This document summarizes various skin manifestations that can be associated with underlying gastrointestinal disorders, infections, malignancies, and nutritional deficiencies. Some key points discussed include inflammatory bowel diseases like ulcerative colitis and Crohn's disease being linked to conditions like erythema nodosum and pyoderma gangrenosum. Liver diseases can cause signs such as spider telangiectasias. Viral hepatitis may relate to diseases like mixed cryoglobulinemia. Several genetic syndromes with increased cancer risk, like Gardner's syndrome and Peutz-Jeghers syndrome, have distinctive cutaneous findings.

1. PROFESSOR M. YOUSRY ABDEL-MAWLA,MD Skin manifestations of some gastrointestinal disorders

2. Gastrointestinal disorders Cutaneous disorders Inflammatory bowel disease Ulcerative colitis Neutrophilic tissue reactions Crohn’s disease Pyoderma gangrenosum Bowel – bypass syndrome Sweet’s syndrome Pustular vasculitis Erythema nodosum Aphthous stomatitis

3. Malabsorption Gluten-sensitive enteropathy Alcoholic liver disease Acrodermatitis enteropathica Dermatogenic enteropathy Pancreatic panniculitis Porphyria cutanea tarda Dermatitis herpetiformis Nutritional and Metabolic disorders

4. Infections Hepatitis B and C Helicobacter pylori Porphyria cutanea tarda Erosive or oral lichen planus Sweet's syndrome

5. Malignancies Glucagonoma Carcinoid Esophageal carcinoma Nonspecific cutaneous signs of gastrointestinal malignancy Necrolytic migratory erythema Flushing Bazex's syndrome Palmar-plantar hyperkeratosis Koilyonychia Glossitis Acanthosis nigricans Erythema nodosum Metastatic skin lesions (eg adenocarcinoma of colon Sister Mary Joseph's nodules)

6. Malignancies Gastrointestinal polyposis syndromes and gastrointestinal cancer Gardner's syndrome Cronkhite-Canada syndrome Peutz-Jeghers syndrome Cowden disease Muir-Torre syndrome

7. Gastrointestinal hemorrhage Vascular disorders Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease) Kaposi's sarcoma Necrotizing angiitis Pseudoxanthoma elasticum Ehlers-Danlos syndrome Degos, disease Henoch-Schönlein purpura

8. Dermatologic Manifestations of liver disease Vascular a. Spider telangiectasia, b. Palmer erythema, c. Corkscrew scleral vessels, d. Caput medusae, e. Plethoric facies, f. Flushing, g. Unilateral nevoid telangiectasia. Jaundice, Pruritus, Urticaria, Nail changes – Terry’s nails, b. Red lunulae, c. Koilonychia, Clubbing. Hyperpigmentation, Skin cancer, Lichenoid dermatitis, Oral Changes – Black hairy tongue, b. Glossitis

14. SKIN MANIFESTATIONS OF VIRAL HEPATITIS HEPATITIS B Polyarteritis nodosa (PAN) The pathogenesis :deposition of immune complexes in the vessel walls including IgM, complement factors (C3), and HBsAg Papular acrodermatitis of childhood (PAC ) A non-relapsing, erythemato-papular dermatitis localized to the face and limbs, lymphadenopathy, , acute hepatitis (mostly anicteric), and HBsAg antigenaemia Serum sickness-like syndrome (SSLP) It is associated with the prodromal phase of the disease . Manifestations: urticaria, angioedema, arthropathy, proteinuria or hematuria, and rash. The pathogenesis : deposition of immune complexes: H BsAg, IgG, IgM, and C3

15. SKIN MANIFESTATIONS OF VIRAL HEPATITIS HEPATITIS C Mixed cryoglobulinemia Cryoglobulins are anti-immunoglobulin immunoglobulins (Igs) that precipitate at temperatures less than 37°C. Mixed cryoglobulins : rheumatoid factors (RF) (usually IgM) complexed with IgG which form immune complexes. Mixed cryoglobulinemia : considered essential if it is not associated with any disease other than Sjogrens syndrome Porphyria cutanea tarda Porphyria cutanea tarda (PCT) is characterized by an abnormal porphyrin metabolism secondary to decreased activity of uroporphyrinogen decarboxylase (URO-D). The cutaneous findings: skin fragility, blister formation, hyperpigmentation and hypertrichosis, by the photosensitizing action of accumulated porphyrins Lichen planus Lichen planus is a chronic inflammatory mucocutaneous disease process. It usually presents as small, pruritic, purple, planar, polygonal papules with superimposed fine, reticulated white lines called Wickham's striae. Mucous membrane lesions are typically lacy white or ulcerative.

