent systematic and meta-analysis including 15 randomized controlled trials (RCTs) and 1118 participants revealed a benefit over placebo to the low-FODMAP diet, with a risk ratio (RR) of 1.21 (95% confidence interval= 0.98-1.51).15
FODMAP Effect on Gut Physiology in Irritable Bowel Syndrome
As the application of the diet showed benefit globally, further research began to better understand the full mechanism of FODMAPs in IBS. Initial mechanistic insights into how FODMAPs triggered IBS symptoms focused on their effects on luminal distention via osmotic effects and fermentation of the poorly absorbed carbohydrates. This was followed by novel magnetic resonance imaging (MRI) studies that revealed that the size of the FODMAP subtype results in variable effects on bowel distention. The monosaccharide, fructose, distends the small bowel with water due to its greater osmotic effects, while fructans, oligosaccharides, distend the colon from release of gases due to bacterial fermentation.16 The smaller the size of the FODMAP, the greater the osmotic effect while longer chain FODMAP fibers such as fructans, have greater effects on distention via fermentation. In the latest innovative research, investigators using mice models have shown that a high-FODMAP diet may lead to dysbiosis, impaired colonic barrier function, mast cell recruitment and activation, and heightened visceral sensitivity. In mice, a high-FODMAP diet promotes the growth of gram-negative bacteria, resulting in elevated levels of luminal lipopolysaccharide (LPS). This LPS can stimulate mast cells via toll-like receptor 4 (TLR4), triggering the release of bioactive compounds such as tryptase, histamine, and prostaglandin E2. These mediators can, in turn, increase intestinal permeability and enhance visceral sensitivity. Collectively, animal data (and interim analysis from a small human IBS trial) suggests a complex interaction of diet, gut microbiota, immune activation, visceral hypersensitivity and resultant colonic barrier dysfunction.17
A Therapeutic Diet for Irritable Bowel Syndrome: The Low-FODMAP Model
With growing data and research assessing the efficacy of this approach in IBS, the low-FODMAP diet remains the most evidence-based nutritional therapy. The 3-phase approach starts with the elimination phase, followed by the reintroduction phase and lastly the personalization phase. The goal of the elimination phase is to identify FODMAP sensitivity, and if present, alleviate GI symptoms. The next step is to systematically reintroduce FODMAP subtypes back into the diet to identify personal triggers, and lastly, the personalization phase which allows for a more liberal diet, adding back tolerated foods. For those that do not experience any symptom improvement with the elimination phase, the diet should be stopped, and different therapeutic approaches should be explored.
Practical Considerations for Success with the Low FODMAP Diet
Initiating a low-FODMAP diet in an individual with IBS, when possible, should be done under the guidance of a dietitian with expertise in the diet. Research has shown that by applying the diet with dietitian guidance versus without, the patients had a greater likelihood of following the 3-phases appropriately and attaining a therapeutic level of FODMAP intake to effectively reduce symptoms.18 An early referral to a dietitian is important to facilitate accurate and effective implementation of the diet from the outset.
The complexity of the diet benefits from expert RD direction to provide patients with the tools to carry out menu planning, grocery shopping, and label reading to decipher suitable food products for consumption. Further assessment should include considering the patient’s lifestyle, cultural preferences, food accessibility, health literacy, and personal goals for nutrition therapy. Appropriate candidates for the diet are selected carefully through screening for a history of eating disorder or excessive food fear to ensure that a restrictive diet does not induce harm. Using a patient-centered approach is important to confirm the patient desires a nutritional approach to treatment and to gain an understanding on how much they are willing to change in their diet on the onset. See Table 2 for candidates for the low-FODMAP diet.
Table 2. Low-FODMAP Suitability: Clinical Cues and Considerations
Eating triggers IBS symptoms No eating disorder currently or in past medical history No evidence of heightened food fear Able to prepare own food or have assistance with special diet preparation No signs of malnutrition Desires a nutritional approach
On the initial visit (generally 45 minutes -1 hour), the RD’s expertise and guidance can reinforce key nutritional principles, including evaluating the patient’s overall dietary adequacy, nutrient balance, eating behaviors (e.g., chewing food thoroughly to maximize digestion, eating in a relaxed state to engage the parasympathetic nervous system for rest and digestion) and promoting a positive, enjoyable relationship with food. While it is essential to encourage mindful adherence to the diet to assess its benefits, care must be taken to avoid fostering hypervigilance. This is particularly important in a population already vulnerable to food-related stress, anxiety and depression due in part to gut-brain axis dysregulation.
Up to one-third of people with IBS also experience anxiety or depression. Individuals with IBS who also experience anxiety or depression may struggle with significant food-related distress. This can include unnecessary and prolonged dietary restrictions, rigid beliefs about certain foods, resistance to altering these beliefs, and fear of eating in situations where they cannot maintain complete control over their diet. For these individuals, it is important to provide clear, evidence-based guidance on appropriate dietary modifications and to dispel common food-related myths. Dietitians can help patients by setting realistic expectations such as noting that diet alone may not resolve GI symptoms and promoting an integrated, multi-disciplinary care approach.19 Integrated care has proven more effective than gastroenterologist-only treatment in improving IBS symptoms, mental health, quality of life, and reducing healthcare costs.20
Figure 2. Top-Down and Bottom-Up Low FODMAP Approach
Potential Downsides of the Low-FODMAP Diet
Stool microbiome analysis research during use of the low-FODMAP diet has highlighted possible adverse effects. During the elimination phase, alterations in the stool microbiome have been observed; however, the potential negative effects of these changes are not yet fully understood. From a gut microbiome impact, the elimination phase of the diet has been shown to increase stool pH, which may provide a more favorable environment for potentially pathogenic microbes to flourish, however this effect is not consistent in the literature.21,22 Further, a reduction in health promoting microbiota, such as bifidobacteria levels are reduced in the elimination phase. However this change has been shown to be mitigated in small clinical trials with use of a probiotic or when the diet is liberalized in the personalization phase.23,24
Nutrient adequacy can be impacted in the elimination phase of the low-FODMAP diet. Diet evaluations of low-FODMAP diet followers appear to be lower in carbohydrates, fiber and calcium.25 It should be noted that in IBS, it is not uncommon for the baseline diet to be nutritionally inadequate. A recent prospective, open-labeled, case-report dietary intervention of 36 patients with IBS showed that an extended low-FODMAP diet (12 weeks) is not inferior to the participants’ baseline diet; revealing the IBS baseline diet has nutrient deficiencies and a low-FODMAP did not exacerbate these.26 The low-FODMAP diet, especially when dietitian-led and appropriately implemented, may be less restrictive than a patient’s baseline diet.
Other concerns about the low-FODMAP diet are its potential impact with food-related quality of life (FRQoL) given its restrictive nature. In fact, finding low-FODMAP suitable food options when dining out can be challenging and the diet requires some level of culinary skills. FRQoL has been found to be reduced in those staying on the elimination phase of the diet versus progressing through the 3 phases.27 Additionally, the potential added costs of following a specialized diet may add another barrier. Low-FODMAP and gluten free products often come at a higher cost compared to traditional wheat-based staples.28
Reintroduction Trials: What Have We Learned
Two trials focused on reintroducing FODMAPs were conducted to determine which FODMAP subtypes are most linked to digestive symptoms in patients with IBS. In one trial, US researchers Eswaran and colleagues carried out a key single-center study to evaluate the effects of reintroducing specific FODMAPs in patients who met the Rome IV criteria for IBS who had shown symptom improvement on a low-FODMAP elimination diet. This small, randomized, double-blind trial involved reintroducing individual FODMAP subtypes, with a final analysis including 20 participants. While maintaining the elimination phase of the low-FODMAP diet, each participant was randomized to follow one of five sequences involving the reintroduction of fructans, excess fructose, galacto-oligosaccharides (GOS), lactose, or polyols, all provided in a brownie. Participants consumed two brownies daily. See Table 3 for reintroduction FODMAP subtype amounts. The study aimed to identify which specific FODMAPs triggered symptoms such as abdominal pain and bloating. Results showed that fructans and GOS were the most common triggers, causing significant increases in abdominal pain, with GOS also linked to increased bloating. In contrast, lactose, excess fructose, and polyols did not significantly affect symptoms. These findings indicate that not all FODMAPs contribute equally to IBS symptoms, supporting a more targeted dietary management approach.29
Table 3. Reintroduction of FODMAP Quantities Administered Each Week29
FODMAP
Moderate Dose (day 1-3)
High Dose (day 4-7)
Lactose
10 g/day
20 g/day
Excess fructose
10.5 g/day
21 g/day
Polyol (sorbitol)
5 g/day
10 g/day
Fructans
0.75 g/day
1.5 g/day
GOS (galacto-oligosaccharides)
2 g/day
4 g/day
In another reintroduction FODMAP diet trial, Belgium researchers, Van den Houte et al. (2024) provides further validation that not all FODMAP subtypes trigger symptoms in most patients with IBS. Their blinded, randomized, crossover trial aimed to identify specific FODMAP triggers and assess their impact on IBS symptoms, quality of life, and psychosocial comorbidities. In this trial, 117 participants with IBS meeting Rome IV criteria who responded favorably to the low-FODMAP elimination diet phase, defined as a reduction of ≥50 points from baseline on the IBS Severity Scoring System (IBS-SSS), progressed to a 9-week reintroduction phase. During this phase, participants continued the low-FODMAP diet while being exposed to six different FODMAPs or glucose (30 g dose/day) as a control. Each FODMAP was provided as a powdered supplement in a randomized, blinded, crossover sequence. See the daily dosages of FODMAP subtypes are outlined in Table 4. Symptom severity was recorded daily using a 0–10 point numerical rating scale. Symptom recurrence was triggered in 85% of the FODMAP powders, by an average of 2.5 ± 2 FODMAPs/patient. The most prevalent triggers were fructans (56%), mannitol (54%), and GOS (35%).30
Table 4. Daily FODMAP Subtypes and Quantities Tested30
FODMAPs
Daily Powder Dose
Fructans
20 g/day
Excess fructose
60 g/day
GOS
12 g/day
Lactose
60 g/day
Mannitol
15 g/day
Sorbitol
15 g/day
These findings sparked interest in the clinical feasibility of achieving adequate symptom control through a more liberal FODMAP restriction.
Variations of the FODMAP Diet
FODMAP Simple
Based on the findings that fructans and GOS are commonly found to be triggers in clinical practice, and both reintroduction studies suggested their common role in instigating symptoms, a 2-center pilot feasibility study was initiated to assess for benefit of a bottom-up approach to FODMAP restriction. The “FODMAP simple” diet only limited fructans and GOS and was compared to the traditional low-FODMAP elimination diet in patients with IBS-with diarrhea (IBS-D). See Figure 2. The pilot feasibility study, which included 10 participants following the traditional low FODMAP diet group and 14 following the FODMAP simple diet, revealed the FODMAP simple approach improved symptoms in majority of patients with IBS-D. Furthermore, the FODMAP simple diet was better tolerated than the traditional low-FODMAP diet (adverse effects rate 12.5% vs. 26.3%).31 Given this was a pilot-feasibility study, the results should be viewed primarily as hypothesis generating versus evidence-based data. While this is not robust data to change clinical practice guidelines, it does provide some signals that a less restrictive approach may be effective for many with IBS.
FODMAP Gentle
In the FODMAP gentle approach, the dietitian modifies FODMAP intake based on the patient’s current intake and symptom profile, identifying only a subset of FODMAP rich foods to eliminate and assess symptom benefit. A FODMAP gentle diet involves selectively reducing certain foods that are highest in FODMAPs. See Table 5 for high-FODMAP foods often excluded in the FODMAP gentle diet.
This approach was introduced by Halmos and Gibson, Monash University researchers suggesting a FODMAP gentle approach may be undertaken when the traditional low-FODMAP elimination diet a “top-down” approach to treatment may not be appropriate.32 The authors highlight that some patients may be more appropriate for a less restrictive form of modifying FODMAPs such as individuals with pre-existing dietary restrictions (e.g., celiac disease, allergies) that may face nutritional deficiencies or those with active eating disorders or with food fear where a highly restrictive diet may exacerbate their psychological and potentially physical health. In such cases, it may be more appropriate to either forgo dietary therapy altogether or adopt a “bottom-up” strategy, such as the FODMAP gentle, a milder form of FODMAP restriction. It’s important to note that the FODMAP gentle approach has not been formally evaluated in the research setting.
Case Vignette: A Targeted FODMAP Gentle Strategy in Practice
A 23-year-old female with a history of IBS-C (IBS with constipation) presents with an increase in gas and bloating, which she finds increasingly frustrating. She has no history of an eating disorder or noted elevation of food fears. Her weight is stable with no alarm signs (e.g., blood in stool, unintended weight loss). She just started a new job at a coffee shop two months ago, where she has been consuming three complimentary soy lattes per shift as part of her employee benefits. While her constipation improved, symptoms of abdominal pain and gas have increased, which she describes as moderate and impacting on her day-to-day living. During the initial consultation, the dietitian recommended a FODMAP gentle approach, restricting her soy milk (a common source of the FODMAP subtype, GOS). The patient was instructed to substitute with almond milk or lactose free cow’s milk in her lattes. This slight change provided adequate symptom relief for this patient—and no further diet modifications were needed.
Caution: Diet is Not Always a Benign Intervention in Patients with GI Disorders
While often viewed as a holistic and natural approach to IBS care, diet change in the GI patient population may come with some unintended consequences. Of great interest and concern is the association of disordered eating particularly in the face of food fear, or a condition called avoidant restrictive food intake disorder (ARFID). ARFID was first included in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition in 2013, with a proposed subgroup highlighted by a pathologic restriction resulting from a fear of negative effects associated with eating.33 Further, individuals with past or a current eating disorder (ED) may develop GI symptoms as a consequence from their disordered eating behaviors. Malnutrition, for instance, can lead to pelvic floor dysfunction due to muscle atrophy, a predictor of abdominal distention and constipation.34 It can be challenging to determine whether GI symptoms are intrinsic features of EDs or consequences of malnutrition resulting from behaviors such as laxative misuse, self-induced vomiting, or food restriction.
