With the improvement of people's living standards, the incidence of melanosis coli has increased. There are few domestic reports on this disease. The etiology and pathogenesis of melanosis coli remain unclear. Patients with this condition may experience electrolyte imbalances, and the incidence of colorectal cancer and adenomatous polyps is higher among them. A small number of patients may also develop pseudo-intestinal stenosis, leading to unnecessary laparotomy.

bubble_chart Etiology

The exact cause of melanosis coli remains unclear, but its incidence has been increasing in recent years. This may be related to improved living standards, increased intake of fats and proteins, reduced fiber consumption, a rise in constipation cases, as well as conditions such as rectocele, rectal intussusception, and slowed colonic transit leading to defecation difficulties, along with widespread misuse of laxatives. Anthraquinone laxatives, in particular, are considered the primary cause of melanosis coli. Among 54 cases of colorectal melanosis examined at Shanghai Changhai Hospital, 44 had a history of laxative use. Anthraquinone laxatives can enhance macrophage activity and chemotaxis while damaging intestinal mucosal epithelial cells, especially those in the crypts. This damage leads to epithelial cell degeneration, nuclear pyknosis, and eventual necrosis and shedding. Some of these necrotic epithelial cells are excreted in feces, while others—degenerated colon epithelial cells—form apoptotic bodies that embed in the lamina propria. These are phagocytized by macrophages, forming lipofuscin and contributing to melanosis. However, lipofuscin alone does not fully explain the deep brown pigmentation seen in some cases. It is hypothesized that the dark brown color of many anthraquinone drugs and their metabolites may adhere to damaged epithelial cell structures, intensifying pigmentation when phagocytized by macrophages. Nevertheless, some patients develop colorectal melanosis without a history of constipation or laxative use. For example, Badiali reported that among 84 cases of rectal melanosis, a quarter had no history of laxative intake. Melanosis has also been observed after colon-bladder procedures, suggesting a possible role of urine exposure. Among Changhai Hospital’s 54 cases, five occurred in patients who had undergone radical large intestine cancer surgery and received chemotherapy for 6–20 months, two of whom had no constipation or laxative history. Thus, while long-term anthraquinone laxative use is a major factor, other drugs and substances affecting the intestinal mucosa may also contribute. For instance, one patient who underwent a Miles procedure without constipation developed melanosis in a 15 cm segment of colon mucosa 5 cm proximal to the stoma. This may have been caused by chemotherapeutic agents or other pigmentation-inducing substances in stool accumulating near the stoma. Chronic use of herbal laxatives like Senna Leaf and Rhubarb Rhizoma has also been linked to the disease, primarily due to sennosides and rhubarb acid. Some theories suggest that food residues stagnate, with protein breakdown products converting into pigment granules under enzymatic action, depositing in the mucosa. Alternatively, pigment granules synthesized by gut bacteria may be absorbed. Generally, the disease is thought to arise from long-term exposure to anthraquinone laxatives or other pigmentation-inducing substances, leading to mucosal epithelial damage. Macrophages phagocytize necrotic organelles (e.g., mitochondria, endoplasmic reticulum, and membrane fragments) as well as residual laxatives. These materials fuse with primary lysosomes to form secondary lysosomes, but lysosomal overload disrupts intracellular catabolism, resulting in excessive lipofuscin accumulation and eventual melanosis. In severe cases, lipofuscin-laden macrophages rupture, dispersing pigment granules into the connective tissue stroma, visible under electron microscopy. Histochemical analysis shows elevated acid phosphatase in areas with abundant pigment-containing macrophages in the lamina propria, but no significant activity of other specific enzymes or β-glucuronidase. The intensity of mucosal pigmentation varies depending on the number of pigment-laden macrophages and extracellular lipofuscin granules in the lamina propria.Macrophages containing abundant lipofuscin granules exhibit deep pigmentation on the mucous membrane, with numerous intracellular and extracellular lipofuscin particles. Antagonism results in lighter pigmentation of the mucous membrane. This pigment can be detected using Nile blue sulfate and Schmorl's methods. Under fluorescence microscopy, this pigment emits red fluorescence.

