Atypical Presentation of Hereditary ATTR Amyloidosis with Gastrointestinal and Hepatic Manifestations in an 88-Year-Old Woman: A Case Report

Introduction

Amyloidosis is a heterogeneous group of disorders characterized by abnormal deposition of amyloids, which are insoluble fibrillar proteins that accumulate extracellularly, disrupting the normal structure and function of affected tissues [1]. It is a multisystemic disease that can disrupt the normal function of affected organs. Amyloidosis is further divided into localized and systemic amyloidosis [2]. Localized amyloidosis is the pathological deposition of insoluble fibrillar proteins in specific organs (eg, skin, lungs, conjunctiva, breast, larynx) and can be an incidental finding with or without any pathological significance. Systemic amyloidosis is classified into 4 primary subtypes: immunoglobulin light-chain amyloidosis (AL), serum amyloid A (AA) amyloidosis, transthyretin (ATTR) amyloidosis, and beta-2 microglobulin (Aβ2M) amyloidosis [2]. Amyloid light-chain (AL) amyloidosis is the most common form of amyloidosis affecting the gastrointestinal (GI) tract, whereas amyloid transthyretin (ATTR) is now recognized as the most prevalent form of amyloidosis globally [1,3].

Classically, amyloidosis presents with a spectrum of systemic manifestations: cardiac involvement with infiltrative cardiomyopathy; peripheral nervous system involvement manifesting as sensorimotor and autonomic neuropathy, which can often result in orthostatic hypotension and sensory loss; and gastrointestinal involvement presenting with symptoms such as malabsorption, diarrhea, weight loss, and gastric motility disorders, contributing to significant morbidity [3]. GI manifestations in amyloidosis are commonly seen in systemic forms of amyloidosis and are defined by the presence of gastrointestinal symptoms and biopsy-confirmed diagnosis of amyloidosis [4]. Of the various subtypes, gastrointestinal amyloidosis is most commonly seen in AL, followed by ATTR and AA [4,5]. The most common presenting symptoms include unintentional weight loss, diarrhea, abdominal pain, malabsorption, and GI bleeding. Isolated GI manifestations are infrequent and can present with concurrent cardiac or nervous system involvement [4].

ATTR amyloidosis typically presents with cardiac and neurologic manifestations [1], usually presenting at age 30–60 years, and diagnosis in people over the age of 80 years is uncommon [1]. Among the different types of amyloidosis, ATTR amyloidosis is noteworthy due to its association with hereditary and acquired forms [6]. Hereditary ATTR amyloidosis is caused by mutations in the transthyretin (TTR) gene, causing misfolded proteins to be deposited in various organ systems, causing peripheral and autonomic neuropathy and cardiomyopathy. Wild-type ATTR amyloidosis does not involve by any genetic mutations; misfolding of the normal transthyretin protein occurs over time, usually affecting older adults. This type usually also affects the heart and the nervous system [7].

Hereditary ATTR amyloidosis is a rare autosomal dominant disorder found globally, with endemic regions in Sweden, Portugal, Brazil, and Japan [8]. Over 100 different mutations in the TTR gene have been identified, with valine substituted by methionine at position 30 (V30M) mutation being the most common in endemic areas. However, the valine substituted by isoleucine at position 122 (V122I) mutation is likely the most prevalent variant worldwide, affecting approximately 4% of African American individuals [9].

In this report, we present a unique case of ATTR amyloidosis that initially manifested as a gastrointestinal and hepatic mass in an elderly patient. The atypical presentation highlights the diagnostic complexity and the need for a high index of suspicion in unexplained GI and hepatic pathology cases. This report describes an 88-year-old African American woman with a history of vaginal squamous cell carcinoma presenting with masses in the liver and gastrointestinal tract and a diagnosis of ATTR.

Case Report

An 88-year-old African American woman with a history of vaginal squamous cell carcinoma treated with chemoradiation, and in remission, presented to the Emergency Department (ED) with progressively worsening abdominal pain and rectal bleeding.

She reported a 3-month history of intermittent, dull, cramping abdominal pain localized to the right lower quadrant, which had progressively worsened over the past 2 weeks. The pain was associated with nausea, early satiety, and intermittent bloating. Additionally, she had occasional non-bloody diarrhea, which was not bothersome for the patient. Two days prior to presentation, she noticed bright red blood per rectum, prompting her to visit the ED. The per-rectal bleeding initially appeared as small streaks on toilet paper but progressed to larger amounts mixed with stool. She also described an episode of maroon-colored stool the day before presentation. The bleeding was not associated with tenesmus, fever, or recent changes in bowel habits, although she had occasional diarrhea. On arrival, she was hemodynamically stable, with a temperature of 98.6°F (37°C), blood pressure of 128/72 mmHg, heart rate of 88 bpm, respiratory rate of 16 breaths per minute, and oxygen saturation of 98% on room air. The initial laboratory evaluation revealed anemia with a hemoglobin of 10.2 g/dL and hematocrit of 31.5%, along with a white blood cell count of 12.3×109/L, suggesting a possible underlying inflammatory or neoplastic process. Platelet count, renal function, and liver function test results were within normal limits. The presence of anemia, in conjunction with her symptoms of rectal bleeding and chronic abdominal pain, raised a concern for a potential GI malignancy, leading to further imaging and endoscopic evaluation. A computed tomography (CT) scan of the abdomen and pelvis revealed a 6.1×4.6×4.7 cm mass in the ascending colon with multiple lymph nodes, as well as sub-centimeter bilobar hepatic lesions, both concerning for malignancy. A colonoscopy identified a large, circumferential, near-obstructing, ulcerative necrotic mass in the ascending colon. Pathology from the colonoscopy revealed a tubular adenoma without high-grade dysplasia. There were no records available for any family history or screening performed in relatives.