Table 5. FODMAP Rich Foods Excluded in the Gentle Low-FODMAP Diet
Food Group
Common High-FODMAP Sources
Grains
Wheat, rye
Vegetables
Onion, leek, cauliflower, mushrooms (button)
Fruit
Apple, pear, dried fruit, stone fruit, watermelon
Dairy
Lactose containing milk or yogurt
Protein
Legumes (e.g., beans, lentils, chickpeas)
Healthcare providers in GI are indeed faced with a patient population at risk for disordered eating. One systematic review and meta-analysis found 23.4%of patients with GI disease (n=691) displayed disordered eating patterns.35 Screening for food fear (Nine Item Avoidant/Restrictive Food Intake Disorder Screen (NIAS)) or eating disorders (Eating Attitudes (EAT-26)) can help assess for maladaptive eating behaviors.36,37 With a positive screening for ARFID or ED, a referral to an ED therapist for a clinical diagnosis and management would be the next step.34,38 It is important to note, there is a need for validated ARFID and ED screening tools in the GI patient population. The NIAS can be used to screen for ARFID among patients with IBS; however, the IBS patient population is different than the population NIAS was developed in, and the validity is a bit unclear.37,38 While disordered eating behaviors benefit from eating disorder expert care, it’s important a GI provider remain engaged in GI care as needed.38
Conclusion
The low-FODMAP diet has emerged as a valuable therapeutic tool for managing IBS, offering symptom relief through strategic carbohydrate restriction. It’s complexity and restrictive nature underscore the critical role of GI-Expert RDs in guiding patients through its phases, ensuring nutritional adequacy, helping guide a positive food relationship and mitigating any potential nutrient and diet related health risks. There is growing interest and initial research underway into less restrictive approaches to the low-FODMAP diet, such as “FODMAP Gentle” and “FODMAP Simple”. Given the increasing concern that elimination diets may lead to disordered eating patterns or worsen conditions such as ARFID, especially among GI patients, the aim is to offer individuals with IBS a personalized and as liberal a diet as possible, while still effectively managing symptoms. Ideally, this approach should be initiated and monitored by a qualified GI-expert RD whenever feasible.
References
1. Lacy BE, Pimentel M, Brenner DM, et al. ACG Clinical Guideline: Management of Irritable Bowel Syndrome. Am J Gastroenterol. 2021;116(1):17-44. 2. Ford AC, Lacy BE, Talley NJ. Irritable bowel syndrome. N Eng J Med 2017; 376:2566–78. 3. Almario CV, Sharabi E, Chey WD, Lauzon M, Higgins CS, Spiegel BMR. Prevalence and Burden of Illness of Rome IV Irritable Bowel Syndrome in the United States: Results from a Nationwide Cross-Sectional Study. Gastroenterology. 2023;165(6):1475-1487. 4. Arnaout AY, Nerabani Y, Douba Z, Kassem LH, Arnaout K, Shabouk MB, Zayat H, Mayo W, Bezo Y, Arnaout I, Yousef A, Zeina MB, Aljarad Z; PRIBS Study Team. The prevalence and risk factors of irritable bowel syndrome (PRIBS study) among adults in low- and middle-income countries: A multicenter cross-sectional study. Health Sci Rep. 2023 Oct 4;6(10): e1592. 5. Tang HY, Jiang AJ, Wang XY, et al. Uncovering the pathophysiology of irritable bowel syndrome by exploring the gut-brain axis: a narrative review. Ann Transl Med. 2021;9(14):1187. 6. Ford AC, Sperber AD, Corsetti M, Camilleri M. Irritable bowel syndrome. Lancet. 2020;396(10263):1675-1688. 7. Drossman DA, Morris CB, Schneck S, et al. international survey of patients with IBS: Symptom features and their severity, health status, treatments, and risk Taking to achieve clinical benefit. J Clin Gastroenterol 2009;43(6):541–50. 8. Lacy BE, Everhart KK, Weiser KT, et al. IBS patients’ willingness to take risks with medications. Am J Gastroenterol 2012; 107: 804-9. 9. Gralnek IM, Hays RD, Kilbourne A, Naliboff B, Mayer EA. The impact of irritable bowel syndrome on health-related quality of life. Gastroenterology. 2000;119(3):654-660. 10. Gibson PR, Shepherd SJ. Personal view: food for thought–western lifestyle and susceptibility to Crohn’s disease. The FODMAP hypothesis. Aliment. Pharmacol. Ther. 2005; 21: 1399–1409. 11. Böhn L, Störsrud S, Törnblom H, Bengtsson U, Simrén M. Self-reported food-related gastrointestinal symptoms in IBS are common and associated with more severe symptoms and reduced quality of life. Am J Gastroenterol. 2013;108(5):634-641. 12. Eswaran SL, Chey WD, Han-Markey T, Ball S, Jackson K. A Randomized Controlled Trial Comparing the Low FODMAP Diet vs. Modified NICE Guidelines in US Adults with IBS-D. Am J Gastroenterol. 2016;111(12):1824-1832. 13. Staudacher HM, Whelan K. The low FODMAP diet: recent advances in understanding its mechanisms and efficacy in IBS. Gut. 2017;66(8):1517-1527. 14. Halmos EP, Power VA, Shepherd SJ, Gibson PR, Muir JG. A diet low in FODMAPs reduces symptoms of irritable bowel syndrome. Gastroenterology. 2014;146(1):67-75. e5. 15. Khan Z, Muhammad SA, Amin MS, Gul A. The Efficacy of the Low-FODMAP (Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyols) Diet in Irritable Bowel Syndrome: A Systematic Review and Meta-Analysis. Cureus. 2025 Jan 7;17(1): e77053. 16. Murray K, Wilkinson-Smith V, Hoad C, et al. Differential effects of FODMAPs (fermentable oligo-, di-, monosaccharides and polyols) on small and large intestinal contents in healthy subjects shown by MRI. Am J Gastroenterol 2014; 109:110–9 17. Singh P, Grabauskas G, Zhou SY, Gao J, Zhang Y, Owyang C. High FODMAP diet causes barrier loss via lipopolysaccharidemediated mast cell activation. JCI Insight. 2021 Nov 22;6(22): e146529. 18. Tuck CJ, Reed DE, Muir JG, Vanner SJ. Implementation of the low practicalgastro.com FODMAP diet in functional gastrointestinal symptoms: A real-world experience. Neurogastroenterol Motil. 2020;32(1): e13730. 19. Staudacher HM, Black CJ, Teasdale SB, Mikocka-Walus A, Keefer L. Irritable bowel syndrome and mental health comorbidity – approach to multidisciplinary management. Nat Rev Gastroenterol Hepatol. 2023 Sep;20(9):582-596. 20. Basnayake C, Kamm MA, Stanley A, et al. Standard gastroenterologist versus multidisciplinary treatment for functional gastrointestinal disorders (MANTRA): an open-label, singlecentre, randomised controlled trial. Lancet Gastroenterol Hepatol. 2020;5(10):890-899. 21. Halmos EP, Christophersen CT, Bird AR, Shepherd SJ, Gibson PR, Muir JG. Diets that differ in their FODMAP content alter the colonic luminal microenvironment. Gut. 2015;64(1):93-100. 22. So D, Loughman A, Staudacher HM. Effects of a low FODMAP diet on the colonic microbiome in irritable bowel syndrome: a systematic review with meta-analysis. Am J Clin Nutr. 2022;116(4):943-952. 23. Staudacher HM, Lomer MCE, Farquharson FM, et al. A Diet Low in FODMAPs Reduces Symptoms in Patients with Irritable Bowel Syndrome and A Probiotic Restores Bifidobacterium Species: A Randomized Controlled Trial. Gastroenterology. 2017;153(4):936- 947. 24. Staudacher HM, Rossi M, Kaminski T, et al. Long-term personalized low FODMAP diet improves symptoms and maintains luminal Bifidobacteria abundance in irritable bowel syndrome. Neurogastroenterol Motil. 2022;34(4): e14241. 25. Staudacher HM. Nutritional, microbiological and psychosocial implications of the low FODMAP diet. J Gastroenterol Hepatol. 2017;32 Suppl 1:16-19. 26. Hillestad EMR, Steinsvik EK, Teige ES, et al. Nutritional safety and status following a 12-week strict low FODMAP diet in patients with irritable bowel syndrome. Neurogastroenterol Motil. 2024;36(7):e14814. 27. Silva H, Porter J, Barrett J, Gibson PR, Garg M. Dietary Intake, Symptom Control and Quality of Life After Dietitian-Delivered Education on a FODMAP Diet for Irritable Bowel Syndrome: A 7-Year Follow Up. Neurogastroenterol Motil. Published online July 1, 2025. 28. Lee AR, Wolf RL, Lebwohl B, Ciaccio EJ, Green PHR. Persistent Economic Burden of the Gluten Free Diet. Nutrients. 2019;11(2):399. 29. Eswaran S, Jencks KJ, Singh P, Rifkin S, Han-Markey T, Chey WD. All FODMAPs Aren’t Created Equal: Results of a Randomized Reintroduction Trial in Patients With Irritable Bowel Syndrome. Clin Gastroenterol Hepatol. 2025;23(2):351-358.e5. 30. Van den Houte K, Colomier E, Routhiaux K, et al. Efficacy and Findings of a Blinded Randomized Reintroduction Phase for the Low FODMAP Diet in Irritable Bowel Syndrome. Gastroenterology. 2024;167(2):333-342. 31. Singh P, Chey SW, Nee J, et al. Is a Simplified, Less Restrictive Low FODMAP Diet Possible? Results From a Double-Blind, Pilot Randomized Controlled Trial. Clin Gastroenterol Hepatol. 2025;23(2):362-364.e2. 32. Halmos EP, Gibson PR. Controversies and reality of the FODMAP diet for patients with irritable bowel syndrome. J Gastroenterol Hepatol. 2019;34(7):1134-1142. 33. American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5). Arlington, VA: American Psychiatric Publishing. 34. Riehl ME, Scarlata K. Understanding Disordered Eating Risks in Patients with Gastrointestinal Conditions. J Acad Nutr Diet. 2022;122(3):491-499. 35. Satherley R, Howard R, Higgs S. Disordered eating practices in gastrointestinal disorders. Appetite. 2015; 84:240-250. 36. Garner DM, Olmsted MP, Bohr Y, Garfinkel PE. The eating attitudes test: psychometric features and clinical correlates. Psychol Med. 1982;12(4):871-878. 37. Zickgraf HF, Ellis JM. Initial validation of the Nine Item Avoidant/ Restrictive Food Intake disorder screen (NIAS): A measure of three restrictive eating patterns. Appetite. 2018; 123:32-42. 38. Scarlata K, Zickgraf HF, Satherley RM, et al. A Call to Action: Unraveling the Nuance of Adapted Eating Behaviors in Individuals with Gastrointestinal Conditions. Clin Gastroenterol Hepatol. 2025;23(6):893-901.e2.
Gastric varices (GV) are a serious complication of portal hypertension, present in about 20% of cirrhotic patients compared to up to 85% with esophageal varices (EV).1,2 Though less common, GV are associated with more severe bleeding, higher mortality, and increased rebleeding rates.1,3 IGV1 (isolated fundal varices) and GOV2 (gastroesophageal varices extending into the fundus) carry the highest bleeding risk, with 2-year incidence rates of up to 78% and 55%, respectively.1 (Figure 1)
Sarin’s classification is the standard system for categorizing GV into four types: GOV1 (extension of EV into the lesser curvature), GOV2 (into the fundus), IGV1 (isolated fundal), and IGV2 (elsewhere in the stomach).1,2 GOV1 is most common (75%), followed by GOV2 (21%), IGV2 (4%), and IGV1 (<2%).1 GV bleeding is more severe, harder to control, and more likely to recur, warranting early recognition and targeted treatment.
Unlike EV, which drain into the azygos system, GV form complex portosystemic collaterals via the gastrorenal or left inferior phrenic veins.1,4 They may rupture at portal pressures below 12 mmHg due to differences in wall tension and shunt dynamics.1,4 Their fundal location, thin walls, and high flow through large shunts increase bleeding risk, often without warning.
Management is challenging due to anatomical variability and limited trial data. Endoscopic cyanoacrylate injection (ECI) is the preferred treatment for cardiofundal varices (GOV2, IGV1), achieving high hemostasis rates.1,2 EBL and sclerotherapy are less effective, with <50% hemostasis and rebleeding rates up to 63% over two years. ECI, while effective, carries embolization risks—particularly with gastrorenal shunts—and requires expertise. Access to glue is also limited. Radiologic options like TIPS and BRTO are used for refractory cases but have drawbacks such as hepatic encephalopathy or worsening of EV.1,2 EUS-guided coiling has emerged as a promising alternative, allowing Doppler-guided coil placement with or without glue. It offers precise targeting and reduced embolic risk compared to direct glue injection.3,7 While early data show high success rates, widespread use is limited by procedural variability and lack of randomized trials. This review explores the rationale, technique, and evidence supporting EUS-guided coiling in GV management.