Macroscopic view: The mucosa exhibits varying degrees of pigmentation, ranging from mild cases resembling leopard skin to severe cases appearing dark brown, with unclear vascular patterns. Pigmentation may occur in a specific segment of the large intestine or throughout the entire colon. The mucosa of the small intestine above the ileocecal valve and the skin below the dentate line of the anal canal show no pigmentation. Microscopically, a large number of densely or sparsely distributed macrophages are observed in the lamina propria of the mucosa. The cell volume is enlarged, and in severe cases, the cytoplasm is filled with pigment granules, obscuring the nuclei. Pigment granules can also be seen outside the macrophages, a phenomenon more common in cases of grade III mucosal pigmentation. In some patients, the pigment granules within the macrophages are scattered, a pattern often seen in colorectal melanosis patients with grade I mucosal pigmentation in the large intestine. In severe cases of colorectal melanosis, macrophages containing pigment granules and free pigment granules can also be observed in the mesenteric lymph nodes. These pigment granules test positive for melanin staining (Fontana silver stain) but negative for iron reaction. Electron microscopy reveals a significant increase in both the number and size of macrophages in the lamina propria. The cytoplasm contains abundant lipofuscin, a type of secondary lysosome. Large amounts of lipofuscin deposits are also found in the surrounding connective tissue, likely due to macrophage disintegration. Near the unmyelinated nerve fibers of the intestinal nerve plexus, macrophages containing lipofuscin granules or scattered pigment granules can also be observed.

Patients with melanosis coli often experience abdominal distension and fullness, constipation, and difficulty in defecation, while a few may have abdominal dull pain and poor appetite. In the past, it was believed that melanosis affected the intestinal nerve plexus, leading to degenerative changes in the submucosal nerve plexus. It was also considered to be related to electrolyte disturbances. Under electron microscopy, a large amount of lipofuscin granules or macrophage fragments containing pigment granules were observed deposited around the unmyelinated nerve fibers of the intestinal nerve plexus. Therefore, it is suggested that symptoms such as abdominal pain, abdominal distension, and fullness in melanosis patients may result from mechanical irritation caused by the deposition of lipofuscin, as well as chemical substances released during the digestion and disintegration of lysosomal enzymes, which stimulate the intestinal nerve plexus. From the perspective of cellular ultrastructure, melanosis can be regarded as a lysosomal disease, but unlike congenital or primary lysosomal diseases, it is classified as a secondary lysosomal disorder. If the abuse of anthraquinone drugs or other factors causing melanosis is stopped, the digestion and decomposition of large amounts of lipofuscin by lysosomes may gradually reduce or even eliminate submucosal pigmentation. Surgery should not be performed blindly or hastily.

bubble_chart Auxiliary Examination

Routine blood tests are generally normal. A minority of patients primarily present with manifestations such as hyponatremia, hypokalemia, and hypocalcemia.

Among the 10 cases of melanosis coli reported by Kargel, all had hypokalemia, hyponatremia, and hypocalcemia. Additionally, two middle-aged patients with abdominal distension and fullness moving qi underwent barium double-contrast imaging, which revealed stenosis of the transverse colon. Partial colectomy was performed, and intraoperatively, only swelling of the intestinal wall at the stenotic site was observed, with no neoplastic changes. However, the melanosis coli was classified as grade III. Balazs reported 45 cases of melanosis coli, among which 14 had annular colonic stenosis. The reason for the lower levels of potassium, sodium, and calcium in patients with colorectal melanosis is believed to be related to the action of large amounts of anthraquinone laxatives on the intestinal membrane, which increases mucus secretion from the intestinal glands, leading to the loss of electrolytes. The loss of potassium and water further stimulates increased aldosterone secretion, resulting in hyperaldosteronemia. Excessive potassium loss can lead to metabolic alkalosis. Although blood potassium levels decrease and the blood becomes more concentrated, these mild impairments are reversible. Among 54 patients with colorectal melanosis at Changhai Hospital, 14 voluntarily underwent blood tests for electrolyte analysis. Only 5 cases showed low potassium or calcium levels, with 3 cases exhibiting grade I hypokalemia ⁺