The patient also underwent surgical resection of the liver mass and a hemicolectomy. Pathological examination of the liver mass showed a hyalinized nodule with amyloidosis, predominantly involving the vessel walls. At the same time, the colon pathology revealed amyloidosis (both vascular and interstitial) in addition to the tubular adenoma without high-grade dysplasia, as shown in Figures 1–3. All 28 resected lymph nodes were benign. Mass spectrometry confirmed the presence of only ATTR (transthyretin-type) amyloid deposition. Notably, there was no evidence of additional amyloid subtypes, such as AL (light-chain) or AA (inflammatory) amyloidosis, which are some of the most common types of amyloid deposition reported in GI involvement. Given the common involvement of the cardiac and nervous systems in ATTR amyloidosis, an investigation for cardiac amyloid was carried out. An echocardiogram (ECHO) and sural nerve biopsy were performed to assess for organ involvement. The ECHO showed normal ventricular size, with no signs indicative of cardiac amyloidosis. Cardiac MRI was done, which showed no suggestion of infiltrative cardiomyopathy or inflammatory process with an LVEF of 77%. The cardiac MRI demonstrated a focal basal septal hypertrophy but no evidence of obstruction. Similarly, the sural nerve biopsy demonstrated mild axonal neuropathy with ongoing Wallerian degeneration but no evidence of amyloid deposition. Genetic testing for ATTR amyloidosis through a laboratory diagnosis of the sample obtained identified a pathogenic variant in the TTR gene (Val122Ile; HGVS: p.Val142Ile) remarkable for hereditary ATTR amyloidosis. However, neither the patient nor her family were investigated further for genetic testing. As the patient carried the pathogenic variant in the TTR gene (Val122Ile; HGVS: p.Val142Ile), we referred her to an outside amyloidosis clinic for further workup to check for cardiac involvement, which is very common in the Val122Ile variant. She also developed bilateral lower-extremity neuropathy during the course of her disease, and was started on vutrisiran.

Additionally, the patient experienced multiple subsequent episodes of gastrointestinal (GI) bleeds in the form of hematemesis and hematochezia. During these admissions, bidirectional endoscopic evaluations were performed. An esophagogastroduodenoscopy (EGD) identified multiple ulcers in the antrum, with clean bases and a mass/polyp in the duodenal bulb. A colonoscopy showed mild erythematous mucosa at the surgical anastomosis site and a single bleeding angioectasia in the rectum, which was treated with argon plasma coagulation. Pathology indicated chronic inactive gastritis, incomplete intestinal metaplasia, and amyloid deposition in the walls of blood vessels. The surgical biopsy site exhibited enteric mucosa with regenerative changes and amyloid deposition. The pathology of the duodenal polyp demonstrated a well-differentiated neuroendocrine neoplasm, WHO Grade 1, involving the lamina propria. The recurrent GI bleeding episodes led to iron-deficiency anemia, necessitating multiple intravenous (IV) iron infusions. Subsequently, she underwent an endoscopic mucosal resection (EMR) of the duodenal lesion, which was identified as a well-differentiated neuroendocrine tumor, WHO Grade II, measuring 1.0 cm, with positive margins. A follow-up EGD showed no residual neuroendocrine neoplasm.

Discussion

Our case illustrates that hereditary transthyretin (ATTR) amyloidosis, particularly the Val122Ile variant, can present with isolated gastrointestinal and hepatic involvement, mimicking malignancy and leading to diagnostic delays in the absence of classic systemic features such as cardiomyopathy or neuropathy.

Our case is unique as this patient presented with recurrent GI bleeding and was found to have a mass in the colon, initially suspected to be malignant given her medical history of vaginal cancer. Given the patient’s age, history of malignancy, and clinical presentation with abdominal pain and rectal bleeding, several differential diagnoses were considered. Colorectal malignancy was a primary concern, especially given the presence of a large, ulcerative, near-obstructing mass in the ascending colon with associated lymphadenopathy and hepatic lesions on imaging, which was supported by the literature [10]. A gastrointestinal stromal tumor (GIST) was also considered due to the necrotic and ulcerative nature of the mass [11]. Metastatic disease from her prior vaginal squamous cell carcinoma was another possibility, particularly given the suspicion of liver involvement. Other considerations included ischemic colitis, given her advanced age and vascular risk factors, as well as inflammatory bowel disease (IBD), although the latter was less likely due to the absence of chronic diarrhea or extraintestinal manifestations [12]. Infectious colitis, such as Clostridium difficile colitis or bacterial enterocolitis, was also on the differential, but the subacute nature of her symptoms and lack of systemic signs of infection made this less likely [13].

