Amyloidosis for the Gastroenterologist: A Comprehensive Systematic Review of Diagnosis and Management of Gastrointestinal Manifestations.

Abbreviations

Serum amyloid A amyloidosis

Immunoglobulin light chain amyloidosis

Transthyretin amyloidosis

Hereditary transthyretin amyloidosis

Wild‐type transthyretin amyloidosis

Computed tomography

Digitally reinforced hematoxylin–eosin polarization

Gastrointestinal

Midarm muscle circumference

Model for end‐stage liver disease

Magnetic resonance imaging

Patient‐Generated Subjective Global Assessment

Protein losing enteroapthy

Serum amyloid A protein

36‐Item Short Form Survey

Small intestinal bacterial overgrowth

Tumor necrosis factor

Total parenteral nutrition

Introduction

Amyloidosis is a rare disorder caused by protein misfolding into insoluble fibrils that deposit extracellularly [ 1 ]. Amyloidosis is an umbrella term encompassing multiple subtypes, each defined by distinct pathological protein fibrils involved. Each subtype is designated “A” followed by the misfolded protein (e.g., “L” in AL amyloidosis for immunoglobulin light chains).

The combination of organ systems affected varies among individuals, although certain patterns have been observed depending on the type of amyloid involved [ 1 ]. Both gastrointestinal (GI) amyloidosis and systemic amyloidosis are commonly underdiagnosed. A 2015 survey of 533 patients found 37.1% were diagnosed more than a year after symptom onset [ 2 ]. The nonspecific nature of GI symptoms often delays recognition, although early intervention improves quality of life [ 3 ].

This review aims to provide an overview of the current literature describing the gastrointestinal manifestations of amyloidosis as well as relevant diagnostic and management options of the most common amyloidosis subtypes—immunoglobulin light chain amyloidosis (AL), transthyretin amyloidosis (ATTR), and serum amyloid A amyloidosis (AA) [ 4 ]. ATTR amyloidosis can be further categorized into hereditary/variant (ATTRv) or wild‐type (ATTRwt) form. Notably, GI bleeding and hepatic involvement are more common in AL and AA amyloidosis and are infrequently observed in ATTR amyloidosis. Furthermore, GI symptoms and autonomic neuropathy are characteristic of ATTRv, while ATTRwt typically presents with cardiac involvement and rarely involves the GI tract. [ 5 ] A summary of implicated proteins and organ involvement is provided in Table 1 .

Search Strategy

A systematic search of Ovid MEDLINE, Embase, and PubMed was conducted using the terms “amyloidosis,” “gastrointestinal,” “upper gastrointestinal tract,” “lower gastrointestinal tract,” “hepatic,” “liver,” and “nutrition” as MeSH terms and text words. Additional references were identified through manual searches of relevant articles and reviews. The search was limited to English‐language studies published between January 2014 and December 2024. Exclusion criteria included duplicates, nonhuman studies, participants under 18, abstracts only, and unpublished data.

Results

The search yielded 1880 articles. After applying exclusion criteria, 138 studies were assessed, and 77 were included in the review (Figure 1 ). The included studies comprised: basic science study ( n = 1), diagnostic accuracy study ( n = 1), cross‐sectional studies ( n = 2), case reports ( n = 15), case series ( n = 6), retrospective cohort studies ( n = 14), prospective cohort studies ( n = 4), narrative reviews ( n = 24), randomized controlled trials ( n = 2), clinical trials ( n = 3), and guidelines/consensus statements ( n = 5). Given the heterogeneity of study designs, no formal quality appraisal tool was applied. Findings were interpreted in the context of each study's design and methodological robustness. A table summarizing the included studies and their designs is provided in the supplementary material.

GI Amyloidosis: Pathophysiology and Clinical Features

The gastrointestinal symptoms of amyloidosis arise from the accumulation of amyloid protein fibrils in the GI tract, disrupting normal bowel function [ 6 ]. A study of 729 amyloidosis patients at a single amyloidosis center found GI involvement in 24.8% of AL, 34.5% of AA, 15.9% of ATTRv, and 3.8% of ATTRwt amyloidosis patients [ 7 ].

Most cases of GI amyloidosis (79%) occur as part of systemic disease, where amyloid precursor proteins are synthesized in distant organs [ 8 ]. Systemic amyloidosis is commonly associated with plasma cell dyscrasias, chronic inflammatory conditions, dialysis, or hereditary disorders, with the GI tract being one of several organs affected by amyloid deposition.

Less commonly (21%), amyloid deposition is localized, meaning precursor protein synthesis, amyloid fibril deposition, and clinical manifestations are confined to the GI tract [ 8 , 9 ]. True localized GI amyloidosis carries an excellent prognosis, with no progression to systemic disease [ 8 , 10 ]. However, patients presenting with GI symptoms alone should undergo thorough screening for systemic amyloidosis. This includes evaluating serum protein electrophoresis, serum free light chain concentrations, urine protein electrophoresis, cardiac biomarkers, inflammatory markers, and bone scintigraphy to detect cardiac uptake characteristic of ATTR amyloidosis. Additionally, symptoms of peripheral and autonomic neuropathy should be carefully assessed [ 8 ].

Different amyloid subtypes exhibit distinct patterns of deposition both along the proximal–distal axis (horizontal distribution) and within different layers of the intestinal wall (vertical distribution).

Regardless of subtype, amyloid is most frequently detected in duodenal biopsies. AL amyloidosis is the most prevalent subtype (66.5%), followed by ATTR amyloidosis (15.7%). Deposition primarily occurs in the submucosa, followed by the muscularis mucosae and lamina propria [ 11 ]. While this pattern is consistent across AL, ATTR, and AA amyloidosis, each subtype has unique preferential sites of deposition. In ATTRv amyloidosis, for example, vascular deposition predominates, while AA amyloidosis shows more interstitial involvement [ 11 ].

Autonomic neuropathy, particularly in ATTRv amyloidosis, disrupts the enteric plexus, leading to loss of inhibitory mechanisms and upregulation of excitatory neurons and subsequently dysmotility symptoms [ 12 , 13 ].

Another factor contributing to dysmotility is the loss of interstitial cells of Cajal, which play a crucial role in regulating GI motility [ 14 ]. In the lower GI tract and colon, amyloid infiltration of the myenteric plexus is a frequent cause of colonic motility disorders. Emerging evidence also suggests that ATTR amyloidosis may affect neuroendocrine cells in the GI tract.

Hepatic amyloidosis is often incidental but may present with portal inflammation, fibrosis, or bile duct injury [ 15 ]. In rare cases, amyloidosis can present as severe acute liver failure [ 16 , 17 , 18 , 19 , 20 ].

Gastrointestinal Manifestations

A single‐center study conducted from 2008 to 2017 by Yen et al. retrospectively estimates that at least one in six patients with amyloidosis experience GI symptoms [ 21 ]. However, autonomic neuropathy and cardiac cachexia can mimic GI symptoms [ 8 ]. A biopsy of the GI tract is required to confirm a diagnosis of true GI amyloidosis [ 22 ].

Symptoms vary but commonly include weight loss (40%–43%), diarrhea (27–29%), and abdominal pain (28%). Other notable features include macroglossia (10%–20%), GI bleeding (16%–36%), early satiety (19%–33%), dysphagia, heartburn, and constipation [ 8 , 21 , 23 ]. Variations in symptom prevalence across studies are expected due to small cohort sizes. GI symptoms can be categorized based on their underlying pathophysiology [ 21 ].

Malabsorption and Nutrition

The mechanisms underlying malabsorption in amyloidosis remain poorly understood. Fewer than 5% of patients with systemic amyloidosis present with malabsorptive symptoms [ 24 ]. Proposed mechanisms include muscular infiltration leading to myopathy, autonomic neuropathy of the enteric nervous system, bacterial overgrowth due to dysmotility, protein‐losing enteropathy, and ischemia from vascular deposits [ 9 ]. The most common resulting symptoms from malabsorption are weight loss (100%) and diarrhea (95%). Occasionally, some individuals can present with steatorrhea (< 5%). Predominant physical findings are weight loss and hypotension or orthostatic changes [ 24 ]. Malabsorption can also lead to vitamin deficiencies, particularly in fat‐soluble vitamins (A, D, E, and K) and vitamin B 12 , which can cause paraesthesia and peripheral sensory loss [ 25 ].

Malnutrition is common at diagnosis. A prospective study of newly diagnosed systemic AL amyloidosis patients found that 66% met criteria for significant malnutrition (Patient‐Generated Subjective Global Assessment [PG‐SGA] score ≥ 4) [ 26 ]. Another study reported that nearly 25% of patients failed to meet their estimated caloric needs, and 45% had midarm muscle circumference (MAMC) scores indicating reduced muscle protein stores, correlating with lower quality‐of‐life scores (SF‐36 survey) [ 27 ]. Nutritional status is an independent predictor of mortality, and appropriate management is associated with improved survival and quality of life [ 28 , 29 , 30 ].

