Melanosis Coli

Etiology

Melanosis coli is mainly associated with chronic laxative use, particularly anthraquinone-containing compounds. Senna glycoside (senna) is the common causative laxative. Other anthraquinones used in herbal remedies include rhubarb, cascara, and aloe. As the laxative travels down the intestinal tract, it remains in the inactive form until it reaches the large intestine. Once in the large intestine, the molecules transform into active forms, leading to cell damage and the apoptosis of colonic epithelial cells. As these cells undergo apoptosis, they create a dark pigment called lipofuscin. These apoptotic bodies containing lipofuscin are phagocytosed by macrophages, leading to darkened pigmentation of the colon wall. Melanosis coli can occur within only a few months of chronic laxative use. 

In a case series of 25 patients with inflammatory bowel disease and concurrent melanosis coli found on colonoscopy, only 20% had documented laxative use.[3] The mean duration of inflammatory bowel disease was more than 7 years. These findings raise the possibility of chronic colitis being a potential cause of melanosis coli. Additionally, studies of melanosis coli in pigs have shown an association between high sulfate-containing drinking water and low vitamin E levels with increased oxidative stress.[4][5]

Epidemiology

Wittoesch et al found the incidence of melanosis coli ranged between 0.8% to 1.1% in patients evaluated in Rochester, Minnesota.[6] Approximately 97% of these patients reported chronic constipation, and 96% used chronic laxative therapies; the majority of patients were aged 45 years or older. In a more recent multicenter, retrospective study from China assessing 342,922 colonoscopies performed for screening, surveillance, and diagnostic purposes, the incidence of melanosis coli was 1.8%, with males aged 60 or older at increased risk.[1] Melanosis coli has been reported in younger individuals, particularly in patients with chronic laxative use. Moreover, melanosis coli is equally common in males and females.[1]

Pathophysiology

Anthraquinones in laxatives have a direct toxic effect on the epithelial cells of the colon. When these laxative molecules change into their active form in the large intestine, they can cause cell damage to the lining of the large intestine, leading to cell death. As the cells undergo apoptosis, they create a dark pigment called lipofuscin. Examination with electron microscopy demonstrates intraepithelial macrophages ingest these apoptotic bodies and migrate to the lamina propria, where intracellular degradation of apoptotic cells result in lipofuscin formation.[7] The dark pigment of lipofuscin stains the macrophages, leading to a black-brown appearance visible on colonoscopy. Melanosis coli is more common in the proximal bowel and much rarer in the distal colon (see Image. Proximal Colon With Melanosis Coli). This is probably due to the difference in the macrophage distribution in the colonic wall. Once laxative use is halted, the dark pigmentation may resolve.[8]

Li et al used expression microarray analyses to show significant downregulation of cytochrome P450-associated genes (CYP3A4, CYP3A7, UGT2B11, and UGT2B15) in melanosis coli, though further research is needed to elucidate clinical significance and pathogenesis.[9]

Histopathology

Special staining and immunohistochemical analyses of tissue with melanosis coli confirm that the pigmented granules ingested within macrophages are consistent with lipofuscin but not melanin, bile pigment, or hemosiderin.[9] Periodic acid–Schiff (PAS) stain helps to identify the presence of lipofuscin under the microscope. Compared to normal colon tissue, tissue with melanosis coli has increased apoptotic bodies within macrophages and the superficial lamina propria of the colonic epithelium.[7][9]

Toxicokinetics

Anthraquinone-based laxatives work in the following ways:

1. They stimulate the active transport of chloride into the gut, which in turn causes an osmotic gradient and pulls water into the gut lumen.
2. They inhibit Na-K adenosine triphosphate (ATP)ase on the enterocytes, which further inhibits the reabsorption of water, sodium, and potassium, ultimately excreting it into the feces.
3. They stimulate local prostaglandins, which stimulate peristalsis and decrease transit time through the bowel.[10][11]

The adverse effects of senna and other stimulant laxatives include nausea, vomiting, diarrhea, and abdominal cramps. Subsequent hypovolemia can lead to dizziness, palpitations, and syncope.

History and Physical

Typically, melanosis coli causes no symptoms and is incidentally found during a colonoscopy performed for other indications. Findings of melanosis coli should prompt an assessment for a history of constipation, chronic use of anthraquinone-based laxatives, and a history of inflammatory bowel disease or colitis. Clinicians should also review any nonprescription, over-the-counter medications, including herbal supplements and teas, to help capture other sources of stimulant-laxative use. 

Evaluation

Melanosis coli is evaluated through colonoscopy and histology, not laboratory studies or other imaging modalities. An endoscopic exam shows a dark-brown discoloration of the colonic mucosa. Characteristically, melanosis coli is most prominent in the proximal colon but can involve other colonic segments.[12][13] Staining of biopsied tissue further demonstrates the presence of lipofuscin particles. If clinical concern for true melanin deposition from diseases, eg, Peutz-Jegher Syndrome, is present, biopsies should be taken for confirmation. 

Treatment / Management

Due to the common finding of melanosis coli in anthraquinone-based laxative use, the primary treatment for melanosis coli is the discontinuation of anthraquinone-containing compounds. Resolution of the condition may take several months to a year.[8][13][14][15][16] Alternative constipation therapies that should be considered in patients with melanosis coli that do not cause mucosal hyperpigmentation include osmotic laxatives (eg, polyethylene glycol), bisacodyl, fiber supplements, and secretagogues.(B3)

Differential Diagnosis

Other etiologies for mucosal hyperpigmentation should be considered within the differential of melanosis coli. True melanin deposition in the skin and mucosa can be seen with Peutz-Jeghers Syndrome, an autosomal dominant disorder that leads to numerous hamartomatous polyps in the bowel. Patients with this disease are at a 15-fold increase in developing colon cancer. Panenteric melanosis may also be a presenting finding of metastatic melanoma with scattered macular, black-pigmented spots throughout the upper and lower gastrointestinal tract seen on endoscopy and colonoscopy.[17] Biopsies of these lesions confirm melanin deposition. 

Pseudomelanosis with hemosiderin deposition has been reported infrequently in the upper gastrointestinal tract.[18][19][20] This finding is more common in patients with underlying hypertension, chronic renal failure, diabetes mellitus, history of upper gastrointestinal bleeding, and oral iron use. Other medications associated with pseudomelanosis include hydralazine, thiazide diuretics, furosemide, and beta-blockers.

Toxicity and Adverse Effect Management

In cases of anthraquinone overdose, treatment is symptomatic and supportive to correct significant fluid and electrolyte abnormalities. In patients where the diagnosis is unclear or symptoms significant, consultation with a poison center or toxicologist is advised.

Prognosis

The prognosis is good in patients with melanosis coli, as the colonic discoloration will typically resolve after discontinuing the causative laxative. However, this can take months to up to 1 year. Rebound constipation can occur with laxative cessation.[21][22]

Complications

Some research suggests an increased risk of melanosis coli and colon polyps. However, consensus or evidence demonstrating an increased risk of colon cancer has not been documented. The association between melanosis and increased adenomatous polyps is thought to be due to higher mucosal detection during colonoscopy from the color contrast, as hyperpigmentation interestingly spares the adenomatous polyps and thus makes polyp tissue stand out in a darker background (see Image. Colon Polyp).[23]

Increased stimulant laxative use and abuse can cause electrolyte derangements due to the rapid transit through the bowel and decreased absorption of nutrition and water reabsorption. In extreme cases, particularly with potassium imbalance and acute renal injury, the consequences may be fatal.