Pseudomelanosis Duodeni after Intravenous Iron Supplementation in a Patient with Multiple Comorbidities: A Case Report Open Access

Pseudomelanosis duodeni (PD) is a rare benign condition defined by multiple speckled appearances of the duodenal mucosa on endoscopy. PD is associated with several comorbid conditions and medications with a variation in prevalence. More specifically, PD has been associated with chronic kidney disease (CKD), hypertension (HTN), iron deficiency anemia (IDA), and diabetes mellitus (DM), as well as chronic use of oral iron and antihypertensive pharmaceuticals containing a sulfur moiety (i.e., furosemide, hydrochlorothiazide, and hydralazine) [1‒3]. While multiple studies have noted an association between PD and chronic use of oral iron [1, 2, 4], only one study has documented an association with intravenous (IV) iron supplementation [5]. Here, we present the first documented case of PD in a patient with multiple comorbid conditions and on sulfur-moiety-based medications who received a short course of IV iron supplementation. We propose a mechanism for the pathogenesis of PD in this patient.

A 69-year-old female with a past medical history of DM, HTN, CKD stage 4, coronary artery disease, metabolic dysfunction-associated fatty liver disease, gastric varices, hyperlipidemia, and IDA presented to the hospital with approximately 1 week of nausea, non-bloody, non-bilious emesis, and poor oral intake. Given the severity of her symptoms, she presented to two outside hospitals 6 weeks and 2 weeks before her presentation, in which her workup included computed tomography imaging and laboratory work, all of which were negative for acute findings. Both times, she was discharged from the emergency department after receiving fluid resuscitation and antiemetics. Other than mild lethargy and a dry buccal mucosa, the patient’s physical examination was unremarkable. Given her persistent symptoms on presentation to our emergency department, she was admitted for further evaluation and resuscitation with IV fluids. Admission laboratory workup was significant for mild normocytic anemia, mildly low serum bicarbonate, and an estimated glomerular filtration rate of 21 mL/min/1.73m². Notably, her liver function test and repeat computed tomography imaging were unremarkable for any defining cause of her symptoms. Her medications before admission included carvedilol, hydralazine, insulin degludec, insulin lispro, bumetanide, isosorbide mononitrate, pregabalin, atorvastatin, tramadol, pantoprazole, ondansetron, and linaclotide (Table 1).

Given her persistent emesis without a clear etiology, the patient underwent an esophagogastroduodenoscopy (EGD) that showed diffuse, dark speckling throughout the duodenal mucosa (shown in Fig. 1, 2). Biopsies of this region were significant for brown/black pigmentation inside macrophages identified at the apex of the duodenal villi (shown in Fig. 3). Perl Prussian blue and Fontana-Masson staining identified the presence of iron in these black/brown pigmentations, confirming the diagnosis of PD (shown in Fig. 3).

Six months before her presentation, the patient received a once-weekly dose of 200 mg IV iron sucrose for 5 weeks for IDA. She had never received any iron supplementation previously but had been maintained on different medications containing sulfur moiety associated with PD over the past 7 years (Table 2).

Of note, the patient had previously undergone two EGDs in the past, 7 and 5 years (shown in Fig. 4) before her latest EGD (shown in Fig. 1, 2). They were both negative for endoscopic evidence of PD. During those procedures, she was taking antihypertensives containing sulfur moiety associated with PD (Table 2).

While inpatient, her symptoms resolved with antiemetics, and she began tolerating oral intake. Her symptoms were thought to be due to either a resolved viral infection or her underlying CKD. She was discharged home without any follow-up planned for the PD.

