Brown bowel syndrome: a systematic review

Introduction

Brown bowel syndrome (BBS), also known as intestinal lipofuscinosis or intestinal ceroidosis, is a rare disorder classically characterized by a brown discoloration of the intestinal wall. The macroscopic brown appearance results from a pathologic accumulation of lipofuscin in the cytoplasm of smooth muscle cells of the muscularis propria and muscularis mucosa of the gastrointestinal tract. Lipofuscin is a yellow-brown lipid-containing granule formed as a waste product of oxidative metabolism, which accumulates in the lysosome of most cells with senescence. BBS was first reported by Pappenheimer and Victor, describing “ceroid” pigmentation in the intestinal musculature of 4 autopsy cases [1]. Whilst the exact pathogenesis of BBS remains unconfirmed, malnutrition from malabsorptive states, such as celiac disease, pancreatitis and post-gastrointestinal surgery (gastric bypass, bowel resection), has been thought to play a role [2-4]. It has been postulated that vitamin E deficiency is significant in contributing to lipofuscin accumulation as a result of oxidative stress to mitochondrial membranes in the relative absence of antioxidant protection. BBS most commonly manifests with non-specific symptoms, including diarrhea, weight loss, nausea and vomiting. Early diagnosis and commencement of medical management, including vitamin E supplementation, has been shown to be beneficial [5-7]. However, many cases have identified associated complications of intestinal dysmotility, such as small bowel dilatation, volvulus, intussusception and pseudo-obstruction, which often result in emergency surgical intervention [8,9].

To date, fewer than 70 cases have been formally documented, with no recent review of the disease. There is no current consensus on the epidemiology of this condition, based on existing literature databases, and a lack of general understanding concerning patient profile and outcomes. The objective of this systematic review was to outline the clinical profile of BBS, as well as investigations, management and outcomes of this rare disorder.

Methods

A combined automated and manual systematic database search was conducted using the electronic search engines PubMed, Embase, Cochrane, Web of Science and Google Scholar to identify relevant studies. The search used the keywords “brown bowel syndrome”, “intestinal lipofuscinosis”, and “intestinal ceroidosis” and was last conducted on 16 February, 2025. Reference lists of included studies were manually screened to identify additional relevant articles.

Inclusion criteria consisted of journal articles reporting on human participants (including children, adolescents, and adults) with a histopathologically confirmed diagnosis of BBS. The eligible study designs included randomized studies, case series, case reports, and conference abstracts. Studies were excluded if they were narrative or systematic reviews, animal studies, or histopathological reports without a corresponding case report.

Studies were independently screened by 2 reviewers (RC, JD) at both the title/abstract and full-text levels. They worked independently, and any discrepancies were resolved through discussion and, if necessary, by consulting a third reviewer (CB). No automation tools were used in the selection process.

Data extraction was performed by 2 independent reviewers using a predefined template. Extracted data included:

Additional extracted data included the presence of gastrointestinal comorbidities, such as ulcers (duodenal, pyloric), liver cirrhosis, diverticulosis, jejunal atresia, hepatomegaly/fatty liver, Crohn’s disease, gastric adenocarcinoma, Whipple’s disease, chronic jejunitis, unspecified malabsorption syndrome and exocrine pancreatic insufficiency. If data were missing or unclear, missing data were managed by assumption-based imputations where applicable, or the study was excluded from specific analyses.

Given that the included studies were primarily case reports and case series, the risk of bias was assessed based on key methodological considerations relevant to these study types. These included the clarity of patient demographics, the adequacy of case definitions, the completeness of clinical details, and the extent of follow-up information provided. Each study was evaluated by 2 independent reviewers, who worked separately to assess potential biases. Any discrepancies in judgment were resolved through discussion. No automation tools were used in the bias assessment process.

Results

Patient characteristics

There were 64 patients with a confirmed diagnosis of BBS. The mean age was 54.1±18.9 years and patients were predominantly male (64.1%). Approximately one-third (28.4%) of the patients had a history of gastrointestinal disease, including gastrointestinal ulcers, Crohn’s disease, Whipple’s disease or unspecified malabsorption syndrome. Twenty-seven patients (40.3%) had previous abdominal surgery and 11 (16.4%) had a diagnosis of celiac disease. A history of bowel obstruction or pseudo-obstruction was noted in 9 (13.4%) patients (Table 1).

