Skin signs of gastrointestinal disease

• Gardner’s syndrome: Osteomas, epidermoid inclusion cysts

It is logical that many diseases of the skin also involve the oral and anal mucosa because, embryologically, the foregut (forming the oral epithelium) and the hindgut (creating the anal mucosa) share a common ectodermal component in the first few weeks of fetal development. Therefore, the skin becomes a “mirror” of underlying pathology, both obvious and occult, in the gastrointestinal (GI) system.

Fitzpatrick JE: Cutaneous manifestations of gastrointestinal disease. In McNally PR, editor: Gastroenterology secrets, ed 3, Philadelphia, 2006, Elsevier Mosby, pp 559–566.

On average, 250 to 350 mg of bilirubin is normally generated daily, with 70% to 80% arising from senescent red blood cells and the remainder coming from heme proteins in the bone marrow and liver. Jaundice is the overaccumulation of bilirubin and various bile pigments in the skin and other organs. It is first seen in the sclera of the eye, skin (especially the face), and hard palate. Jaundice may result from stone obstruction, hemolysis with overproduction of bilirubin, ineffective erythropoiesis, or intrinsic liver disease. Jaundice is best seen in bright daylight and may be overlooked indoors. Jaundice is not clinically apparent until serum bilirubin exceeds 2.0 to 2.5 mg/dL in the adult and 5 mg/dL in the neonate. Jaundice may be the first and sole sign of hepatic dysfunction.

Kliegman R, Nelson WE: Nelson textbook of pediatrics. ed 18. Philadelphia, 2007, Saunders Elsevier, p 3147.

Yellow discoloration of the skin is caused by bilirubin, while orange shades come from xanthorubin (intrahepatic jaundice). A deep green skin color is due to marked biliverdinemia and is characteristic of obstructive jaundice, as seen with pancreatic cancer. Patients with hepatobiliary disease, especially obstructive jaundice, often have severe pruritis; constant scratching results in inflammation of the skin follow by postinflammatory hyperpigmentation. The combination of postinflammatory hyperpigmentation and bile pigments imparts a bronze color to the skin. “Bronzing” is also encountered in hemochromatosis and primary Addison’s disease.

Do not forget about exogenous plant pigments, metabolic diseases, and trematode ingestion when examining a patient who appears jaundiced. The differential diagnosis of jaundice includes carotenemia (excessive ingestion of carotenoids), lycopenia (via tomato juice), Clonorchis sinensis (travel to Asia) or Fasciola hepatica (ingesting watercress) infection, and the sallow skin of myxedema.

Pyoderma gangrenosum (PG) is a severe ulcerative condition that affects 1 in 100,000 United States citizens per year and, in over 70% of cases, affects the lower legs (Fig. 37-2). It is one of the skin lesions associated with the abdominal pain and bleeding of inflammatory bowel disease. PG originates as a small, tender pustule that breaks down to form a painful, rapidly expanding necrotic ulcer with a cyanotic, raised and undermined edge. Lesions may develop at sites of minor trauma, a phenomenon known as pathergy. The ulcers of PG may become quite large. They frequently heal with a thin, atrophic scar.

Table 37-1. Conditions Associated with GI Bleeding and Skin Lesions

INFLAMMATORY CONDITIONS	VASCULAR MALFORMATIONS AND TUMORS
Ulcerative colitis Crohn’s disease Henoch-Schönlein purpura Polyarteritis nodosa	Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu) Kaposi’s sarcoma Blue rubber bleb nevus syndrome
HEREDITARY POLYPOSIS SYNDROMES	MISCELLANEOUS
Gardner’s syndrome Peutz-Jeghers syndrome Multiple hamartoma syndrome (Cowden’s syndrome)	Ehlers-Danlos syndrome Pseudoxanthoma elastica

The exact cause of PG is unknown, but immune complex–mediated neutrophilic vascular reactions in the skin have been postulated. After the diagnosis of PG is made, the next step should be to look for an underlying cause. Important conditions to search for include chronic infectious hepatitis, inflammatory bowel disease (ulcerative colitis or Crohn’s disease), rheumatoid arthritis, lupus erythematosus, HIV infection, and leukemia. About 2% of patients with ulcerative colitis have PG, and the course of both illnesses maybe parallel. Some patients may have PG for several years before developing inflammatory bowel disease. In general, firstline treatment is corticosteroids and cyclosporine. Infliximab (TNF-α antibody) is the treatment of choice for PG with underlying inflammatory bowel disease or rheumatoid arthritis.