2. Current Standards of Care
Initial management of bleeding gastric varices (GV) includes hemodynamic stabilization, vasoactive agents (e.g., octreotide or terlipressin), prophylactic antibiotics, and restrictive transfusion. Endoscopy within 12 hours is recommended for diagnosis and classification. Once stable, AGA and AASLD guidelines advise cross-sectional imaging (CT or MRI) to assess vascular anatomy and suitability for BRTO or TIPS.2,8
Endoscopic cyanoacrylate injection (ECI) is first-line therapy for cardiofundal varices (GOV2, IGV1), supported by AGA, AASLD, Chinese, and Baveno VII guidelines due to its high hemostasis rates. However, its use is limited by glue availability, risk of systemic embolization—especially in gastrorenal shunts—and need for operator expertise.2,8-10
BRTO is preferred in patients with a gastrorenal shunt and preserved liver function, while TIPS is indicated when endoscopic therapy fails or BRTO is not feasible. AASLD recommends repeat ECI every 2–4 weeks until obliteration, with surveillance at 3–6 months, then annually. Routine prophylaxis is not recommended, though high-risk patients may be considered.2,8-10
EUS-guided therapies, though not yet widely adopted, are emerging as valuable options in specialized centers for high-risk or refractory cases.3,7
3. Technique(s) Overview
EUS-guided coil embolization has emerged as an advanced modality for targeted treatment of bleeding and non-bleeding gastric varices (GV), particularly in cases with complex anatomy or high-risk shunts. Using Doppler-enhanced EUS, variceal inflow and outflow can be visualized in real time, enabling targeted therapy even in obscured or actively bleeding fields.11,12
Coils (e.g., Nester® and Tornado®; Cook Medical, USA) are made of soft platinum wires embedded with synthetic Dacron fibers to enhance thrombogenicity. They act as a scaffold to promote hemostasis, either alone or in combination with cyanoacrylate, thrombin, or gelatin sponge. Coil use reduces sclerosant volume and systemic embolization risk, particularly in high-flow varices such as those associated with gastrorenal shunts. EUS also permits access to feeder vessels and deep submucosal varices not amenable to conventional endoscopic therapy.11,12
This approach combines precision targeting, intraprocedural flow monitoring, and direct embolization, making it well suited for both primary and rescue therapy.
Standard Technique of EUS-Guided Coil Embolization
A. Pre-Procedure Preparation
The procedure is typically performed under general anesthesia or monitored anesthesia care, with the patient supine or in the left lateral decubitus position to optimize scope control. Instilling 100–200 mL of sterile water into the stomach may improve visualization by floating the varix.12 Prophylactic antibiotics are commonly administered, and pre-procedural imaging (CT/MRI) is often used to delineate portosystemic shunts like gastrorenal shunts (GRS) for planning and embolic risk assessment.11,13
B. Procedure Steps
Once the gastric fundus is visualized, EUS with color Doppler is used to identify the target varix or feeder vessel, typically seen as an anechoic, tubular submucosal channel. These vessels may appear dilated or tortuous. Doppler imaging is essential for assessing flow direction and hemodynamics before intervention.13,14 A 19G or 22G FNA needle is then used to puncture the target, selected based on coil size:
• 0.035-inch coils for 19G or
• 0.018-inch coils for 22G.11,14
Needle placement is confirmed under direct EUS visualization. If needed, further confirmation can be achieved by
• aspirating blood or
• injecting 1–1.5 mL of distilled water to visualize hyperechoic bubbles under EUS—the preferred method to avoid trauma from suction11
Once confirmed, hemostatic coils are deployed. Coils are often 20–30% larger than the varix diameter to ensure secure anchorage and thrombosis, but if the varices are very wide this is not always possible.11,15 Deployment is performed under continuous EUS guidance with the needle tip in view, using a stylet or guidewire and steady pressure.11,14 Fluoroscopy can be used during deployment but is not mandatory.
Doppler flow can be reassessed post-deployment.13 If residual flow persists and immediate complete cessation of flow is desired, adjunctive agents (cyanoacrylate, thrombin, or gelatin sponge) may be injected through the same needle.11,14,16 It should be noted that complete cessation of flow is not always possible to achieve during the procedure and that the formation of a stable thrombus takes time.
When using glue, the needle is flushed with distilled water or 5% dextrose (not saline) to prevent premature polymerization and catheter blockage.11
The procedure can be performed via either a transgastric or transesophageal route, the latter offering a tamponade effect that may reduce puncture-site bleeding.11 Route selection depends on operator preference, anatomy, and variceal location. (Figures 2 and 3)
C. Post-Procedure Care
Patients are monitored for immediate AEs such as bleeding, embolism, or pain.13 Follow-up is typically conducted at 1–3 months to assess variceal obliteration and recurrence, with further management guided by endoscopic and endosonographic Doppler findings or perceived rebleeding risk.13 Chavan et al. recommend initial follow up at 4 weeks, then at 3 months and every 6 months to monitor variceal status to perform flow studies, but this is often left to the operator and the patient to decide.11
Technique Variations
A. Coil Embolization Alone
As described above, coil embolization involves EUS-guided deployment of thrombogenic platinum coils into the gastric varix or its feeder vessel without adjunctive agents. The coils induce mechanical thrombosis and flow disruption, resulting in clot formation and hemostasis. It avoids glue-related complications such as systemic embolization and endoscope damage. Careful patient and varix selection remains essential for optimal outcomes.15,16
B. Coil Plus Cyanoacrylate Glue (Combination Therapy)
In combination therapy, the key technical modification from coil monotherapy is the sequential injection of cyanoacrylate glue following coil placement. After coil placement, a measured volume of glue is injected through the same FNA needle to promote complete obliteration. The coil acts as a scaffold, reducing glue migration and localizing polymerization within the varix. This technique typically uses less glue than direct endoscopic injection, thereby reducing, but not eliminating, the risk of systemic embolization. Immediate needle flushing with distilled water or 5% dextrose is essential post-injection to prevent in-lumen polymerization, which could occlude the catheter or damage the endoscope.16-18
C. Coil Plus Thrombin Injection
This technique mirrors standard EUS-guided coil embolization up to variceal targeting, with the key distinction being the use of human thrombin instead of cyanoacrylate following coil placement. Once Doppler confirms reduced flow, thrombin is injected through the same FNA needle to enhance thrombosis and achieve obliteration. Unlike glue, thrombin does not polymerize, eliminating the need for rapid flushing and the risk of catheter occlusion or endoscope damage. It is reconstituted in saline and delivered in 1 mL aliquots (total dose: 600–10,000 IU), with injection stopped upon Doppler-confirmed flow cessation or reaching the maximum dose. This approach is particularly useful for patients at high embolic risk, those with glue allergies, or in settings without access to cyanoacrylate. Although data are limited, early series by O’Rourke et al. and Frost et al. report favorable technical success and safety, supporting its role as a viable alternative in select cases.19,20 Of note, most centers do not have ready access to thrombin.
D. Coil Plus Absorbable Hemostatic Agents (e.g., Gelatin Sponge)
In this variation, the key modification from coil monotherapy involves the adjunctive use of absorbable gelatin sponge (AGS) following coil placement. After Doppler-confirmed reduction in flow, a gelatin-based slurry is injected through the same needle to enhance thrombosis and promote complete variceal obliteration. Commercially available AGS products include GELFOAM® (Pfizer, USA), SURGIFOAM® (Ethicon, a Johnson & Johnson company, USA), and INSTASPON® (manufactured in India by INSTASPON Pvt. Ltd.). The coil serves as a mechanical scaffold, while AGS reinforces hemostasis by limiting residual blood flow within the varix. Unlike cyanoacrylate, AGS does not pose a risk of catheter blockage or polymer-related embolization, and therefore does not require rapid needle flushing. Additionally, AGS is biodegradable and dissolves within days, making it especially useful in patients with high embolic risk or contraindications to glue. Doppler reassessment guides further management if persistent flow is detected, and operator judgment remains critical in timing the injection and selecting appropriate patients. This approach has also been applied in cases where TIPS or BRTO were not feasible or had failed. Structured EUS follow-up is used to confirm obliteration and monitor for recurrence.21-22 However, while AGS is widely available in many surgical and interventional settings globally, its use in EUS-guided interventions remains relatively limited and center-specific, likely due to variations in operator familiarity, regulatory approvals, and material availability.
E. Feeder Vessel Embolization
In this variation of EUS-guided therapy, the target shifts from the submucosal variceal complex (SVC) to the feeder or perforator vessel supplying the gastric varices. Under EUS with color Doppler, the inflow vessel is identified—typically facilitated by Type 1 Arakawa anatomy where a dominant perforator is visualized.23 In practice, feeder vessel embolization can be performed using the same core techniques as traditional SVC targeting, including coils, cyanoacrylate, or combination therapy, depending on operator preference and anatomy. In a recent comparative analysis by Samanta et al., this approach demonstrated comparable technical and clinical success to SVC targeting but required fewer coils and less glue, suggesting greater procedural efficiency. However, it is more technically demanding, necessitates anatomical mapping, and current clinical data remain limited.23 In many patients, a feeder can be identified with careful evaluation.
F. Access Route: Transgastric vs. Transesophageal
EUS-guided variceal embolization can be performed via a transgastric or transesophageal route. The transgastric approach, involving direct puncture of the gastric fundus, is straightforward and allows direct visualization but may require the echoendoscope to be in a highly flexed position. However, the transesophageal route may be advantageous when fundal varices are difficult to access, unstable during puncture, or visualization is limited. This route also provides a tamponade effect, as the needle traverses muscular layers, potentially reducing procedural bleeding. Transesophageal approaches allow a straight echoendoscope position and may be easier for the operator with regards to needle operation as well. Ultimately, the choice depends on anatomical factors and operator expertise, and both approaches require continuous needle-tip visualization to minimize complications. No studies have directly compared outcomes between these two approaches, and both are considered acceptable based on clinical context.11
4. Clinical Efficacy and Safety Profile
Technical and Clinical Success
EUS-guided coil embolization consistently achieves high technical success rates (98–100%) across studies, regardless of whether the approach involves coils, CYA, or combination therapy.24,25 In a meta-analysis by McCarty et al., combination therapy had a 100% technical success rate, slightly outperforming glue (97%) and coil (99%) monotherapies (P < 0.001).15 Monotherapy is often favored in practice due to simplicity and ease of use.
Clinical success—defined as immediate hemostasis and early bleeding control—varies by modality. Coil monotherapy achieves success rates of 88.6% to 94.7%, especially in patients with localized or low-flow varices.14,15 CYA monotherapy performs similarly (91.3%–96%) but carries higher embolic risk in high-flow settings.15,26
Combination therapy consistently delivers the best clinical outcomes. McCarty et al. reported a 98.2% success rate with coil + glue, compared to 96% for glue alone and 89.5% for coils (P < 0.001).15 In a randomized trial by Jhajharia et al., combination therapy achieved 100% obliteration vs. 92.3% with glue alone, using fewer sessions and significantly less glue (1.5 mL vs. 3.5 mL).26
Alternative techniques also show promise. Coil plus thrombin injection yielded 95% technical and 85% clinical success in the prospective series by O’Rourke et al., with no thrombin-related complications.19 Coil with absorbable gelatin sponge (AGS) also demonstrated favorable results, although this is not widely performed. Bazarbashi et al. achieved 100% technical success and hemostasis, with no rebleeding at 9 months, versus rebleeding in 11 of 30 patients (38%) in the CYA group.21 Samanta et al. reported complete obliteration in 23 of 24 patients (95.8%) when targeting the feeder vessel, with lower rebleeding (2 of 24; 8.3%), fewer re-interventions (1 of 24; 4.2%), and reduced use of coils and glue, though further validation is needed.23
Safety Profile and Adverse Events
EUS-guided coil embolization has a favorable safety profile, with AE rates ranging from 3% to 9.1%. Romero-Castro et al. reported minor GI bleeding in 9.1% of coil-only cases, with no systemic embolization.27,28 Bhat et al. found a pooled AE rate of 7.2%, mostly transient pain and minor bleeding.25,26 No major series have reported systemic embolization with coil monotherapy, though rare complications such as coil migration and puncture-site bleeding (~10%) have been noted.29
CYA glue monotherapy carries higher AE risks, largely due to systemic embolization and device-related issues. Pulmonary embolism occurred in 47% of patients in Romero-Castro et al.’s study (but these patients were mostly asymptomatic).27,28 Bick et al. reported a 20.3% AE rate, including splenic infarction (3%) and bacteremia (2–6%).30 Device-related adverse events such as needle adhesion and endoscope blockage occurred in 1.4–2.7% of cases.27,31
Combination therapy with coils and glue offers a safer profile than glue alone, with McCarty et al. reporting a 10% adverse event (AE) rate vs. 21% (P < 0.001), and Lobo et al. noting pulmonary embolism in 25% vs. 50% with glue alone (P = 0.144), likely due to coils limiting glue migration.15,32 Across modalities, common AEs include transient abdominal pain (8–15%), fever (5–9%), and minor GI bleeding (6–50%), with major bleeding occurring in up to 10%; the use of real-time Doppler and controlled injection helps minimize these risks.27,29 Alternative approaches are also well-tolerated: thrombin injection resulted in 0% AEs even in emergencies (Frost et al.), gelatin sponge use showed no complications in Ge et al. and only mild AEs in 4.7% of cases in Bazarbashi et al., while feeder vessel embolization preserved safety and reduced the need for coils and glue.20-23
Long-Term Outcomes: Rebleeding and Reintervention
EUS-guided therapies for GV—including coil embolization, CYA glue injection, and combination therapy—demonstrate varying long-term efficacy, with most follow-up data limited to 6–13 months.15,16,33,34
Combination therapy (coil + glue) consistently shows superior outcomes. Rebleeding rates range from 4.8% to 14%, with McCarty et al. reporting a pooled rate of 14% versus 30% for glue alone and only slightly higher at 17% for coil monotherapy.15 Other studies reinforce this: Florencio de Mesquita et al. reported 5% rebleeding with combination therapy versus 24% for glue (P < .001), Chen et al. found 4.8% vs. 27.8% (P = .041), and Robles-Medranda et al. observed 3.3% vs. 20% (P = .04).18,33,34 Of note, Bazarbashi et al. found higher rebleeding rates for combination therapy (14.9%) versus coils alone (10.5%), the difference was not statistically significant (P = .99).14
Reintervention rates are also lowest with combination therapy: McCarty reports 15%, compared to 26% for glue and 25% for coil monotherapy.15 Florencio de Mesquita found reintervention rates of 11.9% with combination therapy vs. 36.4% for glue (P = .03), while Robles-Medranda reported 83.3% did not need further reintervention vs. 60% with coil alone.18,34
Glue monotherapy, while effective for initial hemostasis, has the highest long-term rebleeding rates—ranging from 24% to 57.9% in studies by Florencio de Mesquita, Chen, Mukkada, and Romero-Castro.28,33–35 Reintervention rates range from 15% to 36%.15,34 Coil monotherapy avoids glue-related embolic risks but offers modest long-term durability. Rebleeding rates range from 10.5% to 20%.14,15,18 McCarty et al. reported a 25% pooled reintervention rate with coil monotherapy, though individual study data on reintervention are limited.15
Alternative techniques show early promise but are based on small cohorts. Thrombin injection, though based on a small cohort, showed promising results in the study by Frost et al., which included 8 patients—3 with active bleeding (2 of whom achieved hemostasis) and 5 treated electively, none of whom rebled during follow-up.20 Gelatin sponge adjuncts, though based on limited data, yielded complete obliteration at 4 months in a single-patient case report (Ge et al.) and a 14.1% rebleeding rate among 10 patients in the Bazarbashi cohort, with most cases managed with re-coiling.21,22 Feeder vessel identification with subsequent embolization showed similar durability with fewer coils and less sclerosant, improving efficiency without compromising outcomes.23
Long-term outcomes depend on factors such as treatment indication, variceal anatomy, and technical precision (e.g., coil sizing, Doppler-confirmed obliteration).14,15,33 Among current options, EUS-guided combination therapy provides the most durable control, with consistently lower rebleeding and reintervention rates. However, longer-term prospective studies are needed to confirm its sustained efficacy.