Table 1 Summary of clinical variables for brown bowel syndrome

Clinical presentation

Most symptoms were non-specific, with the most prevalent including diarrhea (51.6%), abdominal pain (37.3%), malnutrition (48.5%) and vomiting (21.9%). Less common symptoms included constipation (20.9%), peripheral edema (16.4%) and abdominal distension (9.0%, Table 1). There were no differences in the symptoms and signs between those with or without celiac disease (P>0.05, Table 2).

Table 2 Comparative analysis of clinical variables and outcomes patients with brown bowel syndrome, with or without celiac disease (*P<0.05)

On presentation, approximately half the cohort (55.2%) had some form of imaging for investigation. The most common imaging modality was X-ray (28.4%), followed by computed tomography (20.9%) then ultrasound (4.5%). However, almost half the cohort (44.8%) did not receive any radiological investigation, and close to a third of patients (31.3%) received a colonoscopy as part of the diagnostic evaluation (Table 1).

Approximately one-third of the patients (31.3%) demonstrated low serum levels of vitamin E and 10 (14.9%) were found to have low serum levels of vitamin D.

Discussion

First described in 1861 by German pathologist Doctor Ernst Wagner, the findings of BBS were reported as a brown discoloration of human intestinal wall [8]. In 1946, Pappenheimer and Victor subsequently described the accumulation of “ceroid” in the smooth muscle cells of the small intestine and postulated the etiologic significance of vitamin E deficiency in BBS [1]. The pathologists observed an accumulation of a similar brown pigment in cirrhotic livers [11] and uterus [12] of rats maintained on a diet low in protein, fat and vitamin E. A century later, Toffler used the term “brown bowel syndrome” to describe a golden yellow pigment found within the muscle cells of the jejunal muscularis layer [9] (Fig. 1A [3]).

Figure 1 (A) Colonic specimen with clear transition point between normal bowel mucosa and diffuse dark brown pigmentation distally in a patient with brown bowel syndrome. (B) 10× magnification of submucosa and mucosa demonstrating brown pigmentation, scale bar = 1000 μm. (C) 40× magnification demonstrating pigmented macrophages on hematoxylin and eosin staining, scale bar = 250μm. Courtesy of Badiani [1], 2021, used with permission

The incidence of BBS would appear to be extremely low, without any formal reporting to date. This could be a result of underdiagnosis, given that its largely non-specific symptoms are likely to contribute to a significant “pre-clinical” phase. Microscopically, BBS is characterized by the deposition of golden-brown granules, predominantly within the cytoplasm of smooth muscle cells of the muscularis propria, and occasionally in the muscularis mucosae and surrounding blood vessels, giving the intestines the typical gross appearance of “brown bowel” (Fig. 1B and C). Ceroid and lipofuscin are auto-fluorescent granules produced in human tissue as a result of oxidative stress [13]. The term “ceroid” is typically used to describe granules generated under pathological conditions such as malnutrition, hypoxia or infection [14], whereas lipofuscin refers to granules formed in aging post-mitotic cells as a result of the incomplete hydrolysis of oxidized lipids and proteins by lysosomal enzymes [15]. These terms are often used interchangeably in the literature to describe the histopathological findings of BBS, probably because of the indeterminate distinction on tissue sections. Many case reports have documented that these granules stain strongly positive for periodic-acid Schiff (PAS) stain [5,9,16]. Histologically, this distinguishes it from melanin, as it is only moderately positive for Fontana-Masson stain [4,5,16], and from iron [17-19], consistent with lipofuscin-like pigment.

Melanosis coli is a differential diagnosis to consider on endoscopic observation of bowel pigmentation. This is a reversible condition characterized by diffuse deposition of brown-black lipofuscin pigment in macrophages of the mucosal lamina propria and widely thought to be linked with chronic anthraquinone laxative use [20]. Although a well-recognized differential for BBS, laxative abuse was not reported in any of these patients.

