CHAPTER 152
The Skin and Disorders of the Digestive System

Sonja Molin and Thomas Ruzicka

Department of Dermatology and Allergology, Ludwig Maximilian University, Munich, Germany

Introduction

This chapter concentrates on gastrointestinal, hepatic and pancreatic diseases in which cutaneous signs or symptoms are prominent, but also discusses situations either where the skin and the digestive system are affected by the same disease process or where a skin disease itself has an effect on the latter [1, 2, 3]. Skin changes related to more general effects of gastrointestinal diseases, such as nutritional defects, are discussed elsewhere in this book.

OESOPHAGUS, STOMACH AND INTESTINE

Bleeding from the gastrointestinal tract may be associated with skin and nail signs of iron deficiency, such as koilonychia, smooth tongue and angular cheilitis (see Chapter 63). The association of longstanding iron deficiency anaemia with dysphagia and an oesophageal web is known as Plummer–Vinson or Paterson–Brown-Kelly syndrome [1]; it may predispose to squamous cell carcinoma of the oesophagus.

Cutaneous metastases may occur from tumours of the oesophagus or stomach. Rarely they arise in the umbilicus and look like a firm but mobile nodule or nodules. This phenomenon has been called Sister Mary Joseph nodules. The most common cancers that metastasize to the umbilicus are those of the stomach, pancreas, colon and ovary [4].

Paraneoplastic eruptions linked to malignant neoplasms of the upper gastrointestinal tract, including palmoplantar keratoderma–oral leukokeratosis–oesophageal carcinoma (Howel–Evans syndrome), acrokeratosis paraneoplastica (Bazex syndrome) and paraneoplastic acanthosis nigricans, are discussed in Chapter 147.

Deficiencies of essential minerals and vitamins may manifest in the skin in a variety of ways. A major cause is impaired absorption from the gastrointestinal tract as the result of specific transport defects (e.g. vitamin B12, zinc), surgery (e.g. gastrectomy, gastro­intestinal bypass) or disease (e.g. Crohn disease) [1]. These are discussed in more detail in Chapter 63.

Helicobacter pylori infection has been reported to be associated with a wide variety of skin disorders including chronic urticaria, rosacea, IgA vasculitis, Sweet syndrome, erythema multiforme, alopecia areata, pruritus, nodular prurigo and atopic eczema [5].

Inflammatory bowel disease

Crohn disease (CD) (see Chapter 97) and ulcerative colitis (UC) are the major causes of what is termed inflammatory bowel disease (IBD). Despite several similarities, including their age distribution and incidence rate, these two diseases are distinct in several ways [2]:

  1. Inflammatory profile: CD is mediated by TH1 cells, whereas UC is mediated by TH2 cells.
  2. Clinical picture: CD can affect the whole gastrointestinal tract, while UC is confined to the colon.
  3. Genetic predisposition: HLA-B27 is associated with UC, whereas other genes such as the caspase recruitment domain 15 gene, CARD15, predispose to CD.
  4. Risk factors: CD is associated with smoking, UC is not.

According to current classifications, skin involvement in IBD can be grouped into four categories [2, 6]: (i) specific conditions; (ii) reactive conditions; (iii) associated conditions; or (iv) complications or treatment of IBD. Specific lesions reflect direct skin involvement by IBD and are found only in CD. Reactive lesions are induced indirectly by the IBD (in both UC and CD). Immune cross-reactivity between the skin and gut seems to play an important role in their development. Certain skin conditions are associated with the HLA predisposition or the chronic inflammatory milieu in IBD. Finally, IBD complications or side effects of IBD treatments may manifest in the skin.

Specific lesions

Direct skin and mucosal involvement

Crohn disease may occur at sites adjacent to the digestive tract, such as the oral cavity or ano-genital region. Anal tags are common. Perineal abscesses, fissures and fistulae occur in about 20–60% of patients with CD and only rarely in UC. They are more commonly seen in patients with CD colitis and may cause severe morbidity (‘watering-can perineum’). Oral CD occurs in about 9% of patients with CD and is manifest as swelling of the lips (Figure 152.1) or as a nodular ‘cobblestone’ oedema of the gingivae and oral mucosa; painful ulceration may develop [2, 6].