GI and Hepatic Hemorrhage

GI bleeding results from mucosal erosion and vascular amyloid deposition, leading to fragility and spontaneous hemorrhage [ 31 ]. Intestinal bleeding may occur because of submucosal or polypoid amyloid lesions, bowel ischemia, or infarction [ 32 ], while gastric bleeding may result from submucosal hematomas or Dieulafoy‐like ulcers [ 33 , 34 ]. GI bleeding is less common but remains a major presentation of localized GI amyloidosis and is more frequently associated with AL and AA amyloidosis subtypes [ 4 , 8 , 9 , 21 ].

Hepatic amyloidosis can lead to life‐threatening complications such as hepatic bleeding, hematoma formation, or, in rare cases, hepatic rupture [ 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. These complications are more commonly seen in AL and AA amyloidosis, due to amyloid deposition in the liver parenchyma or blood vessel walls, resulting in vascular fragility compounded by coagulation abnormalities [ 37 ]. Acquired factor X deficiency, pathognomonic for AL amyloidosis, should be considered in cases of massive hemorrhage [ 42 , 43 ].

Protein‐Losing Enteropathy

Protein‐losing enteropathy (PLE) results from excessive loss of proteins into the GI tract [ 44 ]. In amyloidosis, it is thought to arise from increased permeability of the vasculature, especially the capillaries [ 45 ]. Mucosal inflammation, particularly in AA amyloidosis, may further exacerbate protein loss [ 9 ]. Patients with PLE experience hypoalbuminemia‐related symptoms, including peripheral edema, abdominal distension, dyspnea, and diarrhea [ 44 ].

Gastrointestinal Dysmotility

Amyloid deposition in the enteric and autonomic nerves of the GI tract can lead to significant dysmotility, with considerable heterogeneity in clinical presentation depending on the affected region and whether transit is accelerated or delayed [ 46 ].

In the esophagus, dysmotility may manifest as heartburn, dysphagia, or chest pain. In some cases, the clinical picture resembles achalasia, characterized by aperistalsis of the midesophagus and a “bird‐beak” appearance of the lower esophageal sphincter, which may respond to pneumatic dilatation [ 47 ]. Conversely, some patients exhibit reduced lower esophageal sphincter pressure [ 24 ].

Delayed gastric emptying, more frequently observed in ATTRv amyloidosis, often presents with nausea, vomiting, and early satiety [ 46 ]. Similar symptoms may also arise from gastric outlet obstruction secondary to submucosal masses, large polyps, or antral narrowing [ 48 ].

Diarrhea can result from rapid intestinal transit or bacterial overgrowth, leading to secondary malabsorption of proteins, bile acids, and fats, with consequent steatorrhea and weight loss [ 49 ]. Constipation, more commonly associated with ATTRv amyloidosis, is attributed to prolonged colonic transit time and loss of spontaneous rectal contractions due to amyloid infiltration of the intestinal muscle layer or enteric nervous system [ 50 ].

Pseudo‐obstruction, which can affect the small bowel, colon, or both, presents with obstructive symptoms and radiographic findings of bowel dilation and abnormal luminal gas accumulation. In AL amyloidosis, pseudo‐obstruction is typically caused by amyloid deposition in the intestinal smooth muscle and is associated with a poor prognosis and high mortality [ 51 ]. In contrast, in AA amyloidosis, it is often subacute or self‐limiting, potentially due to differences in amyloid deposition patterns, particularly involvement of the myenteric plexus [ 51 ].

Relationship Between Symptoms and Amyloid Type

AL amyloidosis commonly presents with obstructive symptoms, while AA amyloidosis more often causes diarrhea and malabsorption [ 52 ]. However, symptom profiles overlap, making a diagnostic biopsy with immunohistochemistry (staining for kappa, lambda, transthyretin, and AA) and mass spectrometry essential for accurate subtype classification [ 8 ]. This is especially important in ATTR amyloidosis, where there is significant risk of misdiagnosis as AL amyloidosis due to the frequent detection of monoclonal protein in the blood (~25% of patients with the ATTR subtype) [ 6 ].

Hepatic Involvement

Hepatic involvement is common in systemic amyloidosis, with amyloid deposition in approximately 70% of patients (AL: 60%–90%, AA: 50%–60%) [ 15 ]. However, overt clinical manifestations are uncommon. When present, symptoms such as weight loss, fatigue, and abdominal pain are generally mild [ 53 ]. Hepatomegaly (81%) and elevated ALP (86%) are common due to sinusoidal infiltration, although vascular involvement may also contribute [ 54 ]. Hepatic congestion secondary to cardiac failure, particularly in AL and ATTR amyloidosis, can further complicate the clinical picture [ 53 ]. Fibroscan shows promise in detecting hepatic amyloid infiltration, particularly in AL amyloidosis, although further validation is needed [ 55 ].

Diagnostic Process

Diagnosing amyloidosis requires a high index of suspicion, as symptoms are often nonspecific. A definitive diagnosis of GI or hepatic involvement necessitates both symptomatology and biopsy [ 56 ]. Endoscopic biopsies from prior investigations may contain amyloid deposits upon re‐evaluation. If GI biopsies are negative despite strong clinical suspicion, alternative biopsy sites should be considered. Systemic amyloidosis can often be diagnosed via less invasive methods, such as abdominal fat pad aspiration or labial salivary gland biopsy (particularly in ATTRv amyloidosis) [ 57 ]. In patients with plasma cell dyscrasia detected via serum free light chains or electrophoresis, bone marrow biopsy is used as a screening tool but remains negative in ~30% of AL and 85% of ATTR amyloidosis cases [ 1 ].

Amyloid deposits stain eosinophilic salmon‐pink with Congo red and exhibit apple‐green birefringence under polarized light, a hallmark feature [ 58 ]. Biopsy specimens must undergo amyloid typing using immunohistochemistry (staining for transthyretin, kappa, lambda, and AA), genetic testing, or, more recently, laser microdissection with mass spectrometry [ 6 ]. Accurate subtyping is crucial, as treatment and prognosis differ significantly. Importantly, suspicion of amyloidosis must be explicitly communicated to the pathologist, as specific staining and processing must be requested [ 22 ]. Referral to an amyloidosis center is recommended in uncertain cases.

Endoscopic Findings

Endoscopy is frequently performed in patients presenting with GI symptoms and allows for simultaneous biopsy acquisition [ 59 ]. However, symptoms do not always correlate with macroscopic endoscopic findings. Said et al. found no consistent endoscopic patterns associated with amyloid type in their cohort of 79 patients [ 6 ], emphasizing the need for biopsy even in normal‐appearing mucosa.

Mouth and Esophagus

Macroglossia is the most common oral manifestation of amyloidosis, although it remains relatively rare and is primarily seen in AL amyloidosis [ 9 ]. Esophageal involvement is uncommon, with most reports limited to case series and case reports. Endoscopic findings may include a fine granular mucosal pattern, esophagitis, or luminal narrowing [ 60 ].

Stomach

The stomach is the second most affected site after the small intestine, particularly in AL amyloidosis [ 6 , 60 ]. Endoscopic abnormalities include mucosal erosions, erythema, ulcers, and tumor‐like lesions [ 60 ]. These lesions may resemble submucosal edema with ulceration or mimic gastric malignancies, causing luminal narrowing [ 61 ].

Small Intestine

The small intestine is the most frequently involved site in systemic amyloidosis [ 11 ]. Some studies report duodenal biopsy positivity in up to 100% of patients, although others estimate a diagnostic yield of 50%–70% [ 8 ]. AL amyloidosis is often characterized by polypoid protrusions and thickened duodenal folds, while AA amyloidosis more commonly presents with fine granular lesions and polypoid protrusions [ 62 ]. Additional findings include mucosal elevations, thickened folds, submucosal tumor‐like lesions, ulcerations, erosions, submucosal hematomas, and scalloping [ 63 ]. However, these features are not consistently present in all cases [ 61 ].

Colon and Rectum

Rectal biopsy was historically a sensitive diagnostic method, with AL amyloidosis showing up to 85% positivity. However, ATTR amyloidosis is detected in only 15% of cases [ 57 ]. Deep rectal biopsies are required to examine submucosal vessels for amyloid deposition. Endoscopic findings in the colon and rectum are variable, and amyloid deposits may be present despite normal‐appearing mucosa [ 6 ]. Some studies have described fine granular changes, erosions, and ulcerations, while other studies have reported vascular abnormalities, erythema, edema, and submucosal hematomas [ 61 ].

Biopsy Site

Duodenal biopsy provides the highest diagnostic yield [ 61 ]. Additionally, biopsy site selection may be influenced by amyloid subtype. A retrospective study by Freudenthaler et al. suggests that upper GI biopsies are more diagnostic for AL (kappa) and AA amyloidosis, while lower GI biopsies favor AL (lambda) and ATTR amyloidosis [ 11 ]. Thus, a combination of duodenal and rectal biopsies is recommended, with a minimum of three samples per site to optimize diagnostic accuracy [ 57 ]. A summary of amyloid subtypes and their patterns of deposition in the GI tract can be found in Table 2 .

Endoscopy with biopsy is valuable in excluding amyloidosis as a cause of unexplained GI symptoms. However, symptoms alone do not always indicate pathological GI amyloid deposition. Yen et al. found that half of the patients with systemic amyloidosis and GI symptoms lacked biopsy‐proven amyloid infiltration [ 21 ], possibly due to autonomic neuropathy rather than direct amyloid involvement. Given that most diagnosed patients are older [ 8 ], the risks of biopsy, including perforation and bleeding—especially in cases with extensive vascular amyloid deposition—must be carefully considered [ 61 ].