PD is primarily seen in adults, with a higher frequency in females [2, 3]. The pigment seen on endoscopy and histology is mainly iron sulfide, which is separate from melanin, lipofuscin, or hemosiderin [3]. While the source of the deposited pigment in PD is unclear, the pathogenesis has been proposed to be related to impaired iron transport due to the coupling of iron with sulfur in iron sulfide, resulting in their accumulation in macrophages of the duodenal lamina propria [2‒4]. The source of sulfur, however, has yet to be elucidated, but most patients identified with PD are on sulfur-moiety-containing medications, which has been hypothesized as the likely source [1, 2, 4]. Surprisingly, histology results to detect iron in the macrophages using Prussian blue or Fontana-Masson stains may vary due to varying content of sulfur and spontaneous auto-oxidation of iron sulfide to iron oxide, which can cause variations in the iron staining properties [3, 4].

PD is a condition that has been associated with chronic DM, HTN, CKD, IDA, oral iron intake, and antihypertensive medications with a sulfur moiety. While our patient had several of these comorbidities, including HTN, CKD, IDA, and DM, and had previously been on sulfur-moiety-containing antihypertensives, she did not develop PD until receiving a short course of IV iron. This supports the hypothesis that the interaction between iron and sulfur may be the driving cause of the condition. However, it has been reported that PD can develop in the absence of oral iron supplementation or the lack of medications containing sulfur moieties [3, 4]. According to Giusto and Jakate [2], among the 17 patients with PD, 88% had HTN, 76% were taking oral iron, 59% had end-stage renal disease, and 35% had DM. However, in the control group, most patients taking oral iron without associated comorbid conditions did not develop PD. This suggests that these comorbid conditions are likely important risk factors in the development of PD.

While the association of oral iron supplementation with sulfur-containing medication use and associated comorbid conditions has been noted in multiple studies to play a role in PD, the role of IV iron supplementation in these same patient populations has yet to be identified in the literature. The only other case of PD development in the setting of IV iron therapy was a patient with a history of IDA, receiving IV iron for chronic melena, who was not on any oral medications linked to PD nor did he have any other PD-related chronic comorbid conditions except IDA [5].

It is essential to recognize and distinguish between PD and its differentials, such as iron pill-associated duodenitis, melanoma, or eosinophilic enteritis. As the duodenum is the site of maximal iron absorption, distinguishing between PD and iron pill-associated duodenitis is particularly noteworthy [6]. Endoscopically, PD is characterized by dark spots in the duodenal mucosa without erosion or ulceration (Fig. 1, 2), while iron pill-associated duodenitis typically presents with mucosal erosions or ulceration. Their pathogenesis further appreciates this distinction. PD is thought to be related to impaired iron transport, resulting in the accumulation of iron-laden macrophages within the lamina propria, while iron pill-associated duodenitis is primarily due to the formation of reactive oxygen species, leading to oxidative stress, lipid peroxidation, apoptosis, or necrosis of the duodenal epithelial cells [3, 4, 7].

The clinical importance and prognosis of PD have yet to be clarified. Nonetheless, it has been defined as a benign condition without any documented cases of complications such as fibrosis, stricture, or duodenal inflammation. Therefore, specific therapy or follow-up imaging has yet to be recommended. Once PD is suspected, a biopsy is essential to rule out other differential diagnoses such as melanoma, iron pill duodenitis, and eosinophilic enteritis. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary (for all online suppl. material, see https://doi.org/10.1159/000545562).

We sincerely thank the residents, fellows, and attending physicians from the Divisions of Internal Medicine, Gastroenterology and Hepatology, and the Department of Pathology at West Virginia University Hospitals, Morgantown, who collaborated in the patient's care.

Ethical approval is not required for this retrospective review of patient data in accordance with the West Virginia Network of Ethics Committee. Written informed consent was obtained from the patients for publication of this case report and any accompanying images.

The authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funder.

O.A. and A.A.A. drafted the case report and helped with the draft revision. J.K., E.M.C., F.M., Z.K., and B.A. helped with draft preparation and draft revision. A.A.S. assisted with histological interpretation and preparation. R.S.K. conceived and designed the manuscript and reviewed the manuscript critically for important intellectual content and grammatical edits. All authors have read and agreed to the published version of the manuscript.

All the data used to support the findings of this case series are available as part of the article and references. Further inquiries can be directed to the corresponding author.