Liver Disorders, SERIES #20

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

November 2025 • Volume XLIX, Issue 4
Olivia Babich,Alexandra Savage,Tavankit Singh

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

Introduction

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

Autoimmune Hepatitis 

Vitiligo

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

Pyoderma gangrenosum

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

Hemochromatosis

Hyperpigmentation/bronzing

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

Alopecia

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

Table 1. Liver Diseases and Associated Dermatologic Manifestations

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

Ichthyosis

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

Koilonychia

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

Wilson’s Disease

Lower extremity hyperpigmentation

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

Azure lunulae

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

Alpha-1 Antitrypsin Deficiency 

Panniculitis

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

Primary Biliary Cholangitis 

Pruritis: excoriations, post-inflammatory hyperpigmentation, butterfly sign

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

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

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

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

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

Primary Sclerosing Cholangitis 

Inflammatory bowel disease overlap: erythema nodosum, pyoderma gangrenosum

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

Metabolic Dysfunction-Associated Steatotic Liver Disease 

Psoriasis

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

Acanthosis nigricans

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

Conclusion

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

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

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

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

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

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

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

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

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

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

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

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Frontiers in Endoscopy, Series #100

Pancreaticobiliary Endoscopic Ultrasound: How We Do It

November 2025 • Volume XLIX, Issue 4
Jennifer L. Maranki,Douglas G. Adler

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Introduction

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

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

Intubation of the Esophagus

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

A Station Approach to the Examination

Gastroesophageal Junction (GEJ)

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

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

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

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

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

Duodenal Bulb

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

Ampulla

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

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

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

Second and Third Portion of the Duodenum

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

Identification of Pathology

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

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

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

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

EUS-Guided Tissue Sampling of Solid Pancreatic Lesions

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

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

Conclusion

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

References

References

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

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

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

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

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

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

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

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

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Nutrition Reviews in Gastroenterology, SERIES #28

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

November 2025 • Volume XLIX, Issue 4
Alexander W. Worix,Jennifer C. Lai,Neha D. Shah

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

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

Introduction 

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

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

Table 1. Updates for Steatotic Liver Disease Nomenclature 

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

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

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

Prevalence 

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

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

Diagnosis 

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

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

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

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

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

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

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

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

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

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

Risk Factors 

Metabolic Risk Factors

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

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

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

Lifestyle Risk Factors

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

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

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

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

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

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

Mediterranean Diet 

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

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

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

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

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

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

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

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

Practical Applications

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

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

References

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

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Special Article

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

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

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

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Liver Disorders, SERIES #19

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

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

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

Introduction

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

Cirrhosis

Spider Angiomata

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

Paper money skin

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

Palmar Erythema

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

Disseminated superficial actinic porokeratosis

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

Caput medusae

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

Bier spots

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

Terry’s nails

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

Hepatitis B 

Serum sickness-like reaction

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

Polyarteritis nodosa

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

Papular acrodermatitis of childhood
(Gianotti-Crosti syndrome)

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

Table 1.  Cirrhosis, Hepatitis, and Associated Dermatologic Manifestations

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

Hepatitis C 

Porphyria cutanea tarda

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

Lichen planus 

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

Mixed cryoglobulinemia

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

Necrolytic acral erythema

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

Conclusion

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

References

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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

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From the Pediatric Literature

Eosinophilic Esophagitis in Pediatric Patients Receiving Infliximab

October 2025 • Volume XLIX, Issue 10

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

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

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

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

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

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

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Frontiers in Endoscopy, Series #99

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

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

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Introduction

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

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

Incidence

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

Risk Factors

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

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

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

Classification of Sphincterotomy-Associated Bleeding

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

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

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

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

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

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

Management of Sphincterotomy Induced Bleeding

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

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

Tamponade

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

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

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

Local Injections 

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

Thermal Coagulation

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

Clipping 

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

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

Stenting

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

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

Topical Agents 

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

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

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

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

IR/surgery for Profound Post-ES bleeding

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

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

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

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

Conclusion

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

References

References

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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.

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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.

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Dispatches from the GUILD Conference, Series #71

Global Consensus Statement for the Management of Inflammatory Bowel Disease in Pregnancy: Implications for the Gastroenterologist

September 2025 • Volume XLIX, Issue 9
Arushi Kohli,Uma Mahadevan

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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

DrugRecommended Time to Discontinue Before Conception*
OzanimodAt least 3 months
EtrasimodAt least 1–2 weeks
TofacitinibAt least 4 weeks
UpadacitinibAt least 4 weeks
FilgotinibAt 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 During Pregnancy 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 CategoryManagement
5-ASAContinue for maintenance therapy
SulfasalazineContinue throughout pregnancy. Folic acid 2 mg daily
CorticosteroidsUse when clinically necessary, with appropriate monitoring
Anti-TNF Therapy  (Infliximab, Adalimumab, Golimumab, Certolizumab)Continue throughout pregnancy
IL-23, IL-12/23 Therapy (Risankinumab, Ustekinumab)Continue throughout pregnancy 
Anti-integrin  (Vedolizumab, Natalizumab)Continue throughout pregnancy 
MethotrexateShould 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

Medication CategoryManagement
5-ASA/SulfasalazineMay breastfeed
ThiopurinesMay breastfeed
CorticosteroidsMay breastfeed 
Anti-TNF Agents (Infliximab, Adalimumab, Golimumab, Certolizumab)May breastfeed
Anti-Integrins (Vedolizumab, Natalizumab)May breastfeed
Anti-IL-12/23 and Anti-IL-23 Agents (Ustekinumab, Risankizumab, Mirikizumab, Guselkumab)May breastfeed
BiosimilarsMay 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. 

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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

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Liver Disorders, SERIES #18

Understanding New Nomenclature in Advanced Chronic Liver Disease

September 2025 • Volume XLIX, Issue 9
Cierra Smith,Michael Babich

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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.

Advanced chronic liver disease, clinically significant portal hypertension and compensated cirrhosis

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.13 Acute 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

11. Tsochatzis EA, Bosch J, Burroughs AK. Liver cirrhosis. The Lancet. 2014;383(9930):1749-1761. doi:https://doi.org/10.1016/s0140-6736(14)60121-5

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

25. Badillo R, Rockey DC. Hepatic Hydrothorax. Medicine. 2014;93(3). doi:https://doi.org/10.1097/MD.0000000000000025

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Nutrition Reviews in Gastroenterology, SERIES #27

Gentler Solutions: Adapting the Low FODMAP Elimination Diet for Irritable Bowel Syndrome for Symptom Relief

September 2025 • Volume XLIX, Issue 9
Kate Scarlata

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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 

Table 1. FODMAPs: It’s In The Details 

Acronym Food Components Rich FODMAP Sources (examples) 
F– ermentable 
O-ligosaccharide Fructans and galacto-oligosaccharides (GOS) Wheat, barley, rye, onion, garlic, legumes (e.g., beans, lentils, chickpeas), pistachios, cashews 
D-isaccharide Lactose Cow, sheep, and goat milk, ice cream, yogurt 
M-onosaccharide Excess fructose Honey, apple, pear, watermelon 
A-nd – – 
P-olyols Sugar alcohols: mannitol, sorbitol, xylitol celery, stone fruits (e.g., apricot, peach, plum), apple, pear, sugar free gum + mints

Evolution of Diet as a Therapy in 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. 

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