Brooklyn T, Dunnill G, Probert C: Diagnosis and treatment of pyoderma gangrenosum, BMJ 333(7560):181–184, 2006.

The most likely cause is hereditary hemorrhagic telangiectasia (HHT), also known as Olser-Weber-Rendu syndrome. This is an autosomal dominant genetic disorder with highest prevalence in the Dutch Antilles (1:1330). Two subtypes exist: HHT-1 and HHT-2, due to ENG (9q33-34) and ALK-1 (2q13) TGFB-1 receptor mutations, respectively. Affected individuals develop linear, punctuate, and papular red lesions on the lips, face, mucous membranes, fingers (Fig. 37-3), and toes beginning in childhood. The entire GI tract may also be affected with similar lesions, and bleeding may be minimal (causing a chronic iron-deficiency anemia), or massive (leading to an acute, severe and sometimes fatal blood loss). The disease prevalence of GI manifestation is 15% to 45%. The mucous membranes, especially the nasal mucosa, are also involved. In children, an important early clue to the diagnosis is recurrent severe nosebleeds (epistaxis) prior to the presence of other more typical findings. Diagnosis results from the positive finding of three out of four Curaçao criteria (epistaxis, telangiectasias, visceral lesions, first-degree relative with HHT). Patients continue to develop new lesions throughout life. Individuals with the HHT-1 subtype have an increased risk of arteriovenous malformations of the lungs, liver (causing cirrhosis), and central nervous system.

Letteboer TG, Mager JJ, Snijder RJ, et al: Genotype-phenotype relationship in hereditary haemorrhagic telangiectasia, J Med Genet 43(4):371–377, 2006.

Sabba C, Pasculli G, Lenato GM, et al: Hereditary hemorrhagic telangiectasia: clinical features in ENG and ALK1 mutation carriers, J Thromb Haemost 5(6):1149–1157, 2007.

A number of conditions have pigmented macules on the lips. The most important one concerning the GI tract is Peutz-Jeghers syndrome (PJS). It is one of the “classic” polyposis syndromes with intestinal polyps, an increased risk of cancer, and characteristic skin findings in 95% of cases. PJS is an autosomal dominant disorder that appears at birth or in infancy with small round to oval macules that vary from brown to blue-brown in color. They most often occur on the lips and buccal mucosa, but the nose, palms, soles, fingers, hard palate, and gingiva may also be affected. Be sure to examine the mouth. It is important to remember that the lip macules are not present at birth.

Individuals with PJS also have multiple polyps in the small intestine, most commonly in the jejunum and ileum. Polyps present around 11 to 13 years of age. When only a few polyps are present, there may be no symptoms. However, when present in large numbers, the polyps may cause intussusception with resultant abdominal pain and bleeding (most common) or obstruction. The polyps are hamartomatous polyps, which means that they are composed of benign elements normally present in the gut. There is a 2% to 3% risk, however, of intestinal malignancy in patients with PJS. It is thought that among the masses of benign polyps is the occasional adenomatous polyp that is a precursor lesion of intestinal cancer. There is a 37% chance of any type of cancer by age 65 in PJS. In addition, it has been recently discovered that patients with this syndrome have a higher risk of developing cancer of the ovary, uterus, breast, endometrium, testicles, GI, lungs, and pancreas. Recent studies have indicated that PJS arises from mutations in a tumor supressor gene (19p13.5, gene STK11/LKB1), which normally regulates cell cycle progression. Forty percent of gene mutations are spontaneous.

Thiers BH, Sahn RE, Callen JP: Cutaneous manifestations of internal malignancy, CA Cancer J Clin 59(2):73–98, 2009.

Surgery. The gold standard is prophylaxis and polypectomy of the entire small bowel. Treatment of patients with inhibitors of cyclooxygenase-2 (COX-2 inhibitors, celecoxib) may lead to a dramatic reduction in the burden of polyps and need for surgical resection. Ongoing research indicates that Rapamycin (sirolimus) shows promise for PJS treatment by binding to FKBP12, which results in antiproliferative effects and dramatic reduction of polyp production/size.

Kopacova M, Tacheci I, Rejchrt S, Bures J: Peutz-Jeghers syndrome: diagnostic and therapeutic approach, World J Gastroenterol 15(43):5397–5408, 2009.