5. Advantages and Limitations of EUS-Guided Coil Therapies Compared to DEI and BRTO/TIPS
EUS-guided coil embolization, particularly when combined with cyanoacrylate, offers key advantages over traditional treatments like direct endoscopic injection (DEI), BRTO, and TIPS. Real-time Doppler guidance enables direct visualization of gastric varices and feeder vessels, allowing precise coil placement and immediate confirmation of obliteration. In contrast, DEI is a semi-blind technique with higher risks of incomplete obliteration and systemic embolization.36 EUS-guided therapy also uses less cyanoacrylate (1.4 mL vs. 2.6 mL), reducing glue-related complications such as needle blockage and endoscope damage.33,37
Compared to BRTO, EUS-guided therapy shows similar efficacy with fewer adverse events. A multicenter propensity-matched study reported comparable one-year bleeding rates (15.3% vs. 13.6%) and four-week obliteration rates (83.1% vs. 91.5%), but significantly fewer adverse events with EUS (5.1% vs. 22.0%; P = 0.007). BRTO was associated with higher rates of new or worsening ascites and esophageal variceal progression.38 Unlike TIPS, which alters systemic hemodynamics and increases the risk of hepatic encephalopathy, EUS-guided therapy provides localized variceal treatment without portal decompression.33,36
However, limitations exist. EUS-guided therapy had a higher reintervention rate than BRTO (28.8% vs. 5.1%; P = 0.001), likely due to incomplete obliteration of collateral vessels not addressed endoscopically.38 Additionally, its adoption is constrained by limited availability of equipment and expertise. Variability in technique—including coil size, number, glue volume, and use of Doppler—highlights the need for procedural standardization.15,36
In summary, EUS-guided therapy of gastric varices is a precise, minimally invasive, and safer alternative to DEI, with a favorable safety profile compared to BRTO and TIPS. Broader implementation will require standardized protocols, increased training, and prospective studies evaluating long-term efficacy and cost-effectiveness.
6. Future Directions
As EUS-guided therapy gains traction in the management of gastric varices, several critical gaps remain. While early data support its safety and efficacy—particularly with coil embolization—large randomized trials comparing it to TIPS and BRTO are lacking, especially in patients with complex anatomy or advanced liver disease. Long-term outcomes beyond 12 months are also underreported. These may be difficult trials to conduct given the frequency of gastric varices as compared to esophageal varices.
Another major challenge is the lack of procedural standardization. Variability in coil type, size, number, adjunctive agents, and Doppler criteria highlights the need for consensus protocols to guide practice and training. Similarly, cost-effectiveness analyses are needed, particularly in resource-limited settings where access to cyanoacrylate or interventional radiology may be constrained.
The role of EUS-guided therapy in primary prophylaxis for high-risk varices remains largely unexplored. More data are needed to guide patient selection and preventive efficacy. Emerging techniques—such as biodegradable agents, molecular imaging, and AI-assisted Doppler interpretation—may improve targeting, precision, and scalability. Feeder vessel–targeted embolization also shows promise in reducing material use and procedural time.
In sum, while EUS-guided approaches represent a transformative advance in gastric variceal management, broader adoption will require standardized practices, comparative studies, and continued innovation.
7. Conclusion
Endoscopic ultrasound-guided therapy represents a promising targeted approach for managing gastric varices, offering improved precision and safety compared to conventional therapies. Combination therapy with coil and cyanoacrylate consistently demonstrates superior efficacy, with lower rebleeding and reintervention rates than monotherapies, although coils as monotherapy are also highly effective. Alternative adjuncts like thrombin, gelatin sponge, and feeder vessel embolization show promise but are supported by limited data.
While retrospective studies suggest EUS-guided therapy may be comparable—or even favorable to—BRTO and TIPS in select patients, high-quality, prospective trials are needed. Standardization of technique, broader training, and cost-effectiveness analyses will be essential for wider adoption. With continued research and refinement, EUS-guided coiling has the potential to become a central component of gastric variceal management.
References
References 1. Luo, Xuefeng, and Virginia Hernández-Gea. “Update on the management of gastric varices.” Liver International 42.6 (2022): 1250-1258. 2. Henry, Zachary, et al. “AGA clinical practice update on management of bleeding gastric varices: expert review.” Clinical Gastroenterology and Hepatology 19.6 (2021): 1098-1107. 3. DeWitt, John M. “Endoscopic treatment of gastric variceal bleeding: Where have we come from, and where are we going?.” Gastrointestinal Endoscopy 99.1 (2024): 38-40. 4. Gulamhusein, Aliya F., and Patrick S. Kamath. “The epidemiology and pathogenesis of gastrointestinal varices.” Techniques in Gastrointestinal Endoscopy 19.2 (2017): 62-68. 5. Chandra, Subhash et al. “Endoscopic Cyanoacrylate Glue Injection in Management of Gastric Variceal Bleeding: US Tertiary Care Center Experience.” Journal of clinical and experimental hepatology vol. 8,2 (2018): 181-187. doi:10.1016/j.jceh.2017.11.002 6. Tseng, Yujen et al. “Thromboembolic Events Secondary to Endoscopic Cyanoacrylate Injection: Can We Foresee Any Red Flags?.” Canadian journal of gastroenterology & hepatology vol. 2018 1940592. 3 Apr. 2018, doi:10.1155/2018/1940592 7. Chandan, Saurabh, et al. “EUS–guided therapies for primary and secondary prophylaxis in gastric varices—An updated systematic review and meta-analysis.” Endoscopic ultrasound 12.4 (2023): 351-361. 8. Kaplan, David E., et al. “AASLD Practice Guidance on risk stratification and management of portal hypertension and varices in cirrhosis.” Hepatology 79.5 (2024): 1180-1211 9. De Franchis, Roberto, et al. “Baveno VII–renewing consensus in portal hypertension.” Journal of hepatology 76.4 (2022): 959-974. 10. Xu, Xiaoyuan, et al. “Guidelines for the management of esophagogastric variceal bleeding in cirrhotic portal hypertension.” Journal of Clinical and Translational Hepatology 11.7 (2023): 1565. 11. Chavan, Radhika, et al. “Technical tips for EUS-guided embolization of varices and pseudoaneurysms.” VideoGIE 9.4 (2024): 211-219. 12. Ryou, Marvin, et al. “AGA clinical practice update on interventional EUS for vascular investigation and therapy: commentary.” Clinical Gastroenterology and Hepatology 21.7 (2023): 1699-1705. 13. Binmoeller, Kenneth F. “Endoscopic ultrasound–guided coil and glue injection for gastric variceal bleeding.” Gastroenterology & Hepatology 14.2 (2018): 123. 14. Bazarbashi, Ahmad Najdat, et al. “EUS-guided coil injection therapy in the management of gastric varices: the first US multicenter experience (with video).” Gastrointestinal endoscopy 99.1 (2024): 31-37. 15. McCarty, Thomas R., et al. “Combination therapy versus monotherapy for EUS-guided management of gastric varices: A systematic review and meta-analysis.” Endoscopic Ultrasound 9.1 (2020): 6-15. 16. Xiao, Yong, et al. “Balloon-occluded retrograde transvenous obliteration combined with EUS-guided coil embolization and endoscopic cyanoacrylate injection therapy of gastric varices with huge gastrorenal shunt (with videos).” practicalgastro.com Endoscopic ultrasound 12.1 (2023): 157-159. 17. Bazarbashi, Ahmad Najdat, et al. “Endoscopic ultrasoundguided treatment of gastric varices with coil embolization and absorbable hemostatic gelatin sponge: a novel alternative to cyanoacrylate.” Endoscopy International Open 8.02 (2020): E221-E227. 18. Robles-Medranda, Carlos, et al. “Endoscopic ultrasonography- guided deployment of embolization coils and cyanoacrylate injection in gastric varices versus coiling alone: a randomized trial.” Endoscopy 52.04 (2020): 268-275. 19. O’Rourke, Joanne, et al. “EUS-guided thrombin injection and coil implantation for gastric varices: feasibility, safety, and outcomes.” Gastrointestinal Endoscopy 100.3 (2024): 549-556. 20. Frost, John W., and Srisha Hebbar. “EUS-guided thrombin injection for management of gastric fundal varices.” Endoscopy International Open 6.06 (2018): E664-E668. 21. Bazarbashi, Ahmad Najdat, et al. “Endoscopic ultrasoundguided coil embolization with absorbable gelatin sponge appears superior to traditional cyanoacrylate injection for the treatment of gastric varices.” Clinical and Translational Gastroenterology 11.5 (2020): e00175. 22. Phillip, S. Ge, et al. “Successful EUS-guided treatment of gastric varices with coil embolization and injection of absorbable gelatin sponge.” VideoGIE 4.4 (2019): 154-156. 23. Samanta, J., et al. “Is endoscopic ultrasound-guided angioembolization of feeder vessel as good as targeting submucosal variceal complex in the management of gastric varices: A pragmatic comparative analysis.” Endoscopy 57.S 02 (2025): OP208. 24. Kouanda, Abdul, et al. “Safety and efficacy of EUS-guided coil and glue injection for the primary prophylaxis of gastric variceal hemorrhage.” Gastrointestinal Endoscopy 94.2 (2021): 291-296. 25. Bhat, Yasser M., et al. “EUS-guided treatment of gastric fundal varices with combined injection of coils and cyanoacrylate glue: a large US experience over 6 years (with video).” Gastrointestinal endoscopy 83.6 (2016): 1164-1172. 26. Jhajharia, Ashok, et al. “Endoscopic ultrasonography-guided coil embolization and cyanoacrylate injection versus cyanoacrylate injection alone for gastric varices: a randomized comparative study.” Endoscopy 57.02 (2025): 107-115. 27. Manolakis, Anastasios, Kyriaki Tsagkidou, and Konstantinos Eleftherios Koumarelas. “Endoscopic ultrasound-guided therapies in the treatment of gastric varices: An in-depth examination of associated adverse events.” World Journal of Gastrointestinal Endoscopy 16.12 (2024): 640. 28. Romero-Castro, Rafael, et al. “EUS-guided coil versus cyanoacrylate therapy for the treatment of gastric varices: a multicenter study (with videos).” Gastrointestinal endoscopy 78.5 (2013): 711-721. 29. Khoury, Tawfik, et al. “Endoscopic Ultrasound-Guided Angiotherapy for Gastric Varices: A Single Center Experience.” Hepatology Communications 3.2 (2019): 207- 212. 30. Bick, Benjamin L., et al. “EUS-guided fine needle injection is superior to direct endoscopic injection of 2-octyl cyanoacrylate for the treatment of gastric variceal bleeding.” Surgical Endoscopy 33 (2019): 1837-1845. 31. Guo, Yun-Wei, et al. “Procedure-related complications in gastric variceal obturation with tissue glue.” World journal of gastroenterology 23.43 (2017): 7746. 32. LÔBO, Maíra Ribeiro de Almeida, et al. “Safety and efficacy of EUS-guided coil plus cyanoacrylate versus conventional cyanoacrylate technique in the treatment of gastric varices: a randomized controlled trial.” Arquivos de Gastroenterologia 56.01 (2019): 99-105. 33. Chen, Dawei, Sunya Fu, and Ruiwei Shen. “Efficacy and safety of EUS-guided coil embolization in combination with cyanoacrylate injection versus conventional endoscopic cyanoacrylate injection in the treatment of gastric varices with spontaneous portosystemic shunts.” Gastroenterology Report 12 (2024): goae026. 34. de Mesquita, Cynthia Florencio, et al. “EUS-guided coiling plus glue injection compared with endoscopic glue injection alone in endoscopic treatment for gastric varices: a systematic review and meta-analysis.” Gastrointestinal Endoscopy (2024). 35. Mukkada, Roy J., et al. “Endoscopic ultrasound-guided coil or glue injection in post-cyanoacrylate gastric variceal re-bleed.” Indian Journal of Gastroenterology 37 (2018): 153-159. 36. Amalou, Khellaf, et al. “Endoscopic ultrasound-guided treatment of isolated gastric varices.” World Journal of Gastrointestinal Endoscopy 17.2 (2025): 100556. 37. Samanta, J., et al. “Is EUS-guided angioembolisation a comparable alternative to Balloon-occluded Retrograde Transvenous Obliteration (BRTO) for the management of gastric varices with significant portosystemic shunts: A multicenter tertiary-care experience.” Endoscopy 56.S 02 (2024): OP024. 38. Giri, Suprabhat, et al. “Endoscopic ultrasound-guided therapies versus retrograde transvenous obliteration for gastric varices: Multicenter propensity matched analysis.” Endoscopy International Open 13.continuous publication (2025).