For hepatic amyloidosis, liver biopsy may confirm amyloid infiltration, but a transjugular approach is recommended to mitigate the risk of life‐threatening hemorrhage [ 15 ].

Although biopsy of the clinically involved organ is the most sensitive method for diagnosing amyloidosis, surrogate sites may be used when biopsy is contraindicated or unrevealing despite high clinical suspicion. These include abdominal subcutaneous fat aspiration for systemic amyloidosis, bone marrow biopsy for suspected systemic AL amyloidosis, and minor salivary gland biopsy for AA or AL amyloidosis [ 57 ].

Despite the high sensitivity and specificity of Congo red staining, false negatives can occur due to factors such as amyloid burden, deposit age, section thickness, tissue fixation, or staining technique [ 64 ]. Digitally reinforced hematoxylin–eosin polarization (DRHEP) is a novel technique combining routine light microscopy with digital photography to detect weak birefringence that may be missed under conventional microscopy [ 65 , 66 ]. Although currently limited to renal biopsies, its applicability in GI amyloidosis is under investigation [ 67 ].

Gastric Emptying Studies

Gastric emptying scintigraphy is sometimes used to assess delayed gastric emptying in amyloidosis‐associated dysmotility. A Swedish study by Wixner et al. examined the relationship between gastric emptying and autonomic dysfunction in ATTRv amyloidosis. Although no strong correlation was found between gastric emptying abnormalities and autonomic neuropathy or symptom severity, delayed gastric emptying was highly prevalent in this cohort [ 68 ].

Other Relevant Investigations

Laboratory Testing

Serological tests lack specificity for diagnosing GI amyloidosis. Elevated alkaline phosphatase is the most common abnormality [ 1 ]. Although less commonly detected, increased serum bilirubin suggests cholestasis and portends a poor prognosis, particularly when bilirubin exceeds 1.5 times the upper limit of normal, indicating extensive hepatic involvement [ 69 ]. Higher fecal calprotectin levels in ATTRv amyloidosis hint at an inflammatory component but lack specificity [ 70 ]. Hypoalbuminemia may result from protein‐losing enteropathy or renal proteinuria. Anemia may stem from GI hemorrhage, multiple myeloma, renal dysfunction, or coagulation abnormalities [ 24 , 47 ].

Imaging

Imaging modalities used to assess abdominal amyloidosis include ultrasonography, barium studies, and computed tomography (CT) [ 71 ]. While CT findings are often nonspecific, the small bowel has the highest rate of radiologic abnormalities, with bowel wall thickening being the most common finding. Additional findings include bowel dilatation, mesenteric infiltration, and adenopathy [ 63 ]. Although less frequently used today, barium studies may show focal or symmetrical thickening of bowel folds [ 52 ].

Hepatic Involvement

Imaging plays a key role in evaluating liver function test abnormalities. The most characteristic CT and magnetic resonance imaging (MRI) findings include hepatomegaly and periportal involvement [ 71 , 72 ]. In AL amyloidosis, hepatic involvement is defined as total liver span > 15 cm in the absence of heart failure or alkaline phosphatase > 1.5 times the institutional upper limit of normal [ 73 ]. However, the specificity of these criteria has recently been questioned [ 74 ]. Fibroscan is another noninvasive radiographic modality that can be used to show increased stiffness of the liver secondary to amyloid deposition [ 75 , 76 ]. A prospective study by Loustaud‐Ratti et al. found significantly higher median liver stiffness in patients with AL amyloidosis compared to controls (27.4 kPa vs. 4.8 kPa, p < 0.0001) [ 55 ], suggesting its potential role as an adjunctive tool in assessing hepatic involvement, particularly given the invasiveness of liver biopsy. Although liver biopsy provides a definitive diagnosis, it is generally not recommended and should be approached with caution due to the risk of bleeding. It should only be considered when an alternative diagnosis is suspected [ 77 ]. The Model for End‐Stage Liver Disease (MELD) score may help predict prognosis in patients with AL and ATTR amyloidosis [ 78 ].

A diagnostic flowchart is provided in Figure 2 .

Management

The treatment of systemic amyloidosis involves suppressing amyloid fibril protein precursor synthesis and supporting affected organs. Suppression strategies vary by amyloid subtype. Although not a guarantee, effective treatment of systemic amyloidosis, regression of GI amyloid, and symptoms may occur, though not always. Further accumulation of amyloid, however, almost always leads to deterioration in organ function. Currently, no targeted therapies exist to directly address amyloid deposits in the GI tract.

The management of AL amyloidosis focuses on suppressing the production of monoclonal immunoglobulin light chains through the eradication of malignant plasma cells [ 67 , 73 ]. First‐line therapy for fit patients eligible for disease‐directed therapy is Dara+CyBorD (daratumumab, cyclophosphamide, bortezomib, and dexamethasone) as initial induction therapy [ 22 , 79 ]. Further management—either autologous stem cell transplantation or continued single‐agent daratumumab—depends on the patient's hematologic response [ 80 ]. The role of doxycycline as adjuvant therapy has become controversial based on recent studies [ 81 , 82 ]. Emerging therapeutic agents include CAEL‐101, NEOD001, and birtamimab [ 83 , 84 , 85 ].

The treatment of ATTR amyloidosis aims to prevent amyloid fibril formation by either stabilizing the transthyretin (TTR) tetramer or suppressing its production. TTR stabilizers (tafamidis, diflunisal) prevent amyloid formation, while RNA‐targeted therapies (patisiran, vutrisiran, inotersen, eplontersen) suppress hepatic TTR production [ 65 , 86 ]. Fibril disruptors (doxycycline, EGCG) show promise as adjunct therapies; however, there is low evidence of efficacy [ 87 , 88 ]. Treatment selection is guided by clinical presentation [ 89 ]. For hereditary ATTR amyloidosis (ATTRv), orthotopic liver transplantation (OLT) may be considered to remove the source of mutant TTR, functioning as a form of “surgical gene therapy” [ 90 ]. However, OLT has not been shown to improve gastric emptying or nutritional symptoms and has largely been replaced by pharmaceutical management [ 90 , 91 ]. Emerging therapies include monoclonal antibodies targeting deposited TTR amyloid and CRISPR‐Cas9–based gene editing [ 92 , 93 ].

The treatment of AA amyloidosis focuses on controlling the underlying inflammatory or infectious condition to reduce serum amyloid A (SAA) protein levels and prevent further amyloid deposition [ 9 , 94 ]. Disease‐specific therapies include immunosuppressive agents (e.g., tumor necrosis factor (TNF) inhibitors for rheumatoid arthritis) and antibiotics for chronic infections. Currently, no therapies exist to prevent SAA fibril formation or remove existing amyloid deposits.

Supportive care, often overlooked, is crucial in managing symptoms and correcting nutritional deficiencies [ 9 ].

A summary of current therapeutic strategies is provided in Table 3 .

Upper GI Symptoms

Upper gastrointestinal symptoms (nausea, vomiting, and early satiety) are common dysmotility‐related symptoms and challenging to manage. In patients with symptomatic gastroparesis, the focus is mostly on antiemetics and prokinetic agents [ 95 ]. Notably, symptom severity does not correlate with the degree of gastroparesis. Most studies on gastroparesis have focused on AL and ATTRv amyloidosis, with limited case reports on AA amyloidosis. In AL amyloidosis, domperidone (up to 20 mg every 6 h before meals) and metoclopramide are recommended [ 73 , 96 , 97 ]. In ATTRv amyloidosis, erythromycin (50–250 mg two to three times daily) or domperidone (10 mg twice daily, 5 min before meals) is preferred [ 3 , 98 ]. Lower doses of erythromycin are found to be as effective as the usual dose of 250 mg TDS [ 98 ]. Furthermore, there is a rapid decline in response and an increase in side effects associated with higher doses of erythromycin [ 65 ]. For prolonged treatment, domperidone is recommended long‐term, while metoclopramide (IM or IV) may be used for acute attacks or recurrent vomiting [ 25 , 98 ]. Though not explicitly studied in amyloidosis, novel prokinetic agents such as prucalopride, itopride, levosulpride, and cisapride may be reasonable alternatives due to their similarities in mechanism to diabetic enteropathy [ 25 , 69 , 95 , 98 , 99 ]. Small, frequent meals are better tolerated than large, solid meals. Hypercaloric liquid formulations should be used in patients with poor caloric intake. For those with heartburn, proton pump inhibitors in standard doses are recommended [ 25 ].