In vitamin E deficiency, the pathogenesis of lipofuscin deposition in BBS is thought to be attributed to mitochondrial damage from excess oxidative stress. Vitamin E, which is lipid-soluble, has cellular anti-oxidant properties as a result of its ability to react with peroxyl radicals faster than the polyunsaturated fatty acids of the phospholipid membrane, thus exerting a protective effect on the mitochondrial membrane [17]. The phospholipid bilayer of mitochondrial membranes is exposed to oxidative damage by free radicals [18], leading to lipofuscin formation as a result of lysosomal degradation of the dysfunctional mitochondria [19]. The literature has reported numerous case studies of BBS with malabsorptive disorders, including celiac disease [21-29], following gastrointestinal surgery (bariatric, total gastrectomy), Crohn’s, chronic idiopathic malabsorption [4,5,7,25,30-34] and pancreatitis [23,25,30,35]. In our study 40.3% of patients reported previous abdominal surgery, but more importantly, 16.4% suffered from celiac disease and 28.4% of patients had associated gastrointestinal pathologies, including gastrointestinal ulcers, Crohn’s disease, Whipple’s disease and diverticulosis. The correlation between BBS and intestinal dysmotility and subsequent obstruction or pseudo-obstruction has also been reported in several cases [3,5,16,25]. Our experience showed that a history of obstruction and pseudo-obstruction was indeed relevant, although it did not appear to be a common clinical presentation amongst the combined cohort (n=9, 13.4%, Table 1). One possible explanation is that it may have been underreported. Indeed, several articles included in our study still mentioned symptoms suggestive of either obstruction or pseudo-obstruction on presentation but did not formally record it. We believe that progressive disruption of muscle fiber architecture by lipofuscin accumulation in the myofibrils of the muscularis propria may ultimately lead to gut dysmotility and non-mechanical obstruction if left untreated [36].

BBS presents with a mixture of non-specific symptoms and signs, which renders its clinical diagnosis difficult in the absence of high clinical suspicion. The most common presenting symptoms were diarrhea, abdominal pain and malnutrition (Table 1). Abdominal pain was usually described as diffuse, ranging from colicky, to crampy or constant in nature. Only a small proportion of patients (20.9%) presented with constipation, which is surprising. We suspect this low incidence may be partially explained by a prolonged “pre-clinical” phase of this disease, followed by rapid transition to acute constipation and subsequent bowel obstruction, resulting in emergency surgery, often with a poor outcome.

The diagnosis of BBS relies upon transmural biopsy of the intestinal wall to capture the muscularis propria. Our study found that a significantly higher proportion of patients with vitamin E deficiency received full thickness intestinal biopsies, compared to patients without vitamin E deficiency (57.1% vs. 21.7%, P=0.010). One plausible explanation would be the association between lower serum vitamin E levels and advanced BBS, which in turn would be more likely to require surgical resection of the bowel. The majority (73.1%) of our cases identified lipofuscin-like granules accumulating in the muscularis propria and a smaller proportion (16.4%) distinctive accumulation in the muscularis mucosa. However, transmural biopsies are not commonly performed, compounding the challenges of diagnosis with the aforementioned factors.

Radiological evaluation with X-ray or computed tomography may be beneficial in identifying associated signs of obstruction or pseudo-obstruction. However, it is unlikely to contribute to the diagnosis of BBS. Conversely, colonoscopy may be a more useful diagnostic investigation tool, as BBS will often manifest with gross intestinal wall discoloration. This said, mucosal changes might be too subtle to be recognized endoscopically. Only a third of patients underwent colonoscopies to investigate their presenting symptoms, most probably because of variations in the severity of their clinical findings. Indeed, up to one half of patients presented with acute signs of bowel obstruction, prompting exploratory laparotomy, where the diagnosis of BBS was ultimately made based on histopathological examination of the resected bowel, and therefore bypassing preoperative endoscopic investigation. Additionally, we identified that every case report that described a colonoscopy procedure was dated after 1979, suggesting that the low rate of colonoscopic investigation (31.3%) needs to be interpreted in the context of more limited availability of this diagnostic tool before 1979.