Non-selective beta-blockers improve outcomes in patients with cirrhosis and are recommended in (1) compensated cirrhosis and CSPH (to prevent decompensation), (2) decompensated cirrhosis without prior episodes of VH (to prevent first VH), and (3) patients with prior episodes of VH in combination with EVL (to prevent recurrent VH). NSBB should be started as soon as any of the above indications is identified, as progressive hemodynamic changes (hypotension, decreased renal perfusion) may cause the therapeutic window to be missed. Carvedilol is preferred, starting at 3.125 mg daily and titrated to 12.5 mg daily or a maximum dose of 25 mg daily. Trials have used once daily dosing, but a divided twice daily dose may be better tolerated. A specific HRshould not be targeted with carvedilol, but blood pressure should be monitored, and dose should be reduced or discontinued in patients with MAP <65, systolic BP <90 or in the presence of AKI.
In cirrhosis, both increased hepatic vascular resistance and increased blood flow through the portal vein contribute to the development of portal hypertension. The initial mechanism in the pathogenesis of portal hypertension in cirrhosis is the deposition of collagen in the liver parenchyma causing distortion of the normal vascular architecture and impeding blood flow through the liver.1 In addition to mechanical factors, local imbalance of vasoactive molecules and myofibroblast contraction in the liver results in increased intrahepatic vasoconstriction that further increases resistance.2,3
The initial increase in portal pressure due to intrahepatic architectural distortion is mild but enough to cause shear stress in splanchnic capillaries that lead to the synthesis of vasodilatory molecules such as nitric oxide and release of inflammatory cytokines such as TNF-alpha that cause splanchnic vasodilation, increasing portal venous flow, which leads to a further increase in portal pressure.4,5 These vasodilators also cause systemic vasodilation and lower mean arterial pressure causing activation of neurohormonal systems, such as the renin-angiotensin-aldosterone system and adrenaline, leading to sodium and water retention, increased intravascular volume and increased cardiac output, which in turn lead to an even greater increase in portal venous flow and hence in portal pressure. Additionally, neurohormonal activation also acts at the level of intrahepatic blood vessels causing vasoconstriction and further increasing hepatic resistance to blood flow.6,7
Predicting Decompensation
While cirrhosis refers to the last stage of liver fibrosis caused by any chronic liver disease, patients with cirrhosis have different clinical stages, each with an increasingly worsened prognosis: compensated cirrhosis is a mostly asymptomatic stage where no complications of portal hypertension have occurred and has a median survival greater than 15 years. On the other hand, decompensated cirrhosis is defined by one or more decompensating event (ascites, variceal hemorrhage, or encephalopathy) and carries a high mortality with a median survival of only 1.5 years.8,9
The degree of portal hypertension is the main predictor of decompensation. While portal pressures can’t be measured directly, the hepatic venous pressure gradient (HVPG) can be obtained via central venous access of the hepatic vein, by subtracting the free hepatic from the wedge hepatic venous pressures. A HVPG >5 mmHg suggest a diagnosis of cirrhosis, and ≥10 mmHg indicates the presence of clinically significant portal hypertension (CSPH). The development of CSPH is the main predictor of decompensation, and multiple studies have shown that in patients with compensated cirrhosis, a HVPG ≥10 mmHg predicts the development of decompensated cirrhosis.10,11
To avoid invasive testing in clinical practice, transient elastography (e.g. FibroScan) can be used to measure liver stiffness measurements (LSM). LSM and platelet (PLT) count can be used as an alternative method to diagnose CSPH non-invasively (18). If the LSM is <10 kPa, cirrhosis can be excluded. On the other hand, a patient can be diagnosed with compensated advanced chronic liver disease (cACLD) if the LSM is >15 kPa. The term cACLD is used when liver stiffness measurements are utilized to diagnose advanced liver fibrosis or cirrhosis, given that using the term cirrhosis could be inaccurate as this term implies a histological diagnosis. In clinical practice, patients with cACLD can be usually deemed to have cirrhosis, especially if other ancillary data such as liver nodularity or signs of portal hypertension on imaging, or reduced synthetic function (e.g. hypoalbuminemia, prolonged INR) are present. A LSM of 20-25 kPa with a platelet count <150 or LSM >25 kPa alone can be used to diagnose CSPH non-invasively.12 Therefore, transient elastography allows clinicians to diagnose severe hepatic fibrosis and severe portal hypertension avoiding the need of invasive biopsies or portal pressure measurements.
Mechanism of Action of Beta-Blockers Physiologic activation of beta-1 receptors in the heart increases cardiac output (CO) through positive chronotropic and inotropic effects, while beta-2 receptors in blood vessels increase blood flow by causing smooth muscle relaxation and vasodilation. By blocking beta-1 and beta-2 receptors, non-selective beta blockers (NSBB) lower portal pressures by causing splanchnic vasoconstriction and lowering CO, decreasing portal venous flow, and ameliorating the hyperdynamic circulation that occurs in cirrhosis.10 Carvedilol is a NSBB that, in addition to blocking beta-1 and beta-2 receptors, also inhibits alpha-1 receptors, further decreasing portal pressures by lowering intrahepatic vascular resistance and CO.13
Besides their well-known hemodynamic effects, there is evidence to suggest NSBBs can decrease bacterial translocation from the gut by increasing intestinal transit time, improving mucosal barrier function, and decreasing bacterial virulence. By decreasing bacterial translocation and subsequent inflammation, NSBBs may reduce the synthesis of vasodilators and systemic cytokines such as TNF-alpha that further contribute to the hyperdynamic circulatory state.14
Indications of Beta-Blockers in Cirrhosis
1. Preventing First Decompensation in Patients with Compensated Cirrhosis and Clinically Significant Portal Hypertension (CSPH)
Preventing decompensating events such as variceal hemorrhage (VH), ascites and hepatic encephalopathy is key in the management of patients with cirrhosis, as the development of decompensated cirrhosis portents a poor prognosis. Of these, ascites is the most common decompensation and is the decompensating event associated with the highest mortality.8
NSBBs have shown to decrease the risk of ascites in patients with compensated cirrhosis and CSPH. A randomized clinical trial in patients with compensated cirrhosis and CSPH showed an absolute risk reduction of 11% in the development of a decompensating event or death in patients receiving NSBB compared to placebo, with a number needed to treat (NNT) of 9. The lower risk in patients receiving NSBB was mostly driven by the decreased incidence of ascites, although the progression to high-risk varices was also decreased in patients receiving carvedilol, suggesting that carvedilol likely decreases the risk of variceal hemorrhage in patients with compensated cirrhosis and CSPH.15
In the past, guidelines recommended either endoscopic variceal ligation (EVL) or NSBBs for primary prophylaxis of VH in patients with cirrhosis and at-risk varices, but more recent evidence shows that NSBBs, particularly carvedilol, are more effective in preventing VH and in improving survival in patients with compensated cirrhosis with varices. Because of this, EVL (a local therapy that just acts by obliterating varices) is now only a second line therapy after NSBB, preferably carvedilol (a systemic therapy that addresses different aspects of the pathophysiology of PH).16-18 Therefore, compensated patients with CSPH without prior episodes of VH that are started on NSBBs therapy do not need to undergo screening upper endoscopies, as this will not change their management. On the other hand, patients unable to tolerate NSBB should undergo screening upper endoscopies with EVL of large varices with the aim of preventing a first episode of VH.12
While NSBBs are indicated in patients with CSPH to prevent decompensation, they should be avoided in patients with compensated cirrhosis without CSPH, as they offer no substantial benefits, and exposes these patients to potentially significant side-effects.10
2. Preventing Further Decompensation a. Preventing First Episode of Variceal Hemorrhage in Decompensated Patients with Ascites Patients with ascites have already developed decompensated cirrhosis. In this setting, efforts should be focused on preventing further decompensation by preventing the first occurrence of VH. NSBB in patients with ascites and high risk varices reduce the risk of VH and improve overall survival.16,18 As in patients with compensated cirrhosis and CSPH, screening endoscopy with EVL is mostly reserved to patients with ascites unable to tolerate NSBB.12,17
b. Preventing Recurrent Episodes of Variceal Hemorrhage In patients with prior episodes of VH, a combination of EVL and NSBB is recommended to prevent further episodes of bleeding. Combining EVL and NSBBs is superior to either monotherapy in preventing recurrent VH.19 Furthermore, combination therapy decreases mortality in patients with Child-Pugh class B or C cirrhosis, compared to EVL alone.20 Some data suggests that the main benefit of combination therapy is mostly driven by NSBB, and not EVL.21
The risk of rebleeding is as high as >60% but the risk significant differs depending on factors such as Child-Pugh class and size of esophageal varices.22 The reduction of risk of rebleeding depends on how much HVPG decreases; while it can be as low as <10% when HVPG decreases significantly, patients that fail to achieve an appropriate response in HVPG reduction have a bleeding rate of up to 40% despite receiving adequate therapy.23
Assessing Response to NSBB
Assessing changes in HVPG should not be used to determine response to NSBB in clinical practice given measurements are highly variable when repeated in the same individual. Heart rate has been traditionally used to assess hemodynamic response to beta-blockers, with the assumption that a lower HR is associated with a lower HVPG. Unfortunately, studies have shown a poor correlation between heart rate and HVPG, making the use of HR as a surrogate of HVPG unreliable.24
Studies have shown that less than half of patients achieve a hemodynamic response with traditional NSBB, but most recently, the concept of NSBB “non-responders” has been brought into question, with a recent study suggesting all patients respond to NSBB, and that “non-responders” may represent inaccurate HVPG measurements.25
Carvedilol has shown to be effective in preventing hepatic decompensation and liver-related death even when not monitoring HVPG or HR changes, and to achieve a lower HVPG compared to other NSBB.15,26 The Baveno VII expert consensus and current clinical guidelines recommends carvedilol as the preferred NSBB in patients with cirrhosis given it is more effective in reducing portal pressures and improving clinical outcomes.12,17,27
When Should Beta-Blockers be Used Cautiously? Observational studies raised the concern that beta-blockers may cause harm in patients that already have ascites, mainly by causing acute kidney injury (AKI) and worsening mortality.28,29 Since then, further studies demonstrated that the deleterious effects of NSBBs occur mostly in patients with refractory ascites, mainly by altering the compensatory mechanisms that maintain renal perfusion in these patients.30,31 This is likely reflective of the worsening hemodynamic changes that occur as decompensation progresses; patients with refractory ascites have lower MAP and higher CO compared to patients with diuretic-responsive ascites, indicative of a more pronounced hyperdynamic circulation.6
More recent studies have demonstrated improved survival with NSBBs even in patients with refractory ascites if adequate blood pressures (systolic BP >90 mmHg or MAP >65 mmHg) are maintained. Therefore, NSBB improve survival even in patients with refractory ascites, if the blood pressures are adequate to maintain renal perfusion.30,32 In addition, the recommended maximal dose in patients with ascites is lower than in those without ascites, and the dose should be further reduced or discontinued if patients develop AKI, or a systolic blood pressures <90 mmHg or MAP <60 mmHg.12,17
Case Examples: Are NSBB Recommended?
1. Patient with cirrhosis diagnosed by transient elastography (TE) with a LSM of 16 kPa and a PLT count of 190. The patient has never had ascites, VH or hepatic encephalopathy. A prior endoscopy was normal, there were no esophageal varices.
The patient has compensated cirrhosis without CSPH based on non-invasive tests (LSM >15kPa but <20 kPa and with PLT >150). NSBB are not recommended as they have not shown to be beneficial in patients without CSPH and would likely only expose this patient to undesired side effects.
2. Patient with cirrhosis evidenced by a LSM (by TE) of 23 kPa and a PLT count of 130. The patient has never had an upper endoscopy and has never had ascites, gastrointestinal hemorrhage or encephalopathy.
The patient has compensated cirrhosis with CSPH based on non-invasive tests (LSM >20 kPa and PLT <150). Carvedilol is recommended without the need for an upper endoscopy, with the main goal of preventing decompensation, mainly ascites (the complication of cirrhosis associated with the highest mortality) and possibly a first episode of VH. An endoscopy to screen for varices is not recommended if the patient is able to tolerate NSBBs, as the presence or absence of high-risk varices will not change management at this time.
3. Patient with compensated cirrhosis who undergoes an upper endoscopy for dyspepsia that shows large varices. The patient has no prior TE, and PLT count has fluctuated between 130 and 180. A recent abdominal US showed mild splenomegaly and a patent portal vein.
The patient has compensated cirrhosis with CSPH based on the presence of high-risk varices, independent of LSM or PLT count. Carvedilol is recommended with the goal of preventing ascites and a first episode of VH. If the patient is unable to tolerate carvedilol, endoscopic variceal ligation should be performed with the goal of preventing first VH.