Diarrhea

Diarrhea is a common but difficult‐to‐treat symptom due to its multiple potential etiologies. In AL amyloidosis, a stepwise approach is recommended, beginning with antimotility agents such as loperamide (up to 32 mg daily), codeine (up to 30 mg twice daily), and diphenoxylate [ 73 , 97 ]. For severe cases, octreotide may be beneficial in an outpatient setting [ 73 , 96 ]. In ATTR amyloidosis, octreotide may also improve diarrhea, particularly in ATTRv amyloidosis, where the underlying mechanism is thought to involve a reduction in somatostatin‐secreting neuroendocrine cells in the gut [ 100 ]. A trial of 3–5 days should be instituted with close monitoring of bowel actions to confirm response, as a proportion of patients will not respond. In ATTRv amyloidosis, racecadotril (300 mg daily) may be considered as an alternative to loperamide [ 101 ]. In AA amyloidosis, corticosteroids have been shown to suppress the AA precursor protein SAA while also reducing inflammation and edema, thereby improving diarrhea in patients with chronic autoimmune inflammatory diseases. Case reports suggest that corticosteroids combined with octreotide can be effective in treating severe diarrhea and PLE [ 102 ]. If octreotide is considered, a gentle up titration from 50 mcg twice daily to a maximum of 100 mcg three times daily is recommended [ 98 ]. For bile acid malabsorption, cholestyramine (4 g before meals, twice to four times daily) can be used in conjunction with a fat‐restricted diet [ 103 ].

Constipation

In the management of constipation, osmotic laxatives, particularly polyethylene glycol (macrogel, up to 13–80 mg daily), are the most effective first‐line option [ 3 ]. Lactulose (up to 15–60 mL daily), though associated with greater side effects, may serve as an alternative [ 104 ]. If symptoms persist, picosulfate (10–20 drops daily) can be considered [ 98 ]. In ATTRv amyloidosis, dietary modifications and increased fiber intake are often insufficient [ 25 ] Lubiprostone, prucalopride, and linaclotide, though not specifically studied in AL or AA amyloidosis, are reasonable options in refractory cases [ 25 ]. Prucalopride, a 5HT4 receptor agonist, is particularly recommended as it may enhance both upper and lower gastrointestinal motility [ 104 ].

Pseudo‐Obstruction

Pseudo‐obstruction in amyloidosis is associated with poor prognosis. In AA amyloidosis, it typically presents acutely or subacutely and is usually self‐limiting, responding well to bowel rest and total parenteral nutrition (TPN) [ 51 ]. In AL amyloidosis, the course is more chronic [ 51 ]. Cisapride (up to 10–20 mg QID) has been considered but remains limited in use [ 105 ]. Alternatively, prucalopride (2–4 mg daily) or pyridostigmine can be considered. Avoid other pro‐kinetic agents due to side effects and limited benefit. Surgery is not recommended, and TPN should be initiated to allow for bowel rest [ 95 ].

Small Intestine Bowel Overgrowth

Although treatment for SIBO in amyloidosis has not been extensively studied, management typically involves rotating courses of antibiotics every 14–21 days, depending on symptom recurrence, followed by probiotic supplementation. Diagnosis can be made using a hydrogen/methane breath test before initiating treatment; however, because of its limited sensitivity, a trial of antibiotics may be warranted based on clinical suspicion [ 106 ]. Treatment should be approached with caution, as there is a moderate risk of gut microbiota disruption and antibiotic resistance. While not specifically studied in amyloidosis, commonly used antibiotics include ciprofloxacin (500 mg twice daily), tetracycline (100 mg daily), and metronidazole (500 mg twice daily) [ 104 , 107 ]. For long‐term management, rifaximin (550 mg twice daily) is preferred due to its minimal systemic absorption [ 108 ]. In acute cases, neostigmine may be considered [ 69 ]. Vitamin B 12 supplementation is recommended, as SIBO impairs intrinsic factor function, leading to B 12 deficiency [ 25 ].

GI Hemorrhage

In amyloidosis‐related gastrointestinal hemorrhage, embolization is often the first‐line approach for hemostasis, diverging from conventional endoscopic techniques typically used for gastrointestinal bleeding. Micro‐coil embolization has been employed with some success in cases of lower gastrointestinal bleeding, although there is limited evidence supporting its effectiveness in amyloidosis [ 109 ]. Embolization may be less effective in cases of diffuse amyloid deposition in the gastrointestinal tract [ 110 ]. Endoscopic vessel ligation is another technique that has been utilized, but its efficacy in amyloidosis remains unclear [ 67 ]. Conventional endoscopic interventions such as adrenaline injection, thermal coagulation, and clips have not been clearly demonstrated to be beneficial, likely due to the increased vascular fragility and diffuse nature of amyloid involvement [ 111 , 112 ]. If no contraindications exist, antifibrinolytic agents such as tranexamic acid or epsilon aminocaproic acid may be considered [ 113 ].

Management of hepatic hemorrhage focuses on blood product resuscitation and hemorrhage control. Selective embolization is preferred as the initial intervention [ 35 , 37 ] However, escalation to surgical management, including exploratory laparotomy, liver lobectomy, or hepatic artery ligation, may be necessary in certain cases [ 35 , 37 ] Additionally, correction of any underlying coagulopathy is essential.

Nutritional Support

Nutritional status significantly impacts quality of life and survival, necessitating early assessment and intervention [ 114 ]. Caccialanza et al. conducted a randomized controlled trial evaluating the effects of personalized nutritional counseling on various nutritional parameters. Their findings demonstrated that, compared to the control group—which experienced a mean weight loss of 2.1 kg (95% CI, 0.2 to 4.1; p = 0.003)—the group receiving nutritional counseling largely maintained their initial weight, with a mean loss of only 0.6 kg (95% CI, −1.0 to 2.1; p = 0.214). Additional parameters, including caloric intake and MAMC, also favored the nutritional counseling group [ 28 ]. However, it is important to acknowledge the challenges in establishing a direct causal relationship between nutritional counseling and weight change, given the influence of confounding factors such as chemotherapy regimens in patients with AL amyloidosis.

Despite these limitations, dietary modification and nutritional supplementation remain crucial because of the high prevalence of malnutrition in amyloidosis. In cases where oral intake remains inadequate, parenteral nutrition may be necessary, particularly in patients with gastrointestinal pseudo‐obstruction [ 115 ]. In ATTRv amyloidosis, parenteral nutrition has been shown to alleviate gastrointestinal symptoms and improve nutritional status, although further studies are needed to confirm these findings [ 115 ].

A summary of current supportive management is provided in Table 3 and a treatment flowchart is provided in Figure 3 .

Strengths and Limitations

This comprehensive review offers a clinically focused overview of gastrointestinal and hepatic manifestations across all major amyloidosis subtypes. Current literature is limited by significant heterogeneity in study design and quality, with much of the available data derived from case reports or retrospective cohort studies. Prospective, multicentered studies with standardized outcome measures are lacking. Future research should prioritize larger‐scale prospective cohort studies. Key areas where evidence remains limited include the utility of Fibroscan for hepatic amyloidosis, the impact of nutritional interventions, and the prevalence and management of gastrointestinal dysmotility in systemic amyloidosis.

Conclusions

Although gastrointestinal amyloidosis remains rare, its incidence has risen in recent years due to increased awareness and earlier diagnosis. Given the nonspecific and varied presentations, clinicians must maintain a high index of suspicion to avoid delays in diagnosis, which can significantly impact prognosis. Gastroenterologists should be vigilant, as gastrointestinal symptoms in amyloidosis often mimic other disorders. The development of standardized diagnostic and management guidelines would be invaluable in improving both mortality and, more importantly, quality of life for affected patients.

Ethics Statement

As this is a systematic review, no institutional ethics committee approval was required.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Table S1: Included studies and study designs.

Acknowledgement

Open access publishing facilitated by Monash University, as part of the Wiley ‐ Monash University agreement via the Council of Australian University Librarians.

References

1 P. Mollee , P. Renaut , D. Gottlieb , and H. Goodman , “ How to Diagnose Amyloidosis ,” Internal Medicine Journal 44 , no. 1 ( 2014 ): 7 – 17 . 24024789 10.1111/imj.12288

2 I. Lousada , R. L. Comenzo , H. Landau , S. Guthrie , and G. Merlini , “ Light Chain Amyloidosis: Patient Experience Survey From the Amyloidosis Research Consortium ,” Advances in Therapy 32 , no. 10 ( 2015 ): 920 – 928 . 26498944 10.1007/s12325-015-0250-0 PMC4635176

3 J. Wixner , O. B. Suhr , and I. Anan , “ Management of Gastrointestinal Complications in Hereditary Transthyretin Amyloidosis: A Single‐Center Experience Over 40 Years ,” Expert Review of Gastroenterology & Hepatology 12 , no. 1 ( 2018 ): 73 – 81 . 29073801 10.1080/17474124.2018.1397511

4 H. L. Nienhuis , J. Bijzet , and B. P. Hazenberg , “ The Prevalence and Management of Systemic Amyloidosis in Western Countries ,” Kidney Disease (Basel) 2 , no. 1 ( 2016 ): 10 – 19 . 10.1159/000444206 PMC4946260 27536687

5 J. Wixner , R. Mundayat , O. N. Karayal , et al., “ THAOS: Gastrointestinal Manifestations of Transthyretin Amyloidosis ‐ Common Complications of a Rare Disease ,” Orphanet Journal of Rare Diseases 9 ( 2014 ): 61 . 24767411 10.1186/1750-1172-9-61 PMC4005902

6 S. M. Said , K. L. Grogg , and T. C. Smyrk , “ Gastric Amyloidosis: Clinicopathological Correlations in 79 Cases From a Single Institution ,” Human Pathology 46 , no. 4 ( 2015 ): 491 – 498 . 25649008 10.1016/j.humpath.2014.12.009