16. Other cutaneous associations of HCV Erythema multiforme, Erythema nodosum , Henoch-Schonlein purpura Bechet's syndrome Necrolytic acral erythema Polyarteritis nodosa , Prurigo nodularis , Pyoderma gangrenosum , Urticaria , and Urticarial vasculitis

17. Inflammatory bowel diseases Inflammatory disorders of the bowel discussed here include ulcerative colitis (UC), Crohn's disease, and bowel bypass syndrome Both UC and Crohn's disease (the traditional inflammatory bowel diseases [IBD]) can present with abdominal pain, GI bleeding, or diarrhea. Bowel bypass syndrome : a bacterial overgrowth in the blind loop associated with a dermatosis-arthritis syndrome

27. Inflammatory bowel diseases Inflammatory disorders of the bowel discussed here include ulcerative colitis (UC), Crohn's disease, and bowel bypass syndrome Both UC and Crohn's disease (the traditional inflammatory bowel diseases [IBD]) can present with abdominal pain, GI bleeding, or diarrhea. Bowel bypass syndrome : a bacterial overgrowth in the blind loop associated with a dermatosis-arthritis syndrome

28. Pathogenesis of extraintestinal manifestations of inflammatory bowel syndrome Immunologic mechanisms The mucosa from the underlying bowel disease provides associated immune responses for the inflammatory process in the extraintestinal sites. Autoimmune response increases with the presence of foreign proteins or bacterial products in the intestinal mucosa. Shared epitopes between bacterial proteins and host self-antigens. Microbial peptides cross-reactive to the cellular autoantigenic epitope may initiate the autoimmune response

29. Skin findings Erythema nodosum Pyoderma gangrenosum Angular stomatitis Aphthous stomatitis Pyostomatitis vegetans Psoriasis Erythema multiforme Epidermolysis bullosa acquisita Sweet's syndrome Metastatic Crohn's disease Nonspecific skin findings Fistulas and fissures, are found commonly in Crohn's disease. Painless anal fissures occur. Crohn's disease oral findings:cobblestoning, ulcerations, and nodules. Pustular reactions including pustular vasculitis

35. Nutritional and metabolic disorders ALCOHOL ABUSE AND SKIN 1- Nutritional deficiencies a- Marasmus b- Kwashiorkor c- Pellagra d- Scurvy 2- Endocrine diseases a- Hypogonadism b- Hyperestrogenism c- Pseudo-Cushing's syndrome 3- Porphyria cutanea tarda 4- Infections 5- Acquired purpura fulminans 6-Exacerbations of skin disease a- Psoriasis b- Rosacea c-Discoid eczema

36. Cutaneous eruptions associated with malabsorption Nonspecific Acquired ichthyosis Hair changes Nail changes Hyperpigmentation Altered skin texture Eczematous eruptions Specific Zinc deficiency Acrodermatitis enteropathica Vitamin B deficiency Dermatogenic enteropathy Dermatitis herpetiformis

40. SOME SKIN MANIFESTATIONS OF MALIGNANCY IN G IT Acanthosis nigricans This appears as a brown-to-black, smooth, velvety plaque found in areas of skin folds, most commonly the neck, axillae, and groin. Possibility of an intra-abdominal malignancy should be considered especially if there is large number of plaques, Weight loss, Rapid progression of lesions, The discovery of plaques in unusual locations( lips, oral mucosa, hands, and genitalia)

41. SOME SKIN MANIFESTATIONS OF MALIGNANCY IN G IT Pancreatic panniculitis Pancreatic panniculitis(inflammation of subcutaneous fat) : predominately in alcoholic ,pancreatitis and pancreatic cancer. Erythematous painful plaques and nodules on the extremities or trunk

45. Cutaneous syndromes and the GI Tract Cutaneous syndromes associated with gastrointestinal diseases and malignancy Abbreviations : AD, autosomal dominant; BCC, basal cell carcinoma; GI, gastrointestinal; MEN, multiple endocrine neoplasia; MSH. Syndrome Inheritance Cutaneous findings Internal Associations With increased DEFECT risk of malignancy Gardner’s Syndrome AD Osteoma, desmoid Intestinal polyposis, (familial Chromosome 5 tumors epidermoid colon cancer, thyroid Polyposis cysts, dental cancers, retinal Syndrome) anomalies abnormalities

46. Syndrome Inheritance Cutaneous findings Internal Associations Cronkhite Acquired Alopecia, nail GI polyps, colon Canada dystrophy; macular carcinoma, diarrhea Syndrome hyperpigmentation abdominal pain Cowden’s AD Hamartomas of Hamartomas and disease Mutation PTEN mucous membranes malignancy of colon, (multiple Gene / facial breast, thyroid, Hamatoma chromosome tricholemmonas, renal and bladder Syndrome) 10 papillomas Palmar- colon polyps plantar keratoses, scrotal tongue Muir – Torre ADMutation in Sebaceous gland tumors, Nonpolyposis colon cancer BCC with sebaceous differentiation MSH2 gene on