Image described by caption.

Figure 152.1 Oral Crohn disease.

Cutaneous Crohn disease at other sites

Cutaneous CD may also occur at sites distant from the bowel [2]. The lesions have the same histopathology as the gastro­intestinal lesions [6]. Lesions of cutaneous CD may be solitary or multiple, and may have varied morphology, including intact or eroded plaques and nodules. The lower extremities are commonly involved, but cutaneous CD may affect the flexures, genitalia, face and other sites.

Reactive lesions

A variety of reactive lesions may occur with either UC or CD, usually paralleling the activity of the IBD. All of them are discussed in detail in other chapters of this book. The most common are erythema nodosum and pyoderma gangrenosum [6].

Erythema nodosum (see Chapter 99). Three to 10% of patients with UC and 4–15% of patients with CD develop erythema nodosum. It shows a female predilection [6].

Pyoderma gangrenosum (see Chapter 47). Pyoderma gangrenosum occurs as a complication of IBD (Figure 152.2), haematological disorders, inflammatory arthritis and other medical conditions. It is estimated to occur in about 5–12% of patients with UC, clearly more often than in those with CD (1–2%). Like erythema nodosum it is more common in females [6].

Image described by caption.

Figure 152.2  Pyoderma gangrenosum in a patient with Crohn disease.

Acute febrile neutrophilic dermatosis (see Chapter 49). Acute febrile neutrophilic dermatosis or Sweet syndrome has been reported to be associated with IBD, especially UC [6].

Pyodermatitis–pyostomatitis vegetans. Pyodermatitis–pyostomatitis vegetans or pyodermite végétante Hallopeau [2, 6] is a rare disorder of the oral mucosa and a rare cutaneous manifestation of IBD. Most cases of pyodermatitis–pyostomatitis vegetans are associated with IBD, usually UC. The oral lesions consist of multiple pustules, plaques and erosions, which may have a ‘snail-track’ appearance. The skin lesions are crusted papules and vegetating plaques with surrounding pustules, mainly affecting the major flexures and the scalp (see also Chapter 147).

Cutaneous polyarteritis nodosa. This is a vasculitis of small and medium-sized vessels localized in the dermis and subcutis; 10% of cases are associated with IBD [2].

Leukocytoclastic vasculitis. Leukocytoclastic vasculitis may occur in either UC or CD, but is more common in the former. The clinical picture is one of a leukocytoclastic vasculitis with palpable purpura, typically affecting the lower legs and sometimes causing nodules or ulceration. It can occur in CD during remission or exacerbation, whereas in UC it normally precedes the onset of bowel disease [6]. Involvement of the gastrointestinal tract is the third most common organ manifestation of IgA vasculitis (Henoch–Schönlein purpura), occurring in 50–75% of patients [2].

Thrombosis. The risk of thrombosis is elevated in patients with IBD and directly correlates with bowel disease activity. It may affect atypical locations, such as the heart or brain and the axillary or subclavian venous systems [2].

Oral aphthous ulcers. Oral aphthous ulcers are typically located on the buccal mucosa and the lips. They are more common in CD (10%) than in UC (4%) (Figure 152.3). In CD they are thought to represent specific rather than reactive lesions, but their pathogenesis in UC remains unclear. It has been postulated that they may sometimes be attributable to malnutrition secondary to IBD rather than to the IBD itself [6].

Image described by caption.

Figure 152.3 Recurrent major aphthae in 26-year-old man with longstanding severe Crohn disease.

Associated lesions

Several skin diseases have been reported in the context of IBD, amongst them epidermolysis bullosa acquisita, psoriasis, vitiligo, hidradenitis suppurativa, phlebitis, erythema multiforme, urticaria, lichen planus, secondary amyloidosis, bullous pemphigoid and linear IgA bullous dermatosis. There also appears to be an increased risk of skin cancers such as squamous cell carcinoma [6].