Endoscopic examination revealed varying degrees of pigmentation on the large intestine membrane. The pigmentation is classified into three grades based on its depth: - **Grade I**: Light black-brown, resembling leopard skin, with asymmetrical milky-white spots visible on the lymphatic follicles. The vascular pattern of the membrane is faintly discernible. The lesions often affect the rectum or cecum, or a segment of the colonic membrane. The extent of involvement is usually limited, and the boundary between pigmented and non-pigmented areas is often indistinct. - **Grade II**: Dark black-brown, with linear milky-white membrane interspersed within the dark pigmentation. This is more common in the left colon or a segment of the colonic membrane. The vascular pattern is usually difficult to visualize. The boundary between pigmented and non-pigmented areas is relatively clear. - **Grade III**: Deep black-brown, with fine milky-white linear or spotted membrane interspersed within the dark pigmentation. The vascular pattern is invisible. This presentation is often seen in cases involving the entire colon. The ileum membrane is typically unaffected, and the ileocecal valve membrane is usually spared. The anal skin below the dentate line of the rectum shows no pigmentation. It is generally believed that pigmentation in colorectal melanosis is more common in the cecum. However, among the 54 cases detected at Changhai Hospital, pigmentation was more frequent in the left colon than in the right colon, with 33 and 21 cases, respectively. This discrepancy may be related to different causative factors of melanosis.

bubble_chart Diagnosis

The diagnosis is primarily based on medical history and endoscopic examination, which reveal varying degrees of pigmentation in the intestinal mucosa. Additionally, pathological examination of mucosal biopsies obtained during endoscopy shows a large number of densely or diffusely distributed macrophages containing pigment granules in the cytoplasm within the lamina propria, confirming the diagnosis.

bubble_chart Treatment Measures

Colorectal melanosis is a reversible disease. To address the causes of constipation and difficulty in defecation, measures such as increasing the intake of fiber-rich foods like vegetables and fruits, drinking more water, and exercising more can help reduce constipation or difficulty in defecation. For conditions that cause defecation difficulties, such as rectocele, rectal intussusception, and puborectalis syndrome, corresponding treatments should be taken, such as rectocele repair, rectal intussusception fixation, or partial resection of the puborectalis muscle, to restore normal bowel movements. Preventing the excessive misuse of laxatives is an effective method for treating melanosis. There have been reports of patients with colorectal melanosis caused by long-term laxative use due to rectocele and rectal intussusception. After undergoing rectocele repair and intussusception fixation, their bowel movements returned to normal, and upon re-examination one year after stopping laxatives, the melanosis disappeared. However, for patients with colorectal melanosis who have not used laxatives, treatment methods still need to be further explored based on the combination of disease history, dietary habits, lifestyle, and other characteristics.

bubble_chart Complications

Relationship with tumors: Patients with melanosis of the colon and rectum have a higher incidence of large intestine cancer. Morgenstern examined 511 cases of large intestine cancer resection specimens and found that 5.9% were accompanied by melanosis. Some reports indicate that among 4 cases of melanosis patients, 3 had intestinal tumors and 1 had rectal cancer. Among 54 cases of colon and rectal melanosis patients at Changhai Hospital, 19 had large intestine polyps, of which 11 were adenomas, 8 were hyperplastic or inflammatory polyps, and 2 had large intestine cancer, including 1 case of rectal cancer with local recurrence one and a half years after surgery. The detection rate of large intestine neoplasms in patients with colon and rectal melanosis is higher than in those without melanosis. Additionally, the mucous membranes of cancerous tumors and adenomatous polyps show no pigmentation. If an unpigmented area is found within a pigmented mucous membrane region, a biopsy should be performed at the pigmented site to prevent misdiagnosis of large intestine neoplastic diseases. The absence of pigmentation in tumors and polyps may be related to tumor immunity or to increased secretion of sialomucin and decreased secretion of sulfomucin by the tumor.

bubble_chart Differentiation

This disease should be differentiated from the "brown bowel syndrome" seen in patients with steatorrhea. In steatorrhea patients, pigmentation occurs around the nuclei of intestinal smooth muscle cells, appearing brownish, with no pigmentation in the lamina propria of the intestinal mucosa. Patients with melanosis coli should also be distinguished from ischemic colitis and patchy submucosal hemorrhage, as the latter two conditions are usually more localized, and the affected mucosa appears purplish-red.