7 R. Abe , N. Katoh , Y. Takahashi , et al., “ Distribution of Amyloidosis Subtypes Based on Tissue Biopsy Site ‐ Consecutive Analysis of 729 Patients at a Single Amyloidosis Center in Japan ,” Pathology International 71 , no. 1 ( 2021 ): 70 – 79 . 33112446 10.1111/pin.13041

8 A. J. Cowan , M. Skinner , D. C. Seldin , et al., “ Amyloidosis of the Gastrointestinal Tract: A 13‐Year, Single‐Center, Referral Experience ,” Haematologica 98 , no. 1 ( 2013 ): 141 – 146 . 22733017 10.3324/haematol.2012.068155 PMC3533676

9 P. Sattianayagam , P. Hawkins , and J. Gillmore , “ Amyloid and the GI Tract ,” Expert Review of Gastroenterology & Hepatology 3 , no. 6 ( 2009 ): 615 – 630 . 19929583 10.1586/egh.09.59

10 S. Mahmood , F. Bridoux , C. P. Venner , et al., “ Natural History and Outcomes in Localised Immunoglobulin Light‐Chain Amyloidosis: A Long‐Term Observational Study ,” Lancet Haematology 2 , no. 6 ( 2015 ): e241 – e250 . 26688234 10.1016/S2352-3026(15)00068-X

11 S. Freudenthaler , U. Hegenbart , S. Schonland , H. M. Behrens , S. Kruger , and C. Rocken , “ Amyloid in Biopsies of the Gastrointestinal Tract—A Retrospective Observational Study on 542 Patients ,” Virchows Archiv 468 , no. 5 ( 2016 ): 569 – 577 . 26915034 10.1007/s00428-016-1916-y PMC4856726

12 A. Gonzalez‐Duarte , “ Autonomic Involvement in Hereditary Transthyretin Amyloidosis (hATTR Amyloidosis) ,” Clinical Autonomic Research 29 , no. 2 ( 2019 ): 245 – 251 . 29511897 10.1007/s10286-018-0514-2

13 A. Verrotti , G. Prezioso , R. Scattoni , and F. Chiarelli , “ Autonomic Neuropathy in Diabetes Mellitus ,” Frontiers in Endocrinology (Lausanne) 5 ( 2014 ): 205 . 10.3389/fendo.2014.00205 PMC4249492 25520703

14 O. A. Al‐Shboul , “ The Importance of Interstitial Cells of Cajal in the Gastrointestinal Tract ,” Saudi Journal of Gastroenterology 19 , no. 1 ( 2013 ): 3 – 15 . 23319032 10.4103/1319-3767.105909 PMC3603487

15 R. A. Levine , “ Amyloid Disease of the Liver. Correlation of Clinical, Functional and Morphologic Features in Forty‐Seven Patients ,” American Journal of Medicine 33 ( 1962 ): 349 – 357 . 14464647 10.1016/0002-9343(62)90231-0

16 D. A. Fernandes , G. R. Assis‐Mendoça , L. Costa , L. L. L. Freitas , I. Boin , and F. Reis , “ Amyloidosis: A Rare Cause of Severe Acute Liver Failure ,” Revista Española de Enfermedades Digestivas 116 , no. 1 ( 2024 ): 44 – 45 . 36975149 10.17235/reed.2023.9598/2023

17 F. Charpy , A. Debourdeau , L. Boivineau , M. Meszaros , and L. Meunier , “ Hepatic Amyloidosis as a Case of Fatal Fulminant Liver Failure ,” Clinics and Research in Hepatology and Gastroenterology 45 , no. 1 ( 2021 ): 101506 . 33387856 10.1016/j.clinre.2020.07.011

18 H. Elgouhari , K. Ahmed , M. Niazi , and M. K. Huntington , “ Multiple Myeloma Light Chain Amyloidosis Presenting as Hepatic Failure ,” South Dakota Medicine 71 , no. 3 ( 2018 ): 112 – 115 . 29991097

19 M. Loudin , R. Childers , A. Zivony , C. Lanciault , M. Chang , and J. Ahn , “ Liver Failure Secondary to Amyloid Light‐Chain Amyloidosis ,” American Journal of Medicine 129 , no. 4 ( 2016 ): e19 – e20 . 10.1016/j.amjmed.2015.11.011 26658187

20 M. Elnegouly , K. Specht , H. Zoller , E. Matevossian , F. Bassermann , and A. Umgelter , “ Liver Transplantation Followed by Autologous Stem Cell Transplantation for Acute Liver Failure Caused by AL Amyloidosis. Case Report and Review of the Literature ,” Annals of Hepatology 15 , no. 4 ( 2016 ): 592 – 597 . 27236160

21 T. Yen , F. W. Chen , R. M. Witteles , M. Liedtke , and L. A. Nguyen , “ Clinical Implications of Gastrointestinal Symptoms in Systemic Amyloidosis ,” Neurogastroenterology and Motility 30 , no. 4 ( 2018 ): e13229 . 29024324 10.1111/nmo.13229

22 M. A. Gertz , “ Immunoglobulin Light Chain Amyloidosis: 2024 Update on Diagnosis, Prognosis, and Treatment ,” American Journal of Hematology 99 , no. 2 ( 2024 ): 309 – 324 . 38095141 10.1002/ajh.27177

23 P. S. Lee , L. Jopson , S. J. Needham , C. G. Mountford , and N. P. Thompson , “ Curious Case of gut Dysmotility ,” Gut 70 , no. 1 ( 2021 ): 66 – 126 . 31704884 10.1136/gutjnl-2019-319840

24 S. R. Hayman , M. Q. Lacy , R. A. Kyle , and M. A. Gertz , “ Primary Systemic Amyloidosis: A Cause of Malabsorption Syndrome ,” American Journal of Medicine 111 , no. 7 ( 2001 ): 535 – 540 . 11705429 10.1016/s0002-9343(01)00919-6

25 R. Nakov , O. B. Suhr , G. Ianiro , et al., “ Recommendations for the Diagnosis and Management of Transthyretin Amyloidosis With Gastrointestinal Manifestations ,” European Journal of Gastroenterology & Hepatology 33 , no. 5 ( 2021 ): 613 – 622 . 33394808 10.1097/MEG.0000000000002030

26 P. T. Sattianayagam , T. Lane , Z. Fox , et al., “ A Prospective Study of Nutritional Status in Immunoglobulin Light Chain Amyloidosis ,” Haematologica 98 , no. 1 ( 2013 ): 136 – 140 . 22983575 10.3324/haematol.2012.070359 PMC3533675

27 R. Caccialanza , G. Palladini , C. Klersy , et al., “ Nutritional Status Independently Affects Quality of Life of Patients With Systemic Immunoglobulin Light‐Chain (AL) Amyloidosis ,” Annals of Hematology 91 , no. 3 ( 2012 ): 399 – 406 . 21826471 10.1007/s00277-011-1309-x

28 R. Caccialanza , G. Palladini , E. Cereda , et al., “ Nutritional Counseling Improves Quality of Life and Preserves Body Weight in Systemic Immunoglobulin Light‐Chain (AL) Amyloidosis ,” Nutrition 31 , no. 10 ( 2015 ): 1228 – 1234 . 26250487 10.1016/j.nut.2015.04.011

29 E. Driggin , S. Helmke , J. De Los Santos , et al., “ Markers of Nutritional Status and Inflammation in Transthyretin Cardiac Amyloidosis: Association With Outcomes and the Clinical Phenotype ,” Amyloid 27 , no. 2 ( 2020 ): 73 – 80 . 31825676 10.1080/13506129.2019.1698417

30 R. Caccialanza , G. Palladini , C. Klersy , et al., “ Malnutrition at Diagnosis Predicts Mortality in Patients With Systemic Immunoglobulin Light‐Chain Amyloidosis Independently of Cardiac Stage and Response to Treatment ,” JPEN Journal of Parenteral and Enteral Nutrition 38 , no. 7 ( 2014 ): 891 – 894 . 24072737 10.1177/0148607113501328

31 T. Kon , N. Nakagawa , F. Yoshikawa , et al., “ Systemic Immunoglobulin Light‐Chain Amyloidosis Presenting Hematochezia as the Initial Symptom ,” Clinical Journal of Gastroenterology 9 , no. 4 ( 2016 ): 243 – 251 . 27318996 10.1007/s12328-016-0664-5

32 A. Mallory , J. E. Struthers , Jr. , and F. Kern , Jr. , “ Persistent Hypotension and Intestinal Infarction in a Patient With Primary Amyloidosis ,” Gastroenterology 68 , no. 6 ( 1975 ): 1587 – 1592 . 1132638

33 N. Iijima‐Dohi , A. Shinji , T. Shimizu , et al., “ Recurrent Gastric Hemorrhaging With Large Submucosal Hematomas in a Patient With Primary AL Systemic Amyloidosis: Endoscopic and Histopathological Findings ,” Internal Medicine 43 , no. 6 ( 2004 ): 468 – 472 . 15283181 10.2169/internalmedicine.43.468

34 N. Youssef , N. Carbonell , H. Bonte , L. Serfaty , R. Poupon , and J. F. Flejou , “ Fatal Dieulafoy's Type Ulcer in a Case of Gastric AL‐Amyloidosis ,” Annales de Pathologie 24 , no. 3 ( 2004 ): 256 – 258 . 15480260 10.1016/s0242-6498(04)93960-0