PXE is inherited in an autosomal dominant or autosomal recessive fashion, due to mutations in the ABCC6 gene, which codes for a cellular transport protein. The basic defect is in the elastic tissue in various organs—the skin, blood vessels, eyes, and heart. Recent studies indicate that in PXE, extracellular material accumulates due to a defective MRP6 transmembrane transporter; this is thought to cause the calcification of elastic fibers and fragmentation of the tissue. As a result, a major part of the structural framework in these tissues is weakened, leading to disastrous consequences.

Changes of PXE in the skin develop in adolescence or early adulthood and typically begin on the sides of the neck. The skin lesions consist of asymptomatic, yellowish pebbly plaques on the neck, axillae, antecubital fossae, abdomen, and thighs or other large flexor surfaces. PXE has a peculiar texture and color reminiscent of “plucked chicken skin.” PXE typically presents in a reticular pattern.

Internally, the yellowish papules of PXE are seen in the mouth, esophagus, and stomach. Involvement of the elastic tissue of the gastric arteries may result in sudden, massive hemorrhage. Involvement of the eye, specifically Bruch’s membrane, causes angioid streaks of the retina. Sudden hemorrhage with acute loss of vision may be a presenting sign. Involvement of large vessels results in claudication, hypertension, and angina at an early age.

Finger RP, Charbel Issa P, Ladewig MS, et al: Pseudoxanthoma elasticum: genetics, clinical manifestations and therapeutic approaches, Surv Ophthalmol 54(2):272–285, 2009.

Gardner’s syndrome is another polyposis syndrome inherited in an autosomal dominant fashion. Mutations of the APC gene on chromosome 5c21 are responsible for the syndrome. APC is a tumor suppressor protein with a role in cell-to-cell adhesion, signal transduction, and transcriptional activation. Patients with this syndrome have numerous epidermal inclusion cysts in the skin (50% to 65%), various dental abnormalities including osteomas of the mandible, intraabdominal desmoid tumors, and innumerable premalignant adenomatous polyps throughout the colon (Fig. 37-4). Congenital retinal pigmentation may also develop. The incidence of Gardner’s syndrome in the United States is 1 in a million, average age of onset is 22, and the lifetime risk of colon cancer in untreated patients is 100%. In addition, patients have a predisposition to periampullary and thyroid cancers. Deforming osteomas may require excision although Gardner’s skin manifestations do not typically require treatment. Underlying polyp excision is preferred, and second-line sulindac or tamoxifen is recommended for abdominal desmoid polyps or extraabdominal manifestations.

Schwartz R: Gardner syndrome, eMedicine Dermatology. Available at: http://emedicine.medscape.com/article/1093486-overview. Accessed December 7, 2009.

Nandakumar G, Morgan JA, Silverberg D, Steinhagen RM: Familial polyposis coli: clinical manifestations, evaluation, management, and treatment, Mt Sinai J Med 71:384–391, 2004.

The skin may be involved with GI tract malignancy in several ways. First, the skin may be a site of metastasis from a primary GI tract cancer. This happens most frequently with adenocarcinoma of the colon (Fig. 37-5). Secondly, the skin and GI tract may be both affected by a genetic disease, such as the pancreatic cancer syndrome associated with multiple atypical nevi and melanoma (chromosme 9p21, CDKN2A). There is also a large group of paraneoplastic dermatoses, that is, a skin condition associated with an underlying malignancy (indirect involvement). Examples include “malignant” acanthosis nigricans, superficial migratory thrombophlebitis, and glucagonoma syndrome. In a few instances, such as excess glucagon secretion in the glucagonoma syndrome, the link between the skin and gut is clear. In other cases (such as acanthosis nigricans), the skin condition may occur in many individuals without cancer, so a thorough evaluation of the patient is necessary.

Thiers BH, Sahn RE, Callen JP: Cutaneous manifestations of internal malignancy, CA Cancer J Clin 59(2):73–98, 2009.