Several malabsorptive states can lead to a deficiency of fat-soluble vitamins A, D, E and K, including gastrointestinal causes, such as celiac disease [37-39], chronic pancreatitis [40] and Crohn’s disease [41, 42], as well as post-surgical causes, such as gastrectomy [43, 44]. The impact of fat-soluble vitamin E deficiency has been reported widely, ranging from neurological manifestations, such as peripheral neuropathy or cerebellar dysfunction [45-48], to altered immune function in humans [49]. We demonstrated that vitamin E deficiency was observed in higher proportions in celiac patients compared to non-celiac with BBS (54.5% vs. 26.8%, P=0.086) (Table 2). With a trend towards significance, this may be attributed to the relatively small sample size, but also the increased recognition of asymptomatic celiac disease at an earlier stage throughout the last few decades. Indeed, the advent and widespread use of serological testing for celiac disease has resulted in a decreased percentage of patients presenting with gastrointestinal manifestations from underlying deficiencies and a higher proportion diagnosed with targeted screening [50]. We further demonstrated a significantly higher proportion of vitamin D deficiency in patients who were vitamin E deficient, compared with those who were vitamin E replete (33.3% vs. 6.5%, P=0.008) (Table 3). This may be accounted for by the malabsorptive or malnutritional state resulting in poor absorption of fat-soluble vitamins collectively. Furthermore, the impact of a chronic malabsorptive state showed celiac patients having significantly higher proportions of hypoalbuminemia compared to non-celiac BBS patients (45.5% vs. 16.1%, P=0.043) (Table 2).

Table 3 Comparative analysis of clinical variables and outcomes in patients with brown bowel syndrome, with or without vitamin E deficiency (*P<0.05)

The management of BBS depends on the severity of symptoms and associated complications on presentation. This, in turn, depends on the time of diagnosis. We reported that 70% of patients required laparotomy during their presentation, and that most of the cases published after year 2000 were for emergency indications, such as acute bowel obstruction, volvulus or pneumoperitoneum. In contrast, cases published before 2000 reported a significantly higher proportion of diagnostic exploratory laparotomies performed for non-urgent indications, mainly persistent abdominal pain and unexplained weight loss. This discrepancy is best explained by the increased availability of biochemical and advanced radiological investigation modalities in the 21^st century, resulting in a reduction of unnecessary elective diagnostic laparotomy. Approximately one-fifth of our patients underwent a sub-total or total colectomy, including either end ileostomy, ileo-sigmoid or ileo-rectal anastomosis, with the extent of resection guided by the viability of the bowel at the time of diagnosis. The high proportion of emergency surgical intervention is probably attributed to delayed presentations, often resulting in acute bowel obstruction requiring imminent laparotomy and bowel resection [7,22,27,51,52].

In the case of incidental or early diagnosis of BBS, conservative medical management of the underlying cause of malabsorption, as well as vitamin E supplementation where necessary, may be sufficient to reverse symptoms [31,35,52,53]. In a recent case report of BBS, high-dose replacement of vitamin E at 268 mg twice daily resulted in significant clinical improvement [54]. Vitamin E supplementation has also been shown to reduce lipofuscin accumulation in fibroblasts derived from patients with neuromuscular degenerative disease [55], and murine brains and hearts [56,57]. Less than a third of our cohort were given vitamin E replacement therapy. This is probably an underestimate, as many case reports failed to indicate any specific medical management. Despite this, we still identified a significantly higher rate of vitamin E deficient patients receiving supplements as compared to the vitamin E replete group (47.6% vs. 19.6%, P=0.038). A plausible reason for the inconsistent administration of vitamin E therapy could simply be a failure to measure this critical biochemical parameter, due to incomplete understanding of the pathogenetic role of vitamin E in BBS. Our study indicated a wide variation in vitamin E dosage, ranging from 6 mg daily [22] to 750 mg daily [28], and no clear documentation of therapeutic duration. The lack of consensus on the therapeutic dose and duration outlines the paucity of clinical evidence supporting the benefit of vitamin E supplementation in BBS, mainly because of its extremely low incidence.

Neuronal ceroid lipofuscinosis, an inherited neurodegenerative lysosomal storage disorder, is another significant disease of lipofuscin accumulation. Emerging therapeutic studies in this area have targeted upstream disease mechanisms, including enzyme replacement therapy, gene therapy and stem cell therapy. In cellular models of neuronal ceroid lipofuscinosis disease, the potent antioxidant and nucleophilic agents phosphocysteamine and N-acetylcysteine showed activity in reducing ceroid accumulation [58]. A small follow-up clinical study demonstrated some reduction in ceroid deposits [59], although the clinical significance of this is unclear and it is unlikely to be applicable to BBS patients, as the therapy targets a different upstream mechanism of lipofuscinosis. Recently, research into Stargardt disease (inherited retinal disease of lipofuscin accumulation) and age-related macular degeneration has discovered a promising ability of the molecule soraprazan (renamed Remofuscin) in lipofuscin from retinal pigment epithelium [60-62]. In vitro and in vivo studies in human and murine retinal pigment epithelium cells respectively have shown a reduction of lipofuscin accumulation after treatment with Remofuscin, possibly secondary to generation of reactive oxygen species, specifically superoxide [63]. In murine models of Stargardt disease, supplementation of omega-3 fatty acids reduced lipofuscin accumulation [64].