4. Patient with ascites, well controlled on diuretics with no prior episodes of VH.
The patient has decompensated cirrhosis based on the presence of ascites. Therefore, the only complication of cirrhosis that can be prevented at this point is VH. The main predictor of variceal hemorrhage is the presence of high-risk varices and therefore an upper endoscopy should be performed. If endoscopy shows high-risk varices (large varices or small varices with red wale signs), preference is given to NSBBs (including carvedilol) because of benefits beyond prevention of VH. If patient will be placed on NSBB, blood pressure and renal function should be monitored closely after initiating NSBB and the dose should be decreased or discontinued if patient develops systolic BP <90 or severe adverse effects (e.g. acute kidney injury). Another NSBB such as propranolol or nadolol can be considered if the patient is unable to tolerate carvedilol due to low BP.
5. Patient with ascites requiring weekly large volume paracentesis (LVP) with no prior episodes of VH.
The patient has further decompensated cirrhosis based on the presence of refractory ascites. The only complication of cirrhosis that can be prevented at this point is VH. The main predictor of variceal hemorrhage is the presence of high-risk varices and therefore an upper endoscopy should be performed. If endoscopy shows high-risk varices (large varices or varices with red wale signs) preference would be given to NSBB to prevent VH. Refractory ascites may be associated with lower blood pressure and systolic function that could decrease renal perfusion and lead to AKI and could worsen on NSBB. If patient will be placed on NSBB, blood pressure and renal function should be monitored closely after initiating NSBB and the dose should be decreased or discontinued if patient develops systolic BP <90 or severe adverse effects such as AKI. In these patients, particularly if BP is borderline low, another NSBB such as propranolol or nadolol would be more appropriate than carvedilol.
6. Patient with an episode of VH that occurred one year ago, with no history of ascites or hepatic encephalopathy. The acute episode of VH was treated successfully but the patient was then lost to follow up and has not had any other decompensating event.
The patient has decompensated cirrhosis based on a prior episode of VH. Carvedilol in combination with serial surveillance endoscopies and EVL of high-risk varices is recommended to prevent recurrent episodes of VH. The combination of EVL and NSBB is superior to either therapy alone in preventing recurrent VH.
References
1. Benoit JN, Womack WA, Hernandez L, Granger DN. “Forward” and “backward” flow mechanisms of portal hypertension. Relative contributions in the rat model of portal vein stenosis. Gastroenterology. Nov 1985;89(5):1092-6.
2. Reynaert H, Thompson MG, Thomas T, Geerts A. Hepatic stellate cells: role in microcirculation and pathophysiology of portal hypertension. Gut. Apr 2002;50(4):571-81. doi:10.1136/gut.50.4.571
3. Gupta TK, Toruner M, Chung MK, Groszmann RJ. Endothelial dysfunction and decreased production of nitric oxide in the intrahepatic microcirculation of cirrhotic rats. Hepatology. Oct 1998;28(4):926-31. doi:10.1002/hep.510280405
4. Sarela AI, Mihaimeed FM, Batten JJ, Davidson BR, Mathie RT. Hepatic and splanchnic nitric oxide activity in patients with cirrhosis. Gut. May 1999;44(5):749-53. doi:10.1136/gut.44.5.749
5. Rasaratnam B, Kaye D, Jennings G, Dudley F, Chin- Dusting J. The effect of selective intestinal decontamination on the hyperdynamic circulatory state in cirrhosis. A randomized trial. Ann Intern Med. Aug 5 2003;139(3):186-93. doi:10.7326/0003-4819-139-3-200308050-00008
6. Turco L, Garcia-Tsao G, Magnani I, et al. Cardiopulmonary hemodynamics and C-reactive protein as prognostic indicators in compensated and decompensated cirrhosis. J Hepatol. May 2018;68(5):949-958. doi:10.1016/j.jhep.2017.12.027
7. Schneider AW, Kalk JF, Klein CP. Effect of losartan, an angiotensin II receptor antagonist, on portal pressure in cirrhosis. Hepatology. Feb 1999;29(2):334-9. doi:10.1002/hep.510290203
8. D’Amico G, Pasta L, Morabito A, et al. Competing risks and prognostic stages of cirrhosis: a 25-year inception cohort study of 494 patients. Aliment Pharmacol Ther. May 2014;39(10):1180-93. doi:10.1111/apt.12721
9. D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol. Jan 2006;44(1):217-31. doi:10.1016/j.jhep.2005.10.013
10. Groszmann RJ, Garcia-Tsao G, Bosch J, et al. Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. N Engl J Med. Nov 24 2005;353(21):2254-61. doi:10.1056/NEJMoa044456
11. Sanyal AJ, Harrison SA, Ratziu V, et al. The Natural History of Advanced Fibrosis Due to Nonalcoholic Steatohepatitis: Data From the Simtuzumab Trials. Hepatology. Dec 2019;70(6):1913-1927. doi:10.1002/hep.30664
12. de Franchis R, Bosch J, Garcia-Tsao G, Reiberger T, Ripoll C, Baveno VIIF. Baveno VII – Renewing consensus in portal hypertension. J Hepatol. Apr 2022;76(4):959-974. doi:10.1016/j.jhep.2021.12.022
13. Banares R, Moitinho E, Piqueras B, et al. Carvedilol, a new nonselective beta-blocker with intrinsic anti- Alpha1-adrenergic activity, has a greater portal hypotensive effect than propranolol in patients with cirrhosis. Hepatology. Jul 1999;30(1):79-83. doi:10.1002/hep.510300124
14. Krag A, Wiest R, Albillos A, Gluud LL. The window hypothesis: haemodynamic and non-haemodynamic effects of beta-blockers improve survival of patients with cirrhosis during a window in the disease. Gut. Jul 2012;61(7):967-9. doi:10.1136/gutjnl-2011-301348
15. Villanueva C, Albillos A, Genesca J, et al. beta blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (PREDESCI): a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. Apr 20 2019;393(10181):1597-1608. doi:10.1016/S0140-6736(18)31875-0
16. Tripathi D, Ferguson JW, Kochar N, et al. Randomized controlled trial of carvedilol versus variceal band ligation for the prevention of the first variceal bleed. Hepatology. Sep 2009;50(3):825-33. doi:10.1002/hep.23045
17. Kaplan DE, Ripoll C, Thiele M, et al. AASLD Practice Guidance on risk stratification and management of portal hypertension and varices in cirrhosis. Hepatology. May 1 2024;79(5):1180-1211. doi:10.1097/HEP.0000000000000647
18. Villanueva C, Torres F, Sarin SK, et al. Carvedilol reduces the risk of decompensation and mortality in patients with compensated cirrhosis in a competing-risk meta-analysis. J Hepatol. Oct 2022;77(4):1014-1025. doi:10.1016/j. jhep.2022.05.021
19. Puente A, Hernandez-Gea V, Graupera I, et al. Drugs plus ligation to prevent rebleeding in cirrhosis: an updated systematic review. Liver Int. Jul 2014;34(6):823-33. doi:10.1111/liv.12452
20. Albillos A, Zamora J, Martinez J, et al. Stratifying risk in the prevention of recurrent variceal hemorrhage: Results of an individual patient meta-analysis. Hepatology. Oct 2017;66(4):1219-1231. doi:10.1002/hep.29267
21. Thiele M, Krag A, Rohde U, Gluud LL. Meta-analysis: banding ligation and medical interventions for the prevention of rebleeding from oesophageal varices. Aliment Pharmacol Ther. May 2012;35(10):1155-65. doi:10.1111/j.1365-2036.2012.05074.x
22. North Italian Endoscopic Club for the S, Treatment of Esophageal V. Prediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices. A prospective multicenter study. N Engl J Med. Oct 13 1988;319(15):983-9. doi:10.1056/NEJM198810133191505
23. D’Amico G, Garcia-Pagan JC, Luca A, Bosch J. Hepatic vein pressure gradient reduction and prevention of variceal bleeding in cirrhosis: a systematic review. Gastroenterology. Nov 2006;131(5):1611-24. doi:10.1053/j.gastro.2006.09.013
24. Abraldes JG, Tarantino I, Turnes J, Garcia-Pagan JC, Rodes J, Bosch J. Hemodynamic response to pharmacological treatment of portal hypertension and long-term prognosis of cirrhosis. Hepatology. Apr 2003;37(4):902-8. doi:10.1053/jhep.2003.50133
25. Alsaeid M, Sung S, Bai W, et al. Heterogeneity of treatment response to beta-blockers in the treatment of portal hypertension: A systematic review. Hepatol Commun. Feb 1 2024;8(2)doi:10.1097/HC9.0000000000000321
26. Zacharias AP, Jeyaraj R, Hobolth L, Bendtsen F, Gluud LL, Morgan MY. Carvedilol versus traditional, non-selective beta-blockers for adults with cirrhosis and gastroesophageal varices. Cochrane Database Syst Rev. Oct 29 2018;10(10):CD011510. doi:10.1002/14651858.CD011510.pub2
27. Serper M, Kaplan DE, Taddei TH, Tapper EB, Cohen JB, Mahmud N. Nonselective beta blockers, hepatic decompensation, and mortality in cirrhosis: A national cohort study. Hepatology. Feb 1 2023;77(2):489-500. doi:10.1002/hep.32737
28. Serste T, Melot C, Francoz C, et al. Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites. Hepatology. Sep 2010;52(3):1017-22. doi:10.1002/hep.23775
29. Kim SG, Larson JJ, Lee JS, Therneau TM, Kim WR. Beneficial and harmful effects of nonselective beta blockade on acute kidney injury in liver transplant candidates. Liver Transpl. Jun 2017;23(6):733-740. doi:10.1002/lt.24744
30. Tergast TL, Kimmann M, Laser H, et al. Systemic arterial blood pressure determines the therapeutic window of non-selective beta blockers in decompensated cirrhosis. Aliment Pharmacol Ther. Sep 2019;50(6):696-706. doi:10.1111/apt.15439
31. Tellez L, Ibanez-Samaniego L, Perez Del Villar C, et al. Non-selective beta-blockers impair global circulatory homeostasis and renal function in cirrhotic patients with refractory ascites. J Hepatol. Dec 2020;73(6):1404-1414. doi:10.1016/j. jhep.2020.05.011
32. Chirapongsathorn S, Valentin N, Alahdab F, et al. Nonselective beta-Blockers and Survival in Patients With Cirrhosis and Ascites: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. Aug 2016;14(8):1096-1104 e9. doi:10.1016/j.cgh.2016.01.012
Iron deficiency anemia (IDA) affects about one-third of the global population and has a significant impact on individuals with gastrointestinal (GI) disorders. Its multifactorial etiology includes chronic inflammation, impaired nutrient absorption, GI tract damage, inadequate dietary intake, increased iron requirements, and medication use. Effective clinical management of IDA involves accurate diagnosis, tailored treatment strategies, and ongoing monitoring. This review provides a comprehensive overview of the physiology and pathophysiology of IDA, with a focus on its prevalence in GI populations. The strategies for screening and diagnosis, the challenges posed by inflammation in interpreting iron studies, and individualized treatment considerations are discussed. Addressing these complexities is critical to improving clinical outcomes and the quality of life for those affected by IDA.
Introduction
Iron deficiency anemia (IDA) is among the most prevalent nutritional deficiencies globally, affecting approximately one-third of the population and representing a significant contributor to morbidity worldwide across age groups and socioeconomic classes.1,2 IDA is commonly found in gastrointestinal (GI) disorders, including inflammatory bowel disease (IBD), celiac disease, and among post-bariatric surgery patients. The etiology of IDA involves disruptions of iron homeostasis that are driven by chronic inflammation, impaired nutrient absorption, and structural alterations to the GI tract.1,3 The impact of iron deficiency (ID) even without the presence of anemia is not limited to physical symptoms but can also significantly impair quality of life, increase morbidity, and adversely affect pregnancy outcomes and chronic disease prognosis. If left untreated, IDA can exacerbate fatigue, cognitive deficits, and cardiovascular strain, emphasizing its importance in clinical practice.1,2
Physiology and Pathophysiology
Iron is vital for critical physiological functions, including oxygen transport via hemoglobin, mitochondrial energy production, and enzymatic processes, making it essential for cellular and metabolic health.1,2 Iron absorption occurs primarily in the duodenum after ferric iron (Fe3+) is reduced to ferrous iron (Fe2+) in the acidic gastric environment (refer to Figure 1). Heme iron from animal sources is absorbed more efficiently than non-heme iron from plant-based foods. The absorption mechanism differs between the two with non-heme iron being reduced to Fe2+ and transported into enterocytes by the divalent metal transporter 1 (DMT1), while heme iron enters via heme carrier protein 1 (HCP1). Vitamin C enhances the absorption of non-heme iron by reducing Fe3+ to Fe2+, thereby increasing its efficiency.2 Within enterocytes, iron is either stored as ferritin or exported into the bloodstream by ferroportin, the only known cellular iron exporter.2,3
Once in circulation, iron binds to transferrin and is delivered to tissues, particularly the bone marrow, where it supports erythropoiesis. Excess iron is stored in hepatocytes and macrophages in the form of ferritin, ensuring enough iron is available to meet metabolic demands. Hepcidin regulates iron levels by inhibiting iron transporters, reducing the absorption of dietary iron and release of stored iron; therefore, elevated hepcidin can contribute to developing IDA.1-3 Inflammation or chronic disease can elevate hepcidin levels, disrupting iron transport and utilization, often leading to IDA.