AN may be caused by endocrine disorders (insulin resistance), obesity (Fig. 37-6), medications, genetic abnormalities, or underlying cancer. However, the sudden onset of widespread AN in an adult with weight loss should suggest an underlying malignancy. Many different cancers have been reported with “malignant” AN, but almost 60% of patients have adenocarcinoma of the stomach. In most of these cases, AN develops when the tumor is in an advanced stage. One third of patients have AN before, one third during, and one third present after the discovery of the internal malignancy. In some cases, successful resection of the adenocarcinoma leads to regression of the AN. Gastric adenocarcinoma secrete TNF-α, which inevitably stimulates the epidermal growth factor (EGF) receptor to cause proliferation of keratinocytes.

Malignant AN initially presents abruptly as a darkening and thickening of the skin, occasionally with pruritus. This morphology progresses into symmetrical hyperpigmented, velvety plaques that occur most commonly around the posterior neck, axilla, and groin. Treatment for malignant AN is correction of the underlying pathology.

“Tripe palms” is another form of AN, and refers to AN of the palms in which there is a velvety furrowing of the palmar surfaces. It is almost always associated with internal malignancy. When Tripe palms occurs in the absence of AN, squamous cell carcinoma should be suspected. The sign of Leser-Trélat (increased numbers or the explosive onset of seborrheic keratoses) can also be associated with AN and tripe palms and it stems from the same circulating epidermal growth factors. Leser-Trélat may also be seen with tumors of the female reproductive tract and lymphoproliferative disorders.

Thiers BH, Sahn RE, Callen JP: Cutaneous manifestations of internal malignancy, CA Cancer J Clin 59(2):85–86, 2009. (Triple palms, Leser-Trélat)

Many conditions may produce a state of increased blood coagulability, leading to venous thrombosis. One important GI-related cause is pancreatic cancer, which may be asymptomatic at the time the thrombophlebitis develops. Fifty percent of cases of SMT are associated with an underlying malignancy.

Superficial migratory thrombophlebitis presents as cropped, tender, erythematous, linear cords along the course of superficial veins of the trunk and extremities. Lesions in one area may be resolving, while new lesions are developing elsewhere. It is essential that any patient presenting with superficial migratory thrombophlebitis undergo a thorough evaluation to rule out underlying malignancy.

Recent work has focused on the association of superficial migratory thrombophlebitis and mucin-secreting abdominal adenocarcinomas. A low-grade disseminated intravascular coagulation occurs through mucin interaction with L and P selectins leading to aggregation and emboli formation, none of which requires thrombin generation. The thrombophlebitis is remarkably resistant to oral anticoagulant therapy such as warfarin, but does respond well to low-molecular-weight (LMW) heparin therapy, which is postulated to inhibit tumor growth, instead of acting in its traditional anticoagulatory role. Current research indicates that dalteparin and nadroparin may also illicit improved outcomes and survival rates. SMT is not specific for GI malignancies and has also been associated with carcinoma of the lung and breast, Hodgkin’s disease, and multiple myeloma. Nonmalignant associations include Behçet’s disease and rickettsial infections.

Thayalasekaran S, Liddicoat H, Wood E: Thrombophlebitis migrans in a man with pancreatic adenocarcinoma: a case report, Cases J 2:6610, 2009.

The pancreas is a 99% exocrine- (pancreatic digestive enzyme) and a 1% endocrine- (insulin, glucagon) producing organ. Acute pancreatitis caused by viral infection, drugs, alcohol, pancreatic cancer, or trauma leads to massive outpouring of digestive enzymes. Patients with pancreatitis are often extremely ill with fever, vomiting, eosinophilia, and severe abdominal pain. About 2% to 3% develop tender red fluctuant nodules on the lower legs (Fig. 37-7) associated with joint pain and swelling. Predominantly seen with chronic pancreatitis or pancreatic cancer, these nodules rupture and discharge a thick, oily liquid. Schmid’s triad, (panniculitis, polioarthritis, and eosinophilia) denotes a poor prognosis. The disease is caused by pancreatic lipase, phospholipase, trypsin, and amylase that migrate into tissue to cause the inflammation. It is felt that these pancreatic enzymes cause autodigestion of the fat in the subcutaneous tissue and periarticular fat pads. The histopathology is distinctive, demonstrating lobular liquefactive necrosis and ghostlike fat cells with neutrophils and other inflammatory cells. Administration of octreotide (inhibiting pancreatic enzyme manufacture) results in the cessation of symptoms. Steroids and nonsteroidal antiinflammatory drugs (NSAIDs) do not effectively treat skin nodules.

Garcia-Romero D, Vanaclocha F: Pancreatic panniculitis, Dermatol Clin 26(4): 465–470, 2008.