47. Syndrome Inheritance Cutaneous findings Internal Associations Peutz – AD Periorifical and Hamartomas polyps Jeghers mucosal lentigines, throughout GI tract Syndrome pigmented maculae increased incidence hands and feet of malignancy throughout GI tract, ovarian tumors, pancreatic carcinoma gallbladder cancer, GI bleeding, pancreatic carcinoma

48. Cutaneous syndromes associated with gastrointestinal diseases and malignancy Syndrome Inheritance Cutaneous findings Internal Associations Howell- Palmer - plantar Esophageal carcinoma Evans’ hyperkeratosis syndrome Bazex’s Acquired Acrodermatitis, Esophageal, laryngeal, syndrome nail dystrophy tongue carcinoma MEN type I AD Multiple facial Pituitary, parathyroid, (Wermer’s Mutation in angiofibromas, pancreatic endocrine syndrome) MEN I gene collagenomas, abnormalities, peptic U on chromosome lipomas, confetti-like disease,Zollinger-Ellison 11 hypopigmented syndrome, gastronoma, macules insulinoma, carcinoid.

49. Syndrome Inheritance Cutaneous findings Internal Associations MEN IIA AD Amyloidosis Medullary thyroid ( Sipple’s Mutation in RET carcinoma, syndrome) gene on pheochromocytoma, chromosome 10 hyperparathyroidism, Zollinger – Ellison syndrome, Cushing’s syndrome, malignant melanoma, pitutary ad. MEN IIB AD Multiple mucosal Hirschprung’s disease, Mutation in RET neuromas, cervical medulloblasoma gene on marfinoid body increased risk of chromosome 10 habitus, nasal malignancy neuromas

59. Cutaneous syndromes associated with hemorrhage Cutaneous syndromes associated with gastrointestinal hemorrhage. Abbreviations: AD, autosomal dominant, AR, autosomal recessive; AV, arteriovenous; CNS, central nervous system; GI, gastrointestinal; GIT, gastrointestinal tract; SQ, subcutaneous. Syndrome Inheritance Cutaneous findings Internal Associations Hereditary AD Telangiectasia of skin, GI hemorrhage,epistaxis hemorrhagic oral mucosa arterial aneurysms; AV telangiectasia malformations in liver, lung, eye. Blue rubber bleb AD Compressable SQ GI vascular malformations news syndrome hemangiomas GI hemorrhage Kaposi’s sarcoma Violaceous papules, GI lesions, hemorrhage nodules Necrotizing angiitis Palpable purpura GI bleeding, perforation, ischemia

60. Syndrome Inheritance Cutaneous findings Internal Associations Henoch – Palpable purpura Abdominal cramping Sch öenlein and pain, hmaturia, purpura glomerulonephritis Degos’ disease atrophic Erythematous Vasculitis of GIT, papules infarction, bleeding, CNS infarcts Ehler’s – Danlos AD, AR Easy bruising, thin Arterial rupture, GI syndrome type IV translucent skin hemorrhage, uterine rupture Pseudoxanthoma AD, AR Waxy yellow papules, GI hemorrhage, Angioid elasticum flexural areas, streaks in eyes, elastosis perforans coronary heart disease, serpiginosa vascular calcification

67. Miscellaneous cutaneous diseases associated with GI disorders; Scleroderma (systemic sclerosis The dermatologic changes: sclerotic changes that eventually involve the entire body, telangiectases, hyperpigmentation and hypopigmentation GIT Manifestations The esophageal symptoms :feeling of premature fullness, reflux esophagitis, dysphagia, and epigastric pain. Stomach and small bowel :anorexia, early fullness, diarrhea, nausea/vomiting, and obstipation caused by impaired motility, which, in turn, leading to chronic intestinal pseudo-obstruction, malnutrition, and bacterial overgrowth

70. Pemphigus vulgaris Pemphigus vulgaris (PV) : autoimmune blistering disorder involving the skin and mucous membranes that also can affect the esophagus (persistent sore throat, dysphagia, and odynophagia). Skin lesions: bullous lesions(1-10 cm) superficial, and easily ruptured by trauma. One characteristic finding on lateral palpation of these lesions is extension into adjacent tissue. Mucosal sites also commonly are involved, including the oral mucosa (often the presenting site), anus, cervix, and conjunctivae. Antigenic confirmation of the disease correlation: the target cell adhesion molecule of the PV autoantibodies is strongly expressed in the esophageal epithelia .

74. Summary Early recognition of cutaneous diseases or manifestations associated with the gastrointestinal tract disorders may be lifesaving at times, and may lead to early preventive intervention to decrease risk of morbidity or mortality.