Risk Factors and At-Risk Populations with Gastrointestinal Disorders
The development of IDA in GI disorders can stem from a range of systemic and localized factors. IBD, celiac disease, Helicobacter pylori (H. pylori) infection, gastric and foregut surgeries, and gastrointestinal cancer are among the primary GI disorders associated with IDA.3-5 Key mechanisms include damage and inflammation of the GI tract, inadequate dietary intake, increased iron needs, and use of certain medications (Table 1).3-14
Inflammatory bowel disease
Studies have shown that approximately two-thirds of patients with IBD have anemia at the time of diagnosis.7 The pathogenesis of anemia in IBD is multifaceted and primarily driven by chronic intestinal blood loss due to mucosal ulcerations, impaired iron absorption from inflammation, and systemic cytokine effects that disrupt iron transport and utilization.5 This, combined with reduced dietary intake and intestinal damage, frequently leads to functional iron deficiency (FID) that can progress to IDA.
Celiac disease
Studies have found that 12-82% of patients with new-onset celiac disease also have anemia.6 In celiac disease IDA is due to malabsorption caused by villous atrophy and inflammation in the small intestine triggered by gluten exposure.6 This damage impairs iron absorption which is further exacerbated by elevated hepcidin levels that restrict iron absorption and promote iron sequestration in storage cells. Even after adopting a gluten-free diet (GFD), ID may persist as the underlying malabsorption and inflammation may continue. According to Anniblae et al., only 50% of patients achieve normal iron levels after 12 months on a GFD, despite 94.4% recovering from anemia within the study period.8 Therefore, additional iron supplementation and consistent monitoring and management are necessary to restore and maintain adequate serum iron levels.
Box 1. Signs and Symptoms Associatedwith Iron Deficiency1,20
Pallor of the skin, conjunctiva, oral mucosa,
nail bed (if with anemia)
Koilonychias
Fatigue
Weakness
Reduced work capacity
Glossitis
Angular cheilitis
Alopecia
Poor regulation of body temperature
Decline in cognitive performance
Pica
Sleep disturbances
H. pylori infection
The bacterium H. pylori causes gastritis by destroying parietal cell mass and reducing gastric acid production leading to a less acidic environment in the gastric lumen. Since gastric acid is essential for reducing dietary iron, this increase in pH can hinder iron absorption.5,9 Furthermore, H. pylori directly competes for iron by using iron-binding proteins on its outer membrane to support metabolic needs.10 Studies have shown that eradicating H. pylori improves hemoglobin and ferritin levels.5,9
Gastrointestinal Surgeries
Individuals who have undergone GI surgery, such as sleeve gastrectomy or Roux-en-Y gastric bypass (RYGB), are at an increased risk of IDA due to the restrictive and malabsorptive features of these procedures.5,11 These procedures bypass key absorption sites, including the duodenum and proximal jejunum, reduce gastric acid production, and often involve a restrictive diet. A meta-analysis found that up to 26.5% of patients develop low ferritin levels within three years post-surgery.12 Furthermore, a cross-sectional study revealed that over 50% of patients undergoing gastric bypass experience severe ID 10 years post-surgery, despite regular iron supplementation.11
Gastrointestinal Cancer
Cancer is a major pathologic diagnosis that increases the risk of IDA with studies showing 8–15% of patients diagnosed with GI malignancy have a concomitant diagnosis of IDA.13 Etiologic mechanisms in colorectal, gastric, and esophageal cancers include frequent bleeding, mucosal damage, and an inflammatory response that elevates hepcidin levels.13 The prevalence of IDA increases during treatment with up to 60% of patients with GI cancers experiencing IDA during their disease course. IDA is often compounded by cancer treatments, reduced dietary intake, and poor appetite which can aggravate fatigue and quality of life, ultimately complicating treatment outcomes and prognosis.3
Screening and Diagnosis
Iron screening guidelines have been developed for several at-risk GI patient populations (Table 2).7,15–19 Iron studies should also be considered based on symptomatology and physical exam findings (Box 1).1,20 ID can be identified using a combination of serum laboratory markers including hemoglobin, ferritin, iron, total iron binding capacity (TIBC), and transferrin saturation (Tsat). Because anemia does not develop until ID is more advanced, a normal serum hemoglobin value should not preclude the diagnosis of ID.21 Similarly, the development of anemia may be multifactorial due to causes other than or in conjunction with ID, warranting additional workup. Circulating ferritin reflects iron tissue stores and is generally the first iron biomarker to decline in response to inadequate iron intake.21 Decreases in serum iron and an adaptive rise in TIBC follow, whereas further iron depletion compromises erythropoiesis.
As discussed previously, the presence of active inflammation complicates the evaluation of iron studies. Given that some patients with GI conditions may exhibit chronic, low-grade inflammation or acute inflammation during disease flares, C-reactive protein (CRP) should be obtained in conjunction with iron studies. Because ferritin is a positive acute phase reactant, its elevation can mask an ID.14 There is a lack of consensus on how to diagnose ID in the setting of inflammation, yet ferritin values of up to 100 ng/mL are widely suggested as an indicator of ID when CRP is elevated.7,14,22,23 Although stored iron may be sufficient, pro-inflammatory cytokines upregulate the synthesis of hepcidin, which reduces iron absorption and mobilization by suppressing the expression of ferroportin.7,14,22 This leads to FID where the availability of serum iron to participate in erythropoiesis is insufficient. Inflammatory mediators may also interfere with erythropoiesis and shorten the lifespan of red blood cells.24 FID along with these other inflammation-driven effects contribute to what is considered anemia of chronic disease (also called anemia of inflammation). Thus, patients may present with an absolute ID, FID, or a combination.7,23,25 The ratio of serum iron to TIBC, which is used to calculate Tsat, indicates the amount of iron bound to transferrin and available for tissue distribution. Low Tsat is observed in both absolute ID and FID.7,23,25 An overview of iron biomarkers is presented in Table 3.
Table 1. Mechanisms of Iron Deficiency Anemia in Gastrointestinal Disorders3–14
Cause
Mechanism
Patient Population
Chronic Inflammation and Damage in GI Tract
Chronic inflammation increases hepcidin, which blocks iron release from macrophages and reduces iron available for red blood cell production. Mucosal ulcerations and impaired iron absorption exacerbate ID, leading to anemia.
Celiac disease GI cancer H. Pylori IBD Peptic ulcers
Inadequate Dietary Intake
A diet low in iron-rich foods reduces bioavailable iron intake. Inhibitors in plant-based diets, such as phytates and polyphenols further limit non-heme iron absorption. In GI disorders, dietary restrictions, malabsorption, or poor appetite further contribute to ID.
Disorders with restrictive intake (ex: bariatric and gastric surgeries) Crohn’s disease Vegetarians and vegans
Increased Iron Needs
Physiological states increase iron demand: (1) rapid growth in children and adolescents, (2) pregnancy, where maternal and fetal iron needs rise, (3) heavy menstrual bleeding in women, and (4) intense physical activity, which can induce red blood cell destruction.
Children and adolescent Peptic ulcers Pregnancy IBD GI cancer Elite athletes
Use of Medications
Nonsteroidal anti-inflammatory drugs (NSAIDs) and anticoagulants increase GI bleeding risk by causing or worsening lesions such as ulcers or angiodysplasia. Proton Pump Inhibitors (PPIs) raise gastric pH, reducing the conversion of Fe³+ to Fe²+ iron, which hinders its absorption in the duodenum.
Elderly IBD Gastritis Peptic ulcers
Table 2. Recommendations for Iron Screening in Gastrointestinal Disorders7,15-19
GI Disorder
Organization
Guideline
Chronic pancreatitis (2020)15
ESPEN
Monitor iron status
Celiac disease (2013)16
ACG
Measure at baseline and repeat in 3 to 6 months if previous values abnormal
Cystic fibrosis (2016)17
ESPEN, ESPGHAN, ECFS
Measure annually or more frequently if previous values abnormal
Inflammatory bowel disease (2015)7
ECCO
Measure every 6 to 12 months in patients with quiescent or mild disease. In outpatients with active disease, measure every 3 months.
Metabolic and bariatric surgery (2017)18
ASMBS
Measure prior to weight loss surgery. Measure within 3 months following weight loss surgery and repeat every 3 to 6 months until 12 months after surgery. Continue to measure annually.
Short bowel syndrome (2022)19
AGA
Measure at baseline and at least annually
Abbreviations: ACG: American College of Gastroenterology; AGA: American Gastroenterological Association; ASMBS: American Society for Metabolic and Bariatric Surgery; ECCO: European Crohn’s and Colitis Organization; ECFS: European Cystic Fibrosis Society; ESPEN: European Society for Clinical Nutrition and Metabolism; ESPGHAN: European Society for Pediatric Gastroenterology, Hepatology, and Nutrition
Table 3. Iron Biomarkers Used to Screen for Iron Deficiency7
Overview
Absolute iron deficiency (normal CRP)
Absolute iron deficiency and FID (elevated CRP)
FID (elevated CRP and adequate iron stores)
Ferritin
Marker of storage iron
Low (< 30 ng/mL)*
Low or normal (< 100 ng/mL)
Elevated (> 100 ng/mL)
Serum iron
Measures iron bound to transferrin
Low
Low
Low
TIBC
Reflects available iron binding sites on transferrin
Elevated
Low
Low
Tsat
Percentage of iron binding sites on transferrin occupied by iron
Low
Low
Low
Abbreviations: CRP: C-reactive protein; FID: functional iron deficiency; TIBC: total iron binding capacity; Tsat: transferrin saturation. *cut-offs vary amongst organizations
Treatment of Iron Deficiency
Regardless of the presence of any signs or symptoms of ID, all patients should receive treatment when biochemical ID, FID, or IDA is present. Treatment for ID, FID, or IDA involves an understanding of dietary supplement regulation, third-party certification, and the bioavailability of various product formulations. With these factors understood, the clinician can then devise an appropriate treatment and monitoring plan. Additionally, the treatment strategy will differ based on the severity of the ID and the presence of anemia. The treatment of life-threatening anemia where red blood cell (RBC) transfusion is often necessary with or without additional iron infusions is outside of the scope of this article. However, the clinician should note that each unit of RBC typically contains 200 mg of iron which can impact the treatment strategy.26,27 The treatment reviewed focuses on those being treated in the outpatient setting for the nonpregnant adult.
Table 4. Treatment Options for Iron Deficiency7,27,29,30
Product Formulation
Dosing (elemental iron)
Formulations
Suggested Monitoring and Evaluation
Oral Formulations
Ferrous fumarate
106 mg 1-3 times daily; every other day regimen may be beneficial
Capsule, tablet, liquid
Laboratory parameters: -Check CBC, serum iron, serum ferritin and C-reactive protein every 1 to 3 months Positive response: – Serum reticulocyte increases within days – Hemoglobin increases 1-2 g/dL within 2 to 3 weeks – Ferritin may take up to 6 months to normalize
Ferrous sulfate
65 mg 1-3 times daily; every other day regimen may be beneficial
Capsule, tablet, liquid
Ferrous gluconate
35 mg 1-3 times daily; every other day regimen may be beneficial.
Capsule, tablet, liquid
Polysaccharide-iron complex
50-200 mg daily; every other day regimen may be beneficial
Capsule, liquid
Ferric maltol
30 mg twice daily; every other day regimen may be beneficial
Capsule
Ferrous bisglycinate
25 mg daily
Capsule, tablet, liquid
Intravenous Formulations
Iron dextran
Based on iron deficit Example dosing: 1000 mg x 1
Intravenous
Iron sucrose
Based on iron deficit Maximum 200 mg per infusion 125 mg for eight doses for adults Example dosing: 200 mg x 5 or 300 mg x 3 weekly
Intravenous
Sodium ferric gluconate
125 mg for eight doses Example dosing: 125 mg x 8
Intravenous
Ferumoxytol
50 mg x 1 dose followed by 510 mg 3-8 days later Example dosing: 510 mg x 2 or 1020 mg x 1
Intravenous
Ferric carboxymaltose
15 mg per kg (maximum 750 mg per dose), repeat 7 days later if necessary Example dosing: 750 mg x 2 one week apart of 1000 mg as a single dose
Intravenous
Ferric derisomaltose
1,000 mg per dose Example dosing: 1000 mg x 1
Intravenous
Bioavailability is reported as the amount of the supplement or drug that enters circulation and can be utilized by the body.28 Iron formulations have varying bioavailability with oral formulations having the poorest bioavailability and intravenous formulations having 100% bioavailability (refer to Table 4).7,27,29,30 Since the body can increase the amount of intestinal iron absorbed based on iron status, the presence of ID, FID or IDA will increase dietary/oral iron absorption. In severe cases of anemia or when oral iron supplementation is contraindicated, intravenous iron should be selected.
Oral Formulations
Oral iron absorption can be hindered by the simultaneous consumption of food (e.g., tannins, calcium, phytates) and certain medications such as proton pump inhibitors.27 Therefore, efficacy is improved when taken away from meals. The most commonly administered oral iron formulations include ferrous sulfate, ferrous gluconate, polysaccharide-iron complex, and ferrous fumarate. Absorption and the dose of elemental iron present differ amongst these formulations which may contribute to varying degrees of GI symptoms. Polysaccharide-iron complex is a third-generation ferric iron formulation designed to improve palatability with fewer GI symptoms. However, in the absence of randomized clinical control trials comparing dose-equivalent iron formulations and the impact on GI symptoms and/or palatability, no conclusions can be made. Additionally, ferrous formulations such as ferrous sulfate, ferrous gluconate, and ferrous fumarate are readily absorbed in the GI tract whereas ferric formulations must be reduced by ferrireductase before absorption. Despite these differences, each formulation can be effective in treating and preventing ID, FID, and IDA. The American Gastroenterological Association (AGA) endorses the use of ferrous sulfate given its cost-effectiveness and lack of data suggesting any oral iron supplement is advantageous over another and that supplementation should be consumed with vitamin C to improve absorption.29 However, recommendations for the concomitant use of vitamin C with ferrous iron formulations are theoretical, and more research is needed to support this practice.