35 S. Leonard‐Murali , H. Nasser , T. Ivanics , and A. Woodward , “ Spontaneous Hepatic Rupture due to Primary Amyloidosis ,” BML Case Reports 12 , no. 10 ( 2019 ): e232448 . 10.1136/bcr-2019-232448 PMC6827783 31676504

36 K.‐S. Naito , T. Ichiyama , S. Kawakami , et al., “ AL Amyloidosis With Spontaneous Hepatic Rupture: Successful Treatment by Transcatheter Hepatic Artery Embolization ,” Amyloid 15 , no. 2 ( 2008 ): 137 – 139 . 18484340 10.1080/13506120802006187

37 X. Du , L. Wen , B. Wang , D. Chen , and W. Wang , “ Liver Rupture in Patients With Amyloidosis: Clinical Features and Treatment ,” Annals of Hepatology 29 , no. 3 ( 2024 ): 101500 . 38582246 10.1016/j.aohep.2024.101500

38 A. Y. Mousa , S. Abu‐Halimah , S. Alhalbouni , et al., “ Amyloidosis and Spontaneous Hepatic Bleeding, Transcatheter Therapy for Hepatic Parenchymal Bleeding With Massive Intraperitoneal Hemorrhage: A Case Report and Review of the Literature ,” Vascular 22 , no. 5 ( 2014 ): 356 – 360 . 23929426 10.1177/1708538113492725

39 A. K. Lohana , S. Abid , R. Sayani , U. Tahir , and P. A. Shaikh , “ Hepatobiliary and Pancreatic: Bleeding in Amyloid Liver: A Rare Presentation of Primary Liver Amyloidosis ,” Journal of Gastroenterology and Hepatology 34 , no. 6 ( 2019 ): 965 . 30665256 10.1111/jgh.14567

40 T. Kobayashi , S. Yoshikawa , M. Takeuchi , and S. Terai , “ Hepatobiliary and Pancreatic: AL Amyloidosis Presented as a Hematoma in the Hepatoduodenal Ligament ,” Journal of Gastroenterology and Hepatology 34 , no. 11 ( 2019 ): 1897 . 31342544 10.1111/jgh.14744

41 B. Anderson , J. Andrews , and J. Poterucha , “ Subcapsular Hepatic Hematoma Resulting From Hepatic Microaneurysms in a Patient With Systemic Amyloidosis ,” Clinical Gastroenterology and Hepatology 16 , no. 11 ( 2018 ): A40 . 29360509 10.1016/j.cgh.2018.01.012

42 Y. M. Guo , N. Takahashi , K. Miyabe , et al., “ Immunoglobulin Light Chain Amyloidosis With Severe Liver Dysfunction Accompanied by Factor X Deficiency ,” Internal Medicine 58 , no. 20 ( 2019 ): 3039 – 3043 . 31243220 10.2169/internalmedicine.2864-19 PMC6859402

43 S. Ericson , N. Shah , J. Liberman , and D. M. Aboulafia , “ Fatal Bleeding due to Acquired Factor IX and X Deficiency: A Rare Complication of Primary Amyloidosis; Case Report and Review of the Literature ,” Clinical Lymphoma, Myeloma & Leukemia 14 , no. 3 ( 2014 ): e81 – e86 . 10.1016/j.clml.2013.08.007 24290671

44 D. G. Levitt and M. D. Levitt , “ Protein Losing Enteropathy: Comprehensive Review of the Mechanistic Association With Clinical and Subclinical Disease States ,” Clinical and Experimental Gastroenterology 10 ( 2017 ): 147 – 168 . 28761367 10.2147/CEG.S136803 PMC5522668

45 M. Kawaguchi , F. Koizumi , M. Shimao , and S. Hirose , “ Protein‐Losing Enteropathy due to Secondary Amyloidosis of the Gastrointestinal Tract ,” Acta Pathologica Japonica 43 , no. 6 ( 1993 ): 333 – 339 . 8346710 10.1111/j.1440-1827.1993.tb02576.x

46 J. Wixner , H. Tornblom , P. Karling , I. Anan , and G. Lindberg , “ Abnormal Small Bowel Motility in Patients With Hereditary Transthyretin Amyloidosis ,” Neurogastroenterology and Motility 30 , no. 9 ( 2018 ): e13354 . 29655299 10.1111/nmo.13354

47 E. C. Ebert and M. Nagar , “ Gastrointestinal Manifestations of Amyloidosis ,” American Journal of Gastroenterology 103 , no. 3 ( 2008 ): 776 – 787 . 18076735 10.1111/j.1572-0241.2007.01669.x

48 K. Jensen , S. Raynor , S. G. Rose , S. T. Bailey , and J. R. Schenken , “ Amyloid Tumors of the Gastrointestinal Tract: A Report of Two Cases and Review of the Literature ,” American Journal of Gastroenterology 80 , no. 10 ( 1985 ): 784 – 786 . 4036936

49 M. J. Guirl , C. Högenauer , C. A. Santa Ana , et al., “ Rapid Intestinal Transit as a Primary Cause of Severe Chronic Diarrhea in Patients With Amyloidosis ,” American Journal of Gastroenterology 98 , no. 10 ( 2003 ): 2219 – 2225 . 14572571 10.1111/j.1572-0241.2003.07695.x

50 T. Ito , R. Sakakibara , S. Ito , et al., “ Mechanism of Constipation in Familial Amyloid Polyneuropathy: A Case Report ,” Internal Medicine 45 , no. 20 ( 2006 ): 1173 – 1175 . 17106165 10.2169/internalmedicine.45.1570

51 S. Tada , M. Iida , T. Yao , T. Kitamoto , T. Yao , and M. Fujishima , “ Intestinal Pseudo‐Obstruction in Patients With Amyloidosis: Clinicopathologic Differences Between Chemical Types of Amyloid Protein ,” Gut 34 , no. 10 ( 1993 ): 1412 – 1417 . 8244111 10.1136/gut.34.10.1412 PMC1374552

52 A. Hokama , K. Kishimoto , M. Nakamoto , et al., “ Endoscopic and Histopathological Features of Gastrointestinal Amyloidosis ,” World Journal of Gastrointestinal Endoscopy 3 , no. 8 ( 2011 ): 157 – 161 . 21954412 10.4253/wjge.v3.i8.157 PMC3180620

53 M. A. Park , P. S. Mueller , R. A. Kyle , D. R. Larson , M. F. Plevak , and M. A. Gertz , “ Primary (AL) Hepatic Amyloidosis: Clinical Features and Natural History in 98 Patients ,” Medicine (Baltimore) 82 , no. 5 ( 2003 ): 291 – 298 . 14530778 10.1097/01.md.0000091183.93122.c7

54 J. D. Gillmore and P. N. Hawkins , “ Pathophysiology and Treatment of Systemic Amyloidosis ,” Nature Reviews Nephrology 9 , no. 10 ( 2013 ): 574 – 586 . 23979488 10.1038/nrneph.2013.171

55 V. R. Loustaud‐Ratti , A. Cypierre , A. Rousseau , et al., “ Non‐Invasive Detection of Hepatic Amyloidosis: FibroScan, a New Tool ,” Amyloid 18 , no. 1 ( 2011 ): 19 – 24 . 10.3109/13506129.2010.543443 21219116

56 M. A. Gertz , R. Comenzo , R. H. Falk , et al., “ Definition of Organ Involvement and Treatment Response in Immunoglobulin Light Chain Amyloidosis (AL): A Consensus Opinion From the 10th International Symposium on Amyloid and Amyloidosis, Tours, France, 18–22 April 2004 ,” American Journal of Hematology 79 , no. 4 ( 2005 ): 319 – 328 . 16044444 10.1002/ajh.20381

57 B. Wisniowski and A. Wechalekar , “ Confirming the Diagnosis of Amyloidosis ,” Acta Haematologica 143 , no. 4 ( 2020 ): 312 – 321 . 32544917 10.1159/000508022

58 M. D. Benson , J. N. Buxbaum , D. S. Eisenberg , et al., “ Amyloid Nomenclature 2020: Update and Recommendations by the International Society of Amyloidosis (ISA) Nomenclature Committee ,” Amyloid 27 , no. 4 ( 2020 ): 217 – 222 . 33100054 10.1080/13506129.2020.1835263

59 L. G. Madsen , P. Gimsing , and F. V. Schiodt , “ Primary (AL) Amyloidosis With Gastrointestinal Involvement ,” Scandinavian Journal of Gastroenterology 44 , no. 6 ( 2009 ): 708 – 711 . 19242859 10.1080/00365520902783717

60 S. Tada , M. Iida , A. Iwashita , et al., “ Endoscopic and Biopsy Findings of the Upper Digestive Tract in Patients With Amyloidosis ,” Gastrointestinal Endoscopy 36 , no. 1 ( 1990 ): 10 – 14 . 2311879 10.1016/s0016-5107(90)70913-3

61 T. Iida , H. Yamano , and H. Nakase , “ Systemic Amyloidosis With Gastrointestinal Involvement: Diagnosis From Endoscopic and Histological Views ,” Journal of Gastroenterology and Hepatology 33 , no. 3 ( 2018 ): 583 – 590 . 28940821 10.1111/jgh.13996