Additionally, amyloidosis-associated gastrointestinal involvement, although rare, was considered, particularly in the setting of systemic symptoms and suspected hepatic involvement. Distinguishing systemic amyloidosis from malignancy can be challenging, especially in patients with a history of malignancy [14]. When amyloid deposits accumulate in organs such as the liver, GI tract, or lymph nodes, their appearance on imaging can raise a strong suspicion of malignancy or metastatic disease [15]. In our case, imaging revealed a mass in the colon measuring approximately 6.1×4.6×4.7 cm, with multiple involved lymph nodes and bilobar hepatic lesions. However, pathology identified amyloidosis, with genetic confirmation of ATTR-type amyloid, underscoring the importance of including amyloidosis in the differential diagnosis of unexplained GI masses presenting with bleeding. This is particularly relevant for elderly patients with a history of cancer who present with new organ masses or symptoms such as GI bleeding, as these findings are easily misinterpreted as recurrence or metastatic spread. Given the overlap in presentation, a thorough diagnostic approach that includes histopathological evaluation and confirmation through mass spectrometry and genetic testing is essential for accurate diagnosis and appropriate management [16].

Only 1 published case report has described the long-term prognosis of localized colorectal ATTR amyloidosis, involving an 80-year-old man with wild-type ATTR amyloidosis who developed early-stage colorectal cancer and cytomegalovirus-associated ulcer 8 years after diagnosis, requiring endoscopic submucosal dissection [17]. Our patient presented with extensive amyloid deposition involving the colon and liver, leading to recurrent GI bleeding and anemia, with pathology confirming hereditary ATTR amyloidosis (Val122Ile variant). Unlike previously reported cases of localized colorectal amyloidosis, our patient exhibited systemic involvement, including amyloid deposition in the colon, liver, and vascular walls, along with a concurrent neuroendocrine tumor [18]. Given the potential for complications such as colorectal malignancy over time, these findings emphasize the importance of long-term surveillance in patients with colorectal amyloidosis, particularly those with ATTR variants [17].

A similar case report by Toppeta et al described an elderly man presenting with chronic diarrhea, orthostatic hypotension, malabsorption, and weight loss. Further investigation for his diarrhea revealed the diagnosis of hereditary transthyretin amyloidosis with involvement of the heart, nervous system, and GI tract, and the authors also described the diagnostic challenges, especially in the early stages [19]. Although our suspicious was GI malignancy due to the patient’s relevant history of vaginal squamous cell carcinoma, hereditary transthyretin amyloidosis can also present as chronic diarrhea and should be evaluated further.

The mechanism behind bleeding secondary to amyloidosis stems from local ischemia, infarction, and mucosal injury, which progresses to the formation of erosions, hematomas, or ulcerations. Cases have been reported where submucosal hematoma is described as a distinctive feature of GI amyloidosis on endoscopy and is visualized along the entire length of the GI tract [20,21]. The development of giant submucosal hematomas expands rapidly and may even rupture, which can cause life-threatening GI bleeding. In such cases, endoscopic hemostasis may be ineffective, and other treatment modalities, such as surgical intervention or arterial embolization, may be required [22]. Our patient presented with GI bleeding, which led to the diagnosis of an ATTR type of amyloidosis. We found 1 relevant case report in which a 79-year-old man presented with intra-abdominal hemorrhage requiring emergency partial resection of transverse colon, later being diagnosed with ATTR amyloidosis, similar to our case [23].

Apart from GI bleeding, various cases have been reported in which ATTR amyloidosis was responsible for spontaneous bleeding manifestations. ATTR amyloid is deposited in the vessel walls, causing accelerated microcalcification and vessel ruptures [24]. Most commonly, the presentation is with periorbital ecchymosis or shoulder swelling, also known as pad sign [25,26]. However, the involvement of another organ system, such as the urinary system, presenting as hematuria, or when it presents as GI bleeding, such as ATTR amyloidosis, should be kept in the differential [27].

Conclusions

This case illustrates an uncommon presentation of hereditary ATTR amyloidosis (Val122Ile variant) characterized by isolated gastrointestinal and hepatic involvement, without typical systemic manifestations such as cardiomyopathy or neuropathy. Such atypical presentations may resemble malignancy, resulting in diagnostic delays. This emphasizes the necessity of prompt histopathologic evaluation, Congo red staining, mass spectrometry, and genetic testing in patients with unexplained gastrointestinal bleeding or mass lesions. Timely recognition is essential to guide appropriate management, prevent recurrent bleeding, and inform genetic counseling and surveillance.