Autophagy is a lysosome-dependent cellular mechanism for degrading unnecessary or dysfunctional components. Some studies have observed reduced levels of autophagy in senescent cells, and therefore suggested a role for autophagy enhancement in reducing lipofuscin accumulation. A number of agents have been shown to reduce lipofuscin accumulation, including anti-helminthic flubendazole [65] and zinc [66] in human retinal pigment epithelium, rapamycin in animal cardiomyocytes [67] and murine hepatocytes [68]. Although these results have been focused on extraintestinal cells, they present potential options for further therapeutic research in BBS. Ultimately, however, applying a traditional drug discovery approach (disease mechanism to target to therapy) to BBS is challenging, because of our limited understanding of its pathogenesis.

We identified a higher mortality rate in celiac patients with BBS, compared with non-celiac (36.4% vs. 14.3%, P=0.099), although the difference was not statistically significant (Table 2). This corroborates previous reports showing that patients with celiac disease have higher all-cause mortality rates [69,70]. Surprisingly, there was a trend towards a higher mortality rate in non-vitamin E deficient patients compared to vitamin E deficient patients (23.90% vs. 4.8%, P=0.086, Table 3). One possible explanation is that, although vitamin E deficiency is a likely precursor for the development of BBS, other comorbidity factors may have played a more significant role with regard to the poorer outcomes. Unfortunately, those extended data were lacking.

One major limitation of this study is the incompleteness and inconsistency of the data presented across the case reports, probably because of the rarity of the disease. Given the very low number of cases of BBS documented in the literature, our inclusion criteria encompassed case reports dating back as early as 1946, as well as abstracts, adding heterogeneity of management and diagnostic criteria, as well as details of patient presentation, biochemical investigations and histopathology findings. The evolving availability of such investigations, imaging modalities and knowledge about this disease over the last 75 years partially accounts for the varying level of clinical details included in those case reports. Recent studies generally had broader information with respect to biochemical, endoscopic and radiological investigations. The wide historical span of cases included in our study also captured some of the changing diagnostic and management practices. This evolving availability of technology and advanced investigation modalities poses potential confounding variables for results, including the proportions of patients undergoing colonoscopy or laparotomy, respectively. Additionally, the extremely low incidence of this disease and the paucity of evidence concerning confirmed risk factors for BBS required us to make an informed decision in selecting which variables might be more relevant when comparing patient groups. We chose vitamin E deficiency, as this was understood to be a significant contributor to the pathogenesis of BBS, and celiac disease status, as this was indicated to be the primary diagnosis in several BBS cases [51], based on our literature search. Finally, another limitation is the absence of a definitive cutoff for vitamin E levels that could potentially help with the future development of diagnostic criteria for BBS, and the lack of any specific biochemical diagnostic markers to date. This is a clear limitation, both for our study, and also for the standardized diagnosis of BBS. This said, we have created a clinical algorithm for the diagnosis and management of BBS that may help our readers: it is summarized in Fig. 2.

Figure 2 Clinical algorithm for diagnosis of brown bowel syndrome (BBS)

Concluding remarks

BBS is a rare phenomenon characterized by pathological accumulation of lipofuscin in the muscularis layer of the intestinal wall. BBS is not a primary condition; it is probably a complication resulting from chronic vitamin E deficiency, usually in the context of malnutrition or malabsorption. Currently there are no defined diagnostic parameters for BBS, including vitamin E cutoff levels. This probably contributes to delayed presentations and the development of associated complications, including gut dysmotility and pseudo-obstruction, requiring acute surgical intervention. Management should focus on treating the underlying cause of malnutrition or malabsorption where possible, but replacement of deficient fat-soluble vitamins should be commenced in a timely manner. Our study demonstrated that there was no significant difference in the incidence of vitamin E deficiency and celiac disease in patients with BBS. Further investigations are warranted into the risk factors for BBS, clearer diagnostic parameters and the effectiveness of vitamin E replacement therapy in reversing histopathological BBS.