Porphyria cutanea tarda (PCT) is a metabolic disease characterized by skin fragility, chronic blistering, and scarring of the dorsal hands, forearms, ears, and face associated with photosensitivity to sunlight (Fig. 37-8). In addition to the blistering and scarring, skin findings include thickened, coarse hairs (hypertrichosis) over the temples, forehead, and cheeks; occasional shiny, thickened, scleroderma-like changes of the face, scalp, posterior neck, and torso; and hyperpigmentation or hypopigmentation.

PCT is either of autosomal dominant inheritance with incomplete penetrance or is acquired. There is a high incidence of liver disease and iron overload in patients with PCT. Factors that may trigger attacks of PCT include alcohol abuse, hepatitis C infection, estrogens (especially oral contraceptives), and HIV infection. The biochemical defect in chromosome 3q12 (UROD gene) leads to a deficiency of the hepatic and red blood cell enzyme uroporphyrinogen decarboxylase. This is the fifth enzyme in the metabolic pathway of the synthesis of hemoglobin. The liver’s resultant overproduction of porphyrin precursors (photosensitizing compounds) causes a thickening of the dermal vascular architecture following exposure to sunlight.

A useful laboratory test that can be performed in the office is the demonstration of pink-red fluorescence of the patient’s urine when exposed to ultraviolet light. A Wood’s light emitting ultraviolet A (UVA) can be used for this test. Patients also have increased total body iron stores reflected in increased serum iron and ferritin levels. Quantitative measurement of the urine porphyrins in a 24-hour urine specimen will confirm the diagnosis.

Treatment of PCT includes elimination of alcohol and other predisposing medications, photoprotection, phlebotomy, and low-dose antimalarial therapy (chloroquine).

Kauppinene R: Porphyrias, Lancet 365 (9455):241–252, 2005.

Dermatitis herpetiformis (DH) is an immunobullous skin disease. Onset typically occurs between 20 and 40 years of age and affects men in a 2:1 ratio to women. Patients develop intensely itchy papules, papovesicles, and occasionally tense blisters in a grouped (herpetiform), symmetrical distribution over the scalp and posterior neckline, shoulders and back, elbows, knees, and the lumbosacral region (Fig. 37-9). Rarely, urticarial lesions without papulovesicles may be the only manifestation of the disease. Lesions on the palms are uncommon, and the mucous membranes are only rarely involved. Over 90% of patients will have histologic evidence of a gluten-sensitive enteropathy, ranging from increased intraepithelial lymphocytes to complete villous atrophy of the jejunum.

The disease in the skin and the intestinal tract (small intestine) is triggered by dietary gluten found in many grains (but not in rice, corn, or oats). There are usually no abdominal symptoms but an occasional patient may complain of bloating, cramping, and diarrhea. A diet completely free of gluten will clear the skin and intestinal tract lesions; however, this diet is difficult for many patients to maintain. The skin disease is characterized by the accumulation of polymorphonuclear neutrophils (PMNs) and granular deposits of IgA in the tips of the dermal papillae. These two findings are considered diagnostic of DH. In addition, most patients, as with celiac patients, show increased frequency of HLA-A1, HLA-B8, HLA-DR3, and HLA-DQw2 haplotypes. Current research indicates that epidermal transglutaminase 3 is the autoantigen in DH, which when coupled with gluten and a predisposition to gluten sensitivity, cross reacts with IgA antibodies.

Patricio P, Ferreira C, Gomes MM, Filipe P: Autoimmune bullous dermatoses: a review, Ann N Y Acad Sci 1173:203–210, 2009.

Zone JJ: Skin manifestations of celiac disease, Gastroenterol 128:S87–S91, 2005.

Treatment includes strict adherence to a gluten-free diet and the use of either dapsone (diaminodiphenylsulfone) or sulfapyridine. Dapsone is the more effective of the two. Be sure to check G6PD levels and complete blood count prior to starting dapsone. The condition is lifelong with only rare periods of brief remission. Approximately 1% of patients will develop enteropathy-associated B-cell or less commonly T-cell lymphomas. These patients have a history of poor adherence to a gluten-free diet.

Patricio P, Ferreira C, Gomes MM, Filipe P: Autoimmune bullous dermatoses: a review, Ann N Y Acad Sci 1173:203–210, 2009.