62 S. Tada , M. Iida , T. Yao , et al., “ Endoscopic Features in Amyloidosis of the Small Intestine: Clinical and Morphologic Differences Between Chemical Types of Amyloid Protein ,” Gastrointestinal Endoscopy 40 , no. 1 ( 1994 ): 45 – 50 . 8163134 10.1016/s0016-5107(94)70008-7

63 R. Bansal , U. Syed , J. Walfish , J. Aron , and A. Walfish , “ Small Bowel Amyloidosis ,” Current Gastroenterology Reports 20 , no. 3 ( 2018 ): 11 . 29582184 10.1007/s11894-018-0616-y

64 A. Espargaro , S. Llabres , S. J. Saupe , C. Curutchet , F. J. Luque , and R. Sabate , “ On the Binding of Congo red to Amyloid Fibrils ,” Angewandte Chemie (International Ed. in English) 59 , no. 21 ( 2020 ): 8104 – 8107 . 32073233 10.1002/anie.201916630

65 D. Adams , I. L. Tournev , M. S. Taylor , et al., “ Efficacy and Safety of Vutrisiran for Patients With Hereditary Transthyretin‐Mediated Amyloidosis With Polyneuropathy: A Randomized Clinical Trial ,” Amyloid 30 , no. 1 ( 2023 ): 18 – 26 . 10.1080/13506129.2022.2091985 35875890

66 B. Doganavsargil , G. E. Buberal , H. Toz , et al., “ Digitally Reinforced Hematoxylin‐Eosin Polarization Technique in Diagnosis of Rectal Amyloidosis ,” World Journal of Gastroenterology 21 , no. 6 ( 2015 ): 1827 – 1837 . 25684948 10.3748/wjg.v21.i6.1827 PMC4323459

67 D. S. Dahiya , A. Kichloo , J. Singh , M. Albosta , and F. Wani , “ Gastrointestinal Amyloidosis: A Focused Review ,” World Journal of Gastrointestinal Endoscopy 13 , no. 1 ( 2021 ): 1 – 12 . 33520102 10.4253/wjge.v13.i1.1 PMC7809597

68 J. Wixner , P. Karling , A. Rydh , et al., “ Gastric Emptying in Hereditary Transthyretin Amyloidosis: The Impact of Autonomic Neuropathy ,” Neurogastroenterology and Motility 24 , no. 12 ( 2012 ): 1111 – e568 . 22897426 10.1111/j.1365-2982.2012.01991.x PMC3549473

69 S. Petre , I. A. Shah , and N. Gilani , “ Review Article: Gastrointestinal Amyloidosis ‐ Clinical Features, Diagnosis and Therapy ,” Alimentary Pharmacology & Therapeutics 27 , no. 11 ( 2008 ): 1006 – 1016 . 18363891 10.1111/j.1365-2036.2008.03682.x

70 R. Nakov , S. Sarafov , V. Nakov , et al., “ Fecal Calprotectin Levels Are Elevated in Transthyretin Amyloidosis Patients With Gastrointestinal Manifestations ,” Medicine (Baltimore) 99 , no. 11 ( 2020 ): e19509 . 32176096 10.1097/MD.0000000000019509 PMC7440347

71 H. N. Ozcan , M. Haliloglu , C. Sokmensuer , D. Akata , M. Ozmen , and M. Karcaaltincaba , “ Imaging for Abdominal Involvement in Amyloidosis ,” Diagnostic and Interventional Radiology 23 , no. 4 ( 2017 ): 282 – 285 . 28498108 10.5152/dir.2017.16484 PMC5508951

72 E. Çağlar , G. Özbay , H. Kalyon , and A. Sonsuz , “ Portal Hypertension and Intrahepatic Cholestasis in Primary Amyloidosis ,” Turkish Journal of Gastroenterology 25 , no. Suppl 1 ( 2014 ): 258 – 259 . 10.5152/tjg.2014.4038 25910329

73 Gibbs SMP . Clinical Practice Gudelines: Systemic AL Amyloidosis 2019:[49 p.] .

74 A. F. Brunger , R. van Rheenen , R. O. B. Gans , B. P. C. Hazenberg , and H. L. A. Nienhuis , “ How Well Does Liver Span as Part of the Consensus Criteria for Liver Involvement in AL Amyloidosis Perform? ,” Amyloid 30 , no. 4 ( 2023 ): 437 – 439 . 37318263 10.1080/13506129.2023.2222878

75 E. Lointier , E. Cariou , M. Beneyto , et al., “ Prevalence, Clinical Significance and Prognosis Value of Liver Stiffness Measurement Anomalies in Transthyretin Cardiac Amyloidosis ,” International Journal of Cardiology 416 ( 2024 ): 132485 . 39187068 10.1016/j.ijcard.2024.132485

76 Z. Bayramoglu , Z. N. Akyol Sari , O. Koker , I. Adaletli , and O. R. Eker , “ Shear Wave Elastography Evaluation of Liver, Pancreas, Spleen and Kidneys in Patients With Familial Mediterranean Fever and Amyloidosis ,” British Journal of Radiology 94 , no. 1128 ( 2021 ): 20210237 . 34520686 10.1259/bjr.20210237 PMC8631033

77 M. Ford , B. Disney , V. Shinde , and S. Ishaq , “ Hepatic Amyloidosis: A Cause of Rapidly Progressive Jaundice ,” BML Case Reports ( 2018 ): 2018 , 10.1136/bcr-2017-222942 . PMC5775760 29321198

78 F. Cappelli , S. Baldasseroni , F. Bergesio , et al., “ Liver Dysfunction as Predictor of Prognosis in Patients With Amyloidosis: Utility of the Model for end‐Stage Liver Disease (MELD) Scoring System ,” Internal and Emergency Medicine 12 , no. 1 ( 2017 ): 23 – 30 . 27480755 10.1007/s11739-016-1500-0

79 E. Kastritis , X. Leleu , B. Arnulf , et al., “ Bortezomib, Melphalan, and Dexamethasone for Light‐Chain Amyloidosis ,” Journal of Clinical Oncology 38 , no. 28 ( 2020 ): 3252 – 3260 . 32730181 10.1200/JCO.20.01285

80 D. Dima , S. Mazzoni , F. Anwer , et al., “ Diagnostic and Treatment Strategies for AL Amyloidosis in an Era of Therapeutic Innovation ,” JCO Oncology Practice 19 , no. 5 ( 2023 ): 265 – 275 . 36854070 10.1200/OP.22.00396

81 K. N. Shen , W. J. Fu , Y. Wu , et al., “ Doxycycline Combined With Bortezomib‐Cyclophosphamide‐Dexamethasone Chemotherapy for Newly Diagnosed Cardiac Light‐Chain Amyloidosis: A Multicenter Randomized Controlled Trial ,” Circulation 145 , no. 1 ( 2022 ): 8 – 17 . 34503349 10.1161/CIRCULATIONAHA.121.055953

82 P. Milani , M. Basset , F. Russo , A. Foli , G. Merlini , and G. Palladini , “ Patients With Light‐Chain Amyloidosis and Low Free Light‐Chain Burden Have Distinct Clinical Features and Outcome ,” Blood 130 , no. 5 ( 2017 ): 625 – 631 . 28546143 10.1182/blood-2017-02-767467

83 Y. Koh , “ AL Amyloidosis: Advances in Diagnosis and Management ,” Blood Research 55 , no. S1 ( 2020 ): S54 – S57 . 32719177 10.5045/br.2020.S009 PMC7386888

84 M. A. Gertz , H. Landau , R. L. Comenzo , et al., “ First‐in‐Human Phase I/II Study of NEOD001 in Patients With Light Chain Amyloidosis and Persistent Organ Dysfunction ,” Journal of Clinical Oncology 34 , no. 10 ( 2016 ): 1097 – 1103 . 26858336 10.1200/JCO.2015.63.6530 PMC5470113

85 C. V. Edwards , N. Rao , D. Bhutani , et al., “ Phase 1a/b Study of Monoclonal Antibody CAEL‐101 (11‐1F4) in Patients With AL Amyloidosis ,” Blood 138 , no. 25 ( 2021 ): 2632 – 2641 . 34521113 10.1182/blood.2020009039 PMC8703360

86 J. L. Berk , O. B. Suhr , L. Obici , et al., “ Repurposing Diflunisal for Familial Amyloid Polyneuropathy: A Randomized Clinical Trial ,” Journal of the American Medical Association 310 , no. 24 ( 2013 ): 2658 – 2667 . 24368466 10.1001/jama.2013.283815 PMC4139164

87 C. Tschöpe and A. Elsanhoury , “ Treatment of Transthyretin Amyloid Cardiomyopathy: The Current Options, the Future, and the Challenges ,” Journal of Clinical Medicine 11 , no. 8 ( 2022 ): 1 – 14 . 10.3390/jcm11082148 PMC9031576 35456241

88 E. Karlstedt , V. Jimenez‐Zepeda , J. G. Howlett , J. A. White , and N. M. Fine , “ Clinical Experience With the Use of Doxycycline and Ursodeoxycholic Acid for the Treatment of Transthyretin Cardiac Amyloidosis ,” Journal of Cardiac Failure 25 , no. 3 ( 2019 ): 147 – 153 . 30660664 10.1016/j.cardfail.2019.01.006