Historically, daily to three times daily dosing was the most common method for iron supplementation. However, the frequency of dosing is currently debated as less frequent dosing is hypothesized to improve iron supplementation compliance and intestinal absorption. With GI side effects (i.e., nausea, constipation, and epigastric pain) being common, the risk of noncompliance with iron supplementations is of concern. A reduction in GI side effects with alternate day dosing has been reported by some,31,32 while other studies have shown a lack of improvements.33-36 With data suggesting iron supplementation impacts circulating hepcidin levels, and the concern of noncompliance, investigations into alternate daily dosing were evaluated.36 Stoffel and colleagues investigated the impact of daily and alternate-day iron dosing on hepcidin levels and iron absorption which were both superior in the alternate-day group.33,34 This study, along with others, increased awareness of the potential benefits of alternate daily dosing to improve anemia. However, when this strategy was applied to severely anemic individuals (N=200) in a randomized control trial, there was no difference in serum hemoglobin levels between those on daily (60 mg total) or alternate day dosing (120 mg) (p=0.47). While a definitive dosing strategy is unavailable, it is reasonable to consider alternate-day dosing to provide GI relief when present and when compliance with daily dosing is of concern.36 The AGA expert consensus statement endorses dosing oral iron no more than once daily since there is a lack of evidence for improved absorption with increased frequency and that the risk of side effects increases.29
Intravenous Formulations
Intravenous iron formulations are 100% bioavailable. Intravenous formulations are typically administered under medical supervision and are more commonly prescribed for those unable to consume oral iron, those unresponsive to oral iron, or those with severe anemia. In clinical practice, iron deficit equations are typically used to determine the appropriate dose such as: 27
Hemoglobin iron deficit (mg) = weight (kg) x (14 – Hgb) x 0.24 + 500)
Iron is not routinely included in PN admixtures as intravenous iron has the highest risk of iron toxicity, anaphylaxis (although rare), and incompatibility, particularly with lipid-containing formulations.37 IV iron preparations available in the US include iron dextran, iron sucrose, ferric gluconate, ferumoxytol, and ferric carboxymaltose.37 Iron sucrose and ferric gluconate have a generally lower risk of hypersensitivity and the absence of a requirement for test dosing; however, only iron dextran is compatible with 2-in-1 PN at amino acid concentrations higher than 2%, while it remains incompatible with total nutrient admixtures.37 Furthermore, concern of hypophosphatemia has been reported in those on recurrent intravenous infusions (most commonly with ferric carboxymaltose).28 The AGA recommends intravenous iron for those with IBD, IDA, active inflammation in the GI tract, poor tolerance to oral supplementation, poor response to oral iron, and ongoing bleeding that is unresponsive to oral supplementation.29
Iron Supplementation Recommendations
It is common that clinicians may omit pertinent details for the patient to carry out the finalized recommendation. The finalized prescription or recommendation for ID must include the following items: date of the prescription, patient name, patient date of birth, provider name and address, name of the iron formulation, dosage strength, dosage form, delivery route, dose frequency, pertinent directions for administration, quantity to be provided by the pharmacist or purchased by the patient, number of refills, and the prescriber signature. Since the Dietary Supplement Health and Education Act of 1994 allows dietary supplements to be marketed without prior FDA approval, third-party certification of dietary supplements is recommended (e.g., ConsumerLab.com, National Sanitation Foundation-NSF, United States Pharmacopia-USP).29 Third-party verification can provide insight into the bioavailability of some iron supplements and can be useful to patients looking for over-the-counter iron formulations.
Monitoring and Evaluation
Monitoring treatment strategies are essential to ensure ID, FID, and IDA have been corrected and to prevent toxicities from occurring. As outlined in the assessment section, biochemical indices, signs and symptoms of ID, FID or IDA should be monitored until correction. Refer to Table 4 for suggestions for monitoring parameters.
Case Study
A 50-year-old male with ulcerative colitis (diagnosed 10 years prior) presents in the clinic with fatigue and 3-4 liquid stools daily (50% with overt blood). At home, a patient takes azathioprine 100 mg daily, a standard multivitamin, and ferrous sulfate 65 mg daily (no longer taking x 2 months due to GI effects). Most recent laboratory findings are found below:
Hemoglobin 9.5 g/dL (14.0-17.5 g/dL)
Ferritin 16 ng/mL ( 12-300 ng/mL)
CRP 25 mg/dL (<1.0 mg/dL)
Serum iron 30 mcg/dL (60-160 mcg/dL)
TIBC 370 mcg/dL (300-360 mcg/dL)
Tsat 8.1% (20-50%)
The clinician recommends a referral to hematology for the management of recurrent IDA. Due to a history of poor oral iron tolerance and active inflammation limiting GI iron absorption, an intravenous iron infusion is recommended. Additionally, the clinician changes the standard multivitamin without iron to a daily multivitamin with iron (containing 18 mg of elemental iron). Laboratory parameters are recommended to be repeated in 3 months and include a CBC, iron studies (ferritin, Tsat, TIBC, serum iron), and CRP.
References
References 1. Kumar A, Sharma E, Marley A, Samaan MA, Brookes MJ. Iron deficiency anemia: pathophysiology, assessment, practical management. BMJ Open Gastroenterol. 2022;9(1):e000759. 2. Lanser L, Fuchs D, Kurz K, Weiss G. Physiology and Inflammation Driven Pathophysiology of Iron Homeostasis- Mechanistic Insights into Anemia of Inflammation and Its Treatment. Nutrients. 2021;13(11):3732. 3. Snook J, Bhala N, Beales ILP, et al. British Society of Gastroenterology guidelines for the management of iron deficiency anemia in adults. Gut. 2021;70(11):2030-2051. 4. Ko CW, Siddique SM, Patel A, et al. AGA Clinical Practice Guidelines on the Gastrointestinal Evaluation of Iron Deficiency Anemia. Gastroenterology. 2020;159(3):1085- 1094. 5. Mahadea D, Adamczewska E, Ratajczak AE, et al. Iron Deficiency Anemia in Inflammatory Bowel Diseases Narrative Review. Nutrients. 2021;13(11):4008. 6. Talarico V, Giancotti L, Mazza GA, Miniero R, Bertini M. Iron Deficiency Anemia in Celiac Disease. Nutrients. 2021;13(5):1695. 7. Dignass AU, Gasche C, Bettenworth D, et al. European consensus on the diagnosis and management of iron deficiency and anemia in inflammatory bowel diseases. J Crohn’s Colitis. 2015;9(3):211-222. 8. Annibale B, Severi C, Chistolini A, et al. Efficacy of glutenfree diet alone on recovery from iron deficiency anemia in adult celiac patients. Am J Gastroenterol. 2001;96(1):132- 137. 9. Rahat A, Kamani L. Frequency of iron deficiency anemia (IDA) among patients with Helicobacter pylori infection. Pak J Med Sci. 2021;37(3):776-781. 10. Dhaenens L, Szczebara F, Husson MO. Identification, characterization, and immunogenicity of the lactoferrinbinding protein from Helicobacter pylori. Infect Immun. 1997;65(2):514-518. 11. Sandvik J, Bjerkan KK, Græslie H, et al. Iron Deficiency and Anemia 10 Years After Roux-en-Y Gastric Bypass for Severe Obesity. Front Endocrinol (Lausanne). 2021;12:679066. 12. Weng TC, Chang CH, Dong YH, Chang YC, Chuang LM. Anaemia and related nutrient deficiencies after Roux-en-Y gastric bypass surgery: a systematic review and metaanalysis. BMJ Open. 2015;5(7):e006964. 13. Bouri S, Martin J. Investigation of iron deficiency anemia. Clin Med (Lond). 2018;18(3):242-244. 14. Al-Naseem A, Sallam A, Choudhury S, Thachil J. Iron deficiency without anemia: a diagnosis that matters. Clin Med (Lond). 2021;21(2):107-113. 15. Arvanitakis M, Ockenga J, Bezmarevic M, et al. ESPEN guideline on clinical nutrition in acute and chronic pancreatitis. Clin Nutr. 2020;39(3):612-631. 16. Rubio-Tapia A, Hill ID, Kelly CP, Calderwood AH, Murray JA. American College of Gastroenterology. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol. 2013;108(5):656-677. 17. Turck D, Braegger CP, Colombo C, et al. ESPEN-ESPGHANECFS guidelines on nutrition care for infants, children, and adults with cystic fibrosis. Clin Nutr. 2016;35(3):557-577. 18. Parrott J, Frank L, Rabena R, Craggs-Dino L, Isom KA, Greiman L. American Society for Metabolic and Bariatric Surgery Integrated Health Nutritional Guidelines for the Surgical Weight Loss Patient 2016 Update: Micronutrients. Surg Obes Relat Dis. 2017;13(5):727-741. 19. Iyer K, DiBaise JK, Rubio-Tapia A. AGA Clinical Practice Update on Management of Short Bowel Syndrome: Expert Review. Clin Gastroenterol Hepatol. 2022;20(10):2185- 2194.e2. 20. Auerbach M, Adamson JW. How we diagnose and treat iron deficiency anemia. Am J Hematol. 2016;91(1):31-38. 21. Alleyne M, Horne MK, Miller JL. Individualized treatment for iron-deficiency anemia in adults. Am J Med. 2008;121(11):943-948. 22. Camaschella C. Iron deficiency [published correction appears in Blood. 2023 Feb 09;141(6):682]. Blood. 2019;133(1):30-39. 23. Iolascon A, Andolfo I, Russon R, et al. Recommendations for diagnosis, treatment, and prevention of iron deficiency and iron deficiency anemia. Hemasphere. 2024;8(7):e108. Published 2024 Jul 15. 24. Murawska, N., Fabisiak, A., & Fichna, J. Anemia of Chronic Disease and Iron Deficiency Anemia in Inflammatory Bowel Diseases: Pathophysiology, Diagnosis, and Treatment. Inflammatory bowel diseases.2016;22(5):1198–1208. 25. Nielsen OH, Coskun M, Weiss G. Iron replacement therapy: do we need new guidelines? Curr Opin Gastroenterol. 2016;32(2):128-135. 26. Woei-A-Jin FJSH, Zheng SZ, Kiliçsoy I, et al. Lifetime Transfusion Burden and Transfusion-Related Iron Overload in Adult Survivors of Solid Malignancies. Oncologist. 2020;25(2):e341-e350. 27. Auerback M, DeLoughery TG. Treatment of iron deficiency anemia in adults. In: Means RT, Tirnauer JS, Li H (eds). Up to Date;2024. Accessed January 8, 2025. Uptodate.com 28. Strubbe M, David K, Peene B, et al. No longer to be ignored: Hypophosphatemia following intravenous iron administration. Rev Endocr Metab Disord. 2024;26(1):125-135. 29. DeLoughery TG, Jackson CS, Ko CW, Rockey DC. AGA Clinical Practice Update on Management of Iron Deficiency Anemia: Expert Review. Clin Gastroenterol Hepatol. 2024;22(8):1575-1583. 30. Roberts KM, Estes-Doetsch, H, Nahikian-Nelms M. Pocket Guide to Micronutrient Management. 1st edition. Academy of Nutrition and Dietetics; 2024. 31. von Siebenthal HK, Gessler S, Vallelian F, et al. Alternate day versus consecutive day oral iron supplementation in iron-depleted women: a randomized double-blind placebocontrolled study. EClinicalMedicine. 2023;65:102286. 32. Kamath S, Parveen RS, Hegde S, Mathias EG, Nayak V, Boloor A. Daily versus alternate day oral iron therapy in iron deficiency anemia: a systematic review. Naunyn Schmiedebergs Arch Pharmacol. 2024;397(5):2701-2714. 33. Stoffel NU, Cercamondi CI, Brittenham G, et al. Iron absorption from oral iron supplements given on consecutive versus alternate days and as single morning doses versus twice-daily split dosing in iron-depleted women: two open-label, randomised controlled trials. Lancet Haematol. 2017;4(11):e524-e533. 34. Stoffel NU, Zeder C, Brittenham GM, Moretti D, Zimmermann MB. Iron absorption from supplements is greater with alternate day than with consecutive day dosing in iron-deficient anemic women. Haematologica. 2020;105(5):1232-1239. 35. Lam MC, Khandakar B, Heon I, et al. Daily versus Alternate-Day Iron Supplementation for Pregnant Women with Iron Deficiency Anemia: A Randomized Controlled Trial. Am J Perinatol. 2025;42(6):699-707. 36. Zimmermann MB, Troesch B, Biebinger R, Egli I, Zeder C, Hurrell RF. Plasma hepcidin is a modest predictor of dietary iron bioavailability in humans, whereas oral iron loading, measured by stable-isotope appearance curves, increases plasma hepcidin. Am J Clin Nutr. 2009;90(5):1280-1287. 37. Hwa YL, Rashtak S, Kelly DG, et al. Iron deficiency in long-term parenteral nutrition therapy. JPEN J Parenteral Enteral Nutr. 2016;40(6):869-876.
This website uses cookies to improve your experience. We'll assume you're ok with this, but you can opt-out if you wish. Cookie settingsACCEPT
Privacy & Cookies Policy
Privacy Overview
This website uses cookies to improve your experience while you navigate through the website. Out of these cookies, the cookies that are categorized as necessary are stored on your browser as they are essential for the working of basic functionalities of the website. We also use third-party cookies that help us analyze and understand how you use this website. These cookies will be stored in your browser only with your consent. You also have the option to opt-out of these cookies. But opting out of some of these cookies may have an effect on your browsing experience.
Necessary cookies are absolutely essential for the website to function properly. This category only includes cookies that ensures basic functionalities and security features of the website. These cookies do not store any personal information.
Any cookies that may not be particularly necessary for the website to function and is used specifically to collect user personal data via analytics, ads, other embedded contents are termed as non-necessary cookies. It is mandatory to procure user consent prior to running these cookies on your website.