Epidermolysis bullosa acquisita. This has been associated with both CD and UC, but like vitiligo it is very rare in CD and more often found in UC.

Psoriasis. This is more commonly associated with CD (11.2%) than with UC (5.7%) [6].

Collagenous colitis

This is a type of microscopic colitis characterized clinically by diarrhoea and histologically by a band-like collagen deposit [7]. Cases have been described that have evolved into other forms of IBD such as CD and UC. Concomitant coeliac disease has also been reported. It has been linked to the use of a variety of drugs including non-steroidal anti-inflammatory drugs or proton pump inhibitors. It has been associated with pyoderma gangrenosum.

Coeliac disease

Coeliac disease is an immune-mediated gluten-dependent enteropathy [8]. It is the result of a genetically based inappropriate T-cell-mediated immune response against gluten. It causes malabsorption and diarrhoea but diagnosis is often delayed and may first be discovered after a patient presents with dermatitis herpetiformis. The disease shows a strong HLA association: more than 90% of patients express the HLA-DQ (α1*501,β1*02) heterodimer (HLA-DQ2) and almost all the remainder have HLA-DQ8. Diagnosis of coeliac disease can be made by serological tests for antigliadin, antiendomysial and tissue transglutaminase antibodies. A strict gluten-free diet is mandatory.

The most common skin manifestation of coeliac disease is dermatitis herpetiformis; the association is described in greater detail in Chapter 50. Cutaneous signs of malabsorption may be present in patients with severe coeliac disease. There is an increased incidence of autoimmune disorders that manifest in the skin, including psoriasis, alopecia areata, linear IgA bullous dermatosis and vitiligo. Other skin diseases that have been described in the context of coeliac disease include aphthous stomatitis, urticaria, hereditary angio-oedema, cutaneous vasculitis, erythema nodosum and erythema elevatum diutinum [3].

Bowel-associated dermatosis–arthritis syndrome

Bowel-associated dermatosis–arthritis syndrome (BADAS) comprises flu-like symptoms, polyarthralgia and eruptions of papules and pustules [2]. It shows a chronic and recurring course of disease with flares every 4–6 weeks. Its development had initially been linked to bowel bypass surgery for obesity (jejuno-ileal bypass), but now is also reported after modern bariatric procedures as well as in patients with IBD and cases of diverticulitis with sigmoid stenosis or acute appendicitis. The papules and pustules evolve from erythematous macules mainly on the extremities and the upper trunk.

The pathomechanisms leading to the development of the disease have not yet been fully understood. It seems that bacterial overgrowth in the altered parts of the gut and a production of antibodies against peptidoglycans in the bacterial cell wall play an important role. Deposition of immune complexes against peptidoglycan has been observed in patients with BADAS. Treatment mainly aims at reducing the bacterial load with long-term antibiotics or at correction of the blind loop in a jejuno-ileal bypass. Similar clinical features have been reported in association with severe achalasia of the cardia, in which food remnants are retained in the oesophagus for prolonged periods: a similar mechanism has been postulated [9, 10].

Whipple disease

Whipple disease is a disorder of the small intestine due to infection with Tropheryma whippelii. The disorder usually presents with arthralgia and general malaise. Abdominal pain, diarrhoea and weight loss due to malabsorption occur in most individuals with more advanced disease. Cardiac, pleural, ophthalmic or neurological symptoms also occur [11]. The most common sign of skin involvement is diffuse hyperpigmentation in sun-exposed areas, which is seen in 45–54% of patients Other cutaneous manifestations are rather rare and non-specific: they include subcutaneous nodules, erythroderma, purpura, vasculitis, panniculitis, hyperkeratosis, urticaria, dermatomyositis and eczema [3].

The diagnosis can be confirmed by demonstration of periodic acid–Schiff-positive particles in small bowel biopsies, by polymerase chain reaction examination of synovial fluid or tissue or by immunohistochemistry [11].