89 A. Carroll , P. J. Dyck , M. de Carvalho , et al., “ Novel Approaches to Diagnosis and Management of Hereditary Transthyretin Amyloidosis ,” Journal of Neurology, Neurosurgery & Psychiatry 93 , no. 6 ( 2022 ): 668 . 35256455 10.1136/jnnp-2021-327909 PMC9148983

90 B. Ericzon , H. Wilczek , M. Larsson , P. Wijayatunga , A. Stangou , and J. Pena , “ Liver Transplantation for Hereditary Transthyretin Amyloidosis: After 20 Years Still the Best Therapeutic Alternative? ,” Transplantation 99 ( 2015 ): 1847 – 1854 . 26308415 10.1097/TP.0000000000000574

91 J. Wixner , T. Sundstrom , P. Karling , I. Anan , and O. B. Suhr , “ Outcome of Gastric Emptying and Gastrointestinal Symptoms After Liver Transplantation for Hereditary Transthyretin Amyloidosis ,” BMC Gastroenterology 15 , no. 1 ( 2015 ): 51 . 25908211 10.1186/s12876-015-0284-4 PMC4415350

92 J. D. Gillmore , E. Gane , J. Taubel , et al., “ CRISPR‐Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis ,” New England Journal of Medicine 385 , no. 6 ( 2021 ): 493 – 502 . 34215024 10.1056/NEJMoa2107454

93 O. B. Suhr , M. Grogan , A. M. D. Silva , et al., “ PRX004 in Variant Amyloid Transthyretin (ATTRv) Amyloidosis: Results of a Phase 1, Open‐Label, Dose‐Escalation Study ,” Amyloid 32 , no. 1 ( 2025 ): 14 – 21 . 39472768 10.1080/13506129.2024.2420809

94 M. Ankarcrona , B. Winblad , C. Monteiro , et al., “ Current and Future Treatment of Amyloid Diseases ,” Journal of Internal Medicine 280 , no. 2 ( 2016 ): 177 – 202 . 27165517 10.1111/joim.12506 PMC4956553

95 U. Syed , R. A. Ching Companioni , H. Alkhawam , and A. Walfish , “ Amyloidosis of the Gastrointestinal Tract and the Liver: Clinical Context, Diagnosis and Management ,” European Journal of Gastroenterology & Hepatology 28 , no. 10 ( 2016 ): 1109 – 1121 . 27362550 10.1097/MEG.0000000000000695

96 G. Zumbo , O. Sadeghi‐Alavijeh , P. N. Hawkins , and M. Fontana , “ New and Developing Therapies for AL Amyloidosis ,” Expert Opinion on Pharmacotherapy 18 , no. 2 ( 2017 ): 139 – 149 . 28002971 10.1080/14656566.2016.1274971

97 N. Weber , P. Mollee , B. Augustson , et al., “ Management of Systemic AL Amyloidosis: Recommendations of the Myeloma Foundation of Australia Medical and Scientific Advisory Group ,” Internal Medicine Journal 45 , no. 4 ( 2015 ): 371 – 382 . 25169210 10.1111/imj.12566

98 L. Obici and O. B. Suhr , “ Diagnosis and Treatment of Gastrointestinal Dysfunction in Hereditary TTR Amyloidosis ,” Clinical Autonomic Research 29 , no. Suppl 1 ( 2019 ): 55 – 63 . 10.1007/s10286-019-00628-6 PMC6763516 31452022

99 A. Omer and E. M. M. Quigley , “ An Update on Prucalopride in the Treatment of Chronic Constipation ,” Therapeutic Advances in Gastroenterology 10 , no. 11 ( 2017 ): 877 – 887 . 29147138 10.1177/1756283X17734809 PMC5673021

100 M. Collins , A. Pellat , G. Antoni , et al., “ Somatostatin Analogues for Refractory Diarrhoea in Familial Amyloid Polyneuropathy ,” PLoS ONE 13 , no. 8 ( 2018 ): e0201869 . 30161158 10.1371/journal.pone.0201869 PMC6116977

101 M. Cappello , G. Barbara , M. Bellini , et al., “ Identification and Management of Gastrointestinal Manifestations of Hereditary Transthyretin Amyloidosis: Recommendations From an Italian Group of Experts ,” Digestive and Liver Disease 56 , no. 6 ( 2024 ): 1014 – 1020 . 38105149 10.1016/j.dld.2023.11.025

102 T. Fushimi , Y. Takahashi , Y. Kashima , et al., “ Severe Protein Losing Enteropathy With Intractable Diarrhea due to Systemic AA Amyloidosis, Successfully Treated With Corticosteroid and Octreotide ,” Amyloid 12 , no. 1 ( 2005 ): 48 – 53 . 16076611 10.1080/13506120500032725

103 H. Fromm and M. Malavolti , “ Bile Acid‐Induced Diarrhoea ,” Clinics in Gastroenterology 15 , no. 3 ( 1986 ): 567 – 582 . 3742841

104 C. D. L. Fritz and E. Blaney , “ Evaluation and Management Strategies for GI Involvement With Amyloidosis ,” American Journal of Medicine 135 ( 2022 ): S20 – S23 . 35077702 10.1016/j.amjmed.2022.01.008

105 A. G. Fraser , J. F. Arthur , and I. Hamilton , “ Intestinal Pseudoobstruction Secondary to Amyloidosis Responsive to Cisapride ,” Digestive Diseases and Sciences 36 , no. 4 ( 1991 ): 532 – 535 . 2007373 10.1007/BF01298889

106 A. Gasbarrini , G. R. Corazza , G. Gasbarrini , et al., “ Methodology and Indications of H2‐Breath Testing in Gastrointestinal Diseases: The Rome Consensus Conference ,” Alimentary Pharmacology & Therapeutics 29 , no. Suppl 1 ( 2009 ): 1 – 49 . 19344474 10.1111/j.1365-2036.2009.03951.x

107 D. Real de Asúa , R. Costa , J. M. Galván , M. T. Filigheddu , D. Trujillo , and J. Cadiñanos , “ Systemic AA Amyloidosis: Epidemiology, Diagnosis, and Management ,” Clinical Epidemiology 6 ( 2014 ): 369 – 377 . 25378951 10.2147/CLEP.S39981 PMC4218891

108 S. C. Shah , L. W. Day , M. Somsouk , and J. L. Sewell , “ Meta‐Analysis: Antibiotic Therapy for Small Intestinal Bacterial Overgrowth ,” Alimentary Pharmacology & Therapeutics 38 , no. 8 ( 2013 ): 925 – 934 . 24004101 10.1111/apt.12479 PMC3819138

109 W. T. Kuo , D. E. Lee , W. E. Saad , N. Patel , L. G. Sahler , and D. L. Waldman , “ Superselective Microcoil Embolization for the Treatment of Lower Gastrointestinal Hemorrhage ,” Journal of Vascular and Interventional Radiology 14 , no. 12 ( 2003 ): 1503 – 1509 . 14654483 10.1097/01.rvi.0000099780.23569.e6

110 S. H. Kim , E. J. Kang , J. W. Park , et al., “ Gastrointestinal Amyloidosis Presenting With Multiple Episodes of Gastrointestinal Bleeding ,” Cardiovascular and Interventional Radiology 32 , no. 3 ( 2009 ): 577 – 580 . 18797964 10.1007/s00270-008-9429-y

111 Y. C. Yeh , C. H. Lin , S. C. Huang , and Y. K. Tsou , “ Education and Imaging. Gastrointestinal: Gastric Hematoma With Bleeding in a Patient With Primary Amyloidosis ,” Journal of Gastroenterology and Hepatology 29 , no. 3 ( 2014 ): 419 . 24712044 10.1111/jgh.12528

112 N. Alcaide , C. Herrero , J. Barrio , et al., “ Massive Gastrointestinal Bleeding due to Gastric Ulcer in a Patient With Amyloidosis ,” Gastroenterología y Hepatología 34 , no. 6 ( 2011 ): 411 – 414 . 21684418 10.1016/j.gastrohep.2011.03.018

113 M. Arahata , H. Takamatsu , E. Morishita , et al., “ Coagulation and Fibrinolytic Features in AL Amyloidosis With Abnormal Bleeding and Usefulness of Tranexamic Acid ,” International Journal of Hematology 111 , no. 4 ( 2020 ): 550 – 558 . 31897889 10.1007/s12185-019-02811-x

114 Á. Franco‐López and J. M. Culebras , “ Malnutrition, Pharmaconutrition and Other Considerations in AL Amyloidosis, a Rare Disease With Masquerading Symptoms and Usually Delayed Diagnosis ,” Nutrición Hospitalaria 31 , no. 6 ( 2015 ): 2337 – 2345 . 26040337 10.3305/nh.2015.31.6.7851

115 M. Russo , G. L. Vita , C. Stancanelli , A. Mazzeo , G. Vita , and S. Messina , “ Parenteral Nutrition Improves Nutritional Status, Autonomic Symptoms and Quality of Life in Transthyretin Amyloid Polyneuropathy ,” Neuromuscular Disorders 26 , no. 6 ( 2016 ): 374 – 377 . 27132122 10.1016/j.nmd.2016.03.006