November 2018 Case

Authors

Daniel Manzoor, MD (Resident); Bonnie L. Balzer, MD, PhD (Faculty)

Subject: Gastrointestinal Pathology
Clinical History

95-year-old male with chronic anemia attributed to a combination of stage III chronic kidney disease and a presumed occult gastrointestinal bleed for which no definitive evidence was identified, despite extensive workup. He also had a history of hypertension and peripheral vascular disease with multiple aortic dilations as well as an extensive smoking history and worsening dementia.

He presented to the emergency department with altered mental status, sepsis, and a hemoglobin level of 3.8 g/dL. Imaging studies showed worsening of his aortic dilations and a round lesion in the upper lobe of the right lung which was not previously seen. He was eventually stabilized with plans to be discharged, but suddenly decompensated and suffered a hypotensive episode, after which comfort measures were initiated. He expired two days later, and an autopsy was performed.

A large, advanced sacral decubitus ulcer was seen on external exam, and postmortem blood cultures grew Bacteroides thetaiotaomicron, an enteric bacterium rarely known to cause sepsis, with most instances occurring in elderly patients. The cause of death was established as sepsis due to contamination of the sacral ulcer, an acute condition which was likely exacerbated by his multiple chronic comorbidities.

Though the cause of death was clear, no gross findings were seen at autopsy that could explain this patient's chronic, occult gastrointestinal bleeding.

Figures
Section taken near the gastroesophageal junction

Figure 1: A) H&E, 4x. Section taken near the gastroesophageal junction shows a large submucosal vessel with several prominent, waxy, pink deposits within the vessel wall (green arrows), as well as a smaller, nearby, similarly affected vessel (blue arrow). B) H&E, 10x. Higher magnification view of the large vessel deposits. C) Congo red, 10x. Large vessel deposits with 'salmon pink' appearance on Congo red stain. D) Transthyretin immunostain, 10x. Large vessel deposits highlighted in brown by immunohistochemical stain for transthyretin. E) H&E, 20x. Smaller vessel shown in (A) at higher magnification with pink deposit, F) also highlighted by Congo red stain.

Section of small bowel

Figure 2: A) H&E, 10x. Section of small bowel with submucosal small vessel pink deposits, B) also highlighted by Congo red stain. Note prominent postmortem autolysis of the mucosa. 

Figure 3: A) H&E, 10x. Section of stomach with submucosal small vessel deposit, B) with more appearing on Congo red stain. C) H&E, 20x. Additional area with prominent pink deposit in submucosal vessel, D) again highlighted by Congo red stain. 

Diagnosis

Transthyretin amyloidosis

Discussion

Histologic examination of several areas of the gastrointestinal tract as well as the heart, liver, and lungs revealed abundant amyloid deposition, predominantly within the vessel walls. Immunohistochemical staining showed that the amyloid was of the transthyretin subtype. Thus, in addition to the previously mentioned comorbidities, this patient suffered from systemic transthyretin amyloidosis, which was likely the cause of his unexplained gastrointestinal bleed.

Amyloidosis represents a set of systemic diseases caused by the deposition of insoluble aggregates of misfolded proteins ('amyloid') in the form of β-pleated sheets. Several subtypes exist, each distinguished by the type of protein precursor that forms the amyloid. Transthyretin amyloid results from the breakdown of the protein transthyretin, also known as prealbumin. Normally involved in transporting thyroxine and retinol binding protein (from which its name is derived), transthyretin, a tetramer, dissociates into monomers which can then misfold and form amyloid fibrils. Transthyretin amyloidosis can be due to the spontaneous dissociation and misfolding of transthyretin ('wild-type' disease) or can be hereditary, owing to a destabilizing genetic mutation that facilitates breakdown of the protein.

When amyloidosis involves the gastrointestinal tract, it can cause bleeding that is extremely difficult to diagnose. Up to 57% of patients with systemic disease can experience gastrointestinal bleeding, among several other nonspecific gastrointestinal symptoms such as early satiety and diarrhea. Autopsy studies have shown that up to 40.6% of individuals over the age of 80 have amyloid deposits in the gastrointestinal tract with the predominating form being transthyretin.

References
  • Gertz, Morie A., et al. "Diagnosis, prognosis, and therapy of transthyretin amyloidosis." Journal of the American College of Cardiology 66.21 (2015): 2451-2466.
  • James DG, Zuckerman, GR, Sayuk, GS, Wang, HL, Prakash C. Clinical Recognition of AL Type Amyloidosis of the Luminal Gastrointestinal Tract. Clinical Gastroenterology and Hepatology. 2007;5(5):582-588.
  • Levy DJ, Franklin GO, Rosenthal WS. Gastrointestinal bleeding and amyloidosis. Am J Gastroenterol. 1982;77(6):422–26.
  • Petre S, Shah IA, Gilani N. Review article: gastrointestinal amyloidosis – clinical features, diagnosis and therapy. Alimentary Pharmacology & Therapeutics. 2008;27:1006–1016.
  • Saelices, Lorena, et al. "Uncovering the mechanism of aggregation of human transthyretin." Journal of Biological Chemistry 290.48 (2015): 28932-28943.
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