Intestinal polyposis

A number of usually inherited gastrointestinal polyposis disorders also have cutaneous features. They are discussed in detail elsewhere in this book. The most important are:

  • Peutz–Jeghers syndrome
  • Gardner syndrome
  • Cowden's disease (multiple hamartoma and neoplasia syndrome)
  • Bannayan–Riley–Ruvalcaba syndrome
  • Cronkhite–Canada syndrome (non-inherited)
  • Birt–Hogg–Dubé syndrome
  • Naevoid basal cell carcinoma syndrome
  • Neurofibromatosis.

LIVER AND GALL BLADDER

Hepatobiliary diseases are frequently associated with abnormalities of the skin, nails and hair [12, 13]. However, these are mostly non-specific as they may be present in other diseases and absent even in patients with advanced liver dysfunction. Additionally, many diseases may share the same cutaneous features (for example, most causes of cirrhosis have a commonality of clinical signs), and there is no clear correlation between the degree of the skin changes and the severity of liver dysfunction. However, there may be constellations of features that suggest specific diagnoses (e.g. pigmentation, jaundice and xanthomas in primary biliary cirrhosis). The overall picture of the patient may therefore be as useful as the presence of particular cutaneous signs. Cutaneous features of chronic liver disease are listed in Box 152.1. This section will discuss some of the main groups of hepatobiliary disease, followed by some of the more important symptoms and signs in the next section.

Hepatitis and acute liver disease

Acute hepatic damage is most often due to viral hepatitis, alcohol or drugs. Cutaneous features may be absent, or there may be jaundice. This section considers the dermatological associations of infective hepatitis.

Hepatitis A virus infection. This is usually asymptomatic and transient. Dermatological features, if present, are jaundice, urticaria (less than 2%) and exanthema [14]. Chronic liver disease does not occur but a relapsing variant has been described in which itch, purpura and urticarial lesions are present [15]. Histology in such cases demonstrates a small-vessel vasculitis. More severe vasculitis or panniculitis is rare.

Hepatitis B virus infection HBV infection is of major relevance to health care workers as it may be transmitted parenterally. It is also transmitted sexually and HBV infection may be associated with other sexually transmitted diseases. HBV screening and vaccination are recommended for all health care workers. Vaccination is not without dermatological side effects: provocation of granuloma annulare, lichen planus, Gianotti–Crosti syndrome and urticaria, and contact allergy to preservatives have all been reported [16–18]. Twenty to 30% of patients with acute HBV infection develop a serum sickness-like disease, which occurs weeks before the clinical onset of liver disease. Up to 8% of patients with acute HBV infection develop polyarteritis nodosa. Other dermatoses that have been associated with acute HBV infection include urticaria, erythema multiforme, Gianotti–Crosti syndrome, mixed cryoglobulinaemia, lichen planus and dermatomyositis [12].

Hepatitis C virus (HCV) infection. This is usually transmitted parenterally. Necrolytic acral erythema is a specific feature of acute HCV infection [12]. Well-demarcated, acral (mainly dorsa of the feet), dusky discoloration with peripheral blister formation progresses to form keratotic erythrokeratoderma-like chronic inflammation (Figure 152.4). Histology and the clinical picture are similar to those of other necrolytic erythemas. Treatment comprises interferon, usually combined with ribavirin, or zinc and amino acid/zinc supplementation [12].

Image described by caption.

Figure 152.4 Necrolytic acral erythema in patient with longstanding hepatitis C.

(Courtesy of Dr Vesarat Wessagowit, Institute of Dermatology, Bangkok.)

Up to 75% of patients with HCV fail to eradicate the virus after the initial infection [12]. Many of these may present with skin disorders. Mixed cryoglobulins can be detected in up to half of patients with HCV infection but only a small proportion of patients develop manifest cryoglobulinaemic vasculitis (see Chapter 102) [19]. Other dermatological conditions that have been associated with persistent infection include polyarteritis nodosa, porphyria cutanea tarda, lichen planus, sicca syndrome, manifestations of chronic liver disease such as pruritus and prurigo and reactions to antiviral drugs. Less well-corroborated associations with HCV infection include pyoderma gangrenosum, antiphospholipid syndrome, Behçet disease, vitiligo, amyloidosis, sarcoidosis and Sjögren syndrome.

Liver cirrhosis

Skin signs of liver cirrhosis are similar to those seen in general in chronic liver disease. They reflect the various components of functional hepatic impairment and are discussed in the section ‘Liver diseases and the skin’.

Haemochromatosis [14] Haemochromatosis (‘bronze diabetes’) is a disorder in which iron overload leads to iron deposition in various organs, including the liver and the skin (see Chapter 88). Classic idiopathic haemochromatosis usually presents in males over the age of 40 years. An acquired form also occurs, secondary to haemosiderosis or alcohol abuse. Skin pigmentation occurs in up to 90% of patients with haemochromatosis. It typically has a bronze-coloured or grey hue, and is most prominent on sun-exposed skin. This pigmentation seems to be a result of elevated melanin production. Stigmata of chronic hepatic failure may also be present. Ichthyosiform dryness of the skin, koilonychia and loss of body hair also occur.

Primary biliary cirrhosis and biliary tract disease. From the dermatological point of view, primary biliary cirrhosis (PBC) is the most important biliary tract disease. Nearly 40% of PBC patients first present with skin signs or symptoms [12]. The cutaneous features of significance are marked itch (discussed in more detail later in this chapter), excoriation, hyperpigmentation and various xanthomatous lesions due to secondary hyperlipidaemia [12]. Xanthelasmas, palmar xanthomas and tuberous xanthomas may all occur. PBC occurs mainly in middle-aged women as an autoimmune disease and is strongly associated with the presence of antimitochondrial antibodies. It can be associated with numerous other autoimmune conditions, among them Raynaud disease, keratoconjunctivis sicca and systemic sclerosis [20]. The constellation of systemic sclerosis and its variants with PBC is also known as Reynolds syndrome [21].

Cholestasis and bile stones may cause acute or chronic jaundice and other features of liver disease. Pigment bile stones may occur due to erythropoietic protoporphyria, a disease which may also rarely cause fulminant hepatic failure [22].

Congenital biliary tract hypoplasia with consecutive cholestasis is a feature of Alagille syndrome (arteriohepatic dysplasia) [12], a dominantly inherited disorder. Affected individuals have a characteristic facies, jaundice, severe pruritus, widespread xanthomas and retardation of growth and mental development. Various skeletal, ocular and vascular defects are associated.

PANCREATIC DISEASE

Apart from jaundice and panniculitis, skin changes associated with pancreatic disease are uncommon. The glucagonoma syndrome is a rare but highly characteristic skin disorder, which is discussed in the section on necrolytic migratory erythema. Skin disorders associated with diabetes are discussed in Chapter 64.

Acute pancreatitis

Jaundice and fat necrosis may both be prominent. Purpura or bruising may occur in patients with acute pancreatitis. Note, however, that none of these are specific for pancreatitis [23]. They may also occur due to retroperitoneal haemorrhage or bleeding from sources such as splenic rupture, ectopic pregnancy, metastatic tumour or aortic aneurysm. Four eponymous signs occur with retroperitoneal bleeding or the tracking of haemorrhagic fluid:

  1. Grey Turner's sign: tracks from the pararenal space to the edge of the quadratus lumborum muscle, then through a defect in the fascia to the subcutaneous tissues of the flank (left-sided in pancreatitis).
  2. Cullen's sign: tracks into the falciparum ligament, then through the connective tissues of the round ligament to the periumbilical area.
  3. Fox's sign: tracks along the fascia of the psoas and iliac muscles to the subcutaneous tissues of the upper thigh.
  4. Bryant's sign: tracks to the scrotum to produce the ‘blue scrotum’ sign [24].

Features related to the aetiology of the pancreatitis may also be present, such as signs of alcohol abuse or hepatic cirrhosis, or xanthomas due to hypertriglyceridaemia.

Panniculitis/subcutaneous fat necrosis

Patients with pancreatic disease develop lobular panniculitis in 2–3% of cases (see Chapter 99) [25, 26]. It may be associated with acute or chronic pancreatitis, pancreatic carcinoma or other pancreatic diseases [23]. Histopathologically, subcutaneous fat necrosis is pathognomonic together with ghost-like anucleated cells [23]. Arthritis with intraosseous fat necrosis may accompany the pancreatitis and the panniculitis, together called PPP syndrome [22]. Nodular lesions are usually 1–3 cm in diameter and are tender or symptomless. The areas of predilection are the lower extremities, but lesions may occur anywhere. Lesions persist for 2–3 weeks and then heal. They may leave atrophic, hyperpigmented scars.

Migratory thrombophlebitis

The highest risk of developing migratory superficial thrombophlebitis seems to be associated with adenocarcinoma of the pancreas [27].

Necrolytic migratory erythema

Necrolytic migratory erythema is the cutaneous manifestation of the glucagonoma syndrome, which results from a glucagon-secreting α-cell tumour of the pancreas (see Chapter 147). Necrolytic migratory erythema may also occur without glucagonoma: what has been termed pseudoglucagonoma syndrome has been described in association with zinc and protein deficiency, liver cirrhosis, IBD, pancreatitis and non-pancreatic malignancies [1].

Lesions are annular and erythematous with erosions, crusting, desquamation and hyperpigmentation fluctuating in extent and severity. The rash is itchy or painful and particularly affects sites exposed to friction and pressure including flexural sites on the lower abdomen, groin, buttocks and thighs.

Apart from elevated serum glucagon levels, the clinical spectrum also includes diarrhoea, weight loss, weakness, thrombosis and psychiatric disturbances.

Other dermatological features of pancreatitis

The main dermatological features of acute and chronic pancreatitis have been described in this chapter, or are the result of malabsorption attributable to pancreatic failure (see Gastrointestinal malabsorption and the skin in this chapter). Livedo reticularis has also been described in pancreatitis as Walzel's sign [23].

DERMATOLOGICAL MANIFESTATIONS OF OTHER DISORDERS INVOLVING THE DIGESTIVE SYSTEM

Bullous diseases may affect the pharynx, oesophagus or stomach. Epidermolysis bullosa is of particular relevance as some forms may affect all parts of the digestive system [28].

Immunobullous diseases, particularly those with an IgA basement membrane zone immunoreactant, may cause mucosal blistering and erosions. Examples include mucous membrane pemphigoid, linear IgA disease and the IgA variant of epidermolysis bullosa acquisita. Mucous membrane pemphigoid may also cause oesophageal scarring and stenosis.

Sclerodermatous processes also affect the oesophagus, in particular limited systemic sclerosis, formerly known as CREST (calcinosis, Raynaud phenomenon, oesophageal dysmotility, sclerodactyly, telangiectasia). This disorder is discussed more fully in Chapter 56. Gastrointestinal involvement occurs in up to 90% of patients with diffuse systemic sclerosis [29]. It can affect all parts of the gastrointestinal tract and is associated with decreased peristalsis throughout the bowel, leading to malabsorption, constipation and diverticula. Sjögren syndrome may also cause dysphagia, as may dermatomyositis in cases in which there is involvement of the pharyngeal musculature. Several patterns of cutaneous vasculitis may be associated with mesenteric vasculitis and/or thrombosis, leading to bleeding or ulceration. Various gastrointestinal symptoms have been reported in relation to systemic lupus erythematosus, and include gastro-oesophageal reflux, dysphagia, abdominal pain, impaired digestion, perforation and bleeding [30].

Several other inflammatory disorders such as lichen planus may affect the mouth, pharynx or oesophagus [31].

Skin disorders associated with gastrointestinal bleeding

These are listed in Table 152.1. All are discussed elsewhere in this book.

Table 152.1 Skin lesions associated with gastrointestinal disorders that may present with bleeding.

Disease Gastrointestinal lesion Skin manifestation
Vascular defects and inherited
Osler–Weber–Rendu disease Telangiectasia Telangiectasia
Blue rubber bleb naevus syndrome Haemangiomas Haemangiomas
Pseudoxanthoma elasticum Involvement of visceral arteries Yellowish papules and plaques
Ehlers–Danlos syndrome (type IV) Fragility of visceral arteries Hyperelasticity of skin and joints
Polyposis
Neurofibromatosis (von Recklinghausen) Neurofibromas Café-au-lait spots, neurofibromas
Cronkhite–Canada syndrome Gastrointestinal polyposis Diffuse hyperpigmentation, alopecia, nail defects
Gardner syndrome Polyposis of colon (cancer) Lipomas, epidermoid cysts
Peutz–Jeghers syndrome Polyposis, especially small intestine Hyperpigmentation on lips, circumoral area and fingertips
Cowden's disease Polyposis Papules, lipomas, angiomas
Inflammatory bowel disease
Crohn disease, ulcerative colitis Inflammatory changes of the intestinal wall Erythema nodosum
Aphthous stomatitis
Pyoderma gangrenosum, other neutrophilic dermatoses
Necrotizing vasculitis
Epidermolysis bullosa acquisita
Erythema multiforme
Vasculitis and systemic disease
IgA vasculitis (Henoch–Schönlein purpura) and other vasculitides Mesenteric vasculitis, gastric ulcers (polyarteritis nodosa) Purpura, livedo, nodules, necrosis
Cholesterol emboli Intestinal arterial occlusion Vasculitis, necrosis, livedo
Degos disease Intestinal perforation White atrophic papules
Amyloidosis Vascular fragility Purpuric lesions
Neoplasia
Primary gastrointestinal cancers Neoplasm Metastases, paraneoplastic eruptions, features of polyposis syndromes
Kaposi sarcoma Kaposi sarcoma of bowel Kaposi sarcoma of skin

Gastrointestinal malabsorption and the skin

Malabsorption may be associated with skin changes in a number of different ways: (1) malabsorption can cause a skin disorder; (2) a skin disorder can cause malabsorption; (3) skin abnormalities and malabsorption may have a common cause; and (4) skin disease and malabsorption can be related indirectly [32]. The skin changes from the first category may be due to deficiencies of macronutrients, including proteins, fat and carbohydrates, or of micronutrients, including minerals, trace elements and fat-soluble vitamins [33]. Some causes of malabsorption are listed in Box 152.2. Non-specific cutaneous manifestations of malabsorption are listed in Box 152.3. The cutaneous manifestations of specific vitamin and mineral deficiencies are discussed in Chapter 63. Patients presenting with skin changes suggestive of malabsorption should be thoroughly investigated to identify the cause.

Skin complications of stomas

Stomas are most frequently required for the management of gastro-intestinal disorders including IBD, bowel cancer, diverticulosis or bowel obstruction (e.g. volvulus or intussusception). There is an increased prevalence of psoriasis in patients with IBD and peristomal psoriasis may cause problems with stoma management in affected patients [32]. Parastomal pyoderma gangrenosum is particularly associated with Crohn disease. Skin problems of stomas are fully discussed in Chapter 114.

Liver disease and the skin

Systemic diseases and the liver

A large number of systemic diseases may affect the liver, many with cutaneous features. Most are discussed in other chapters in this book. For example, sarcoidosis is associated with subclinical hepatic involvement in over 50% of patients, but may cause overt hepatomegaly or abnormalities of liver function in conjunction with skin lesions.

Porphyrias (see Chapter 60), especially porphyria cutanea tarda, may occur as a consequence of liver disease but severe liver disease is also a feature in some patients with erythropoietic protoporphyria.

Hereditary haemorrhagic telangiectasia, mentioned earlier as a cause of gastrointestinal bleeding, is associated with portal hypertension due mainly to portosystemic shunting, so bleeding in such patients may be from varices [33].

pruritus

Pruritus is the most common skin symptom associated with liver disease. It may precede the diagnosis of liver disease. Liver diseases in which itch is most prominent are PBC, sclerosing cholangitis and any other biliary tract obstruction, and disorders causing cholestasis. Itch is less prominent in haemochromatosis, alcoholic cirrhosis and autoimmune chronic active hepatitis [34]. The symptoms are generally most severe at acral sites and at areas of tight clothing, and are more prominent nocturnally.

The precise mechanism of itch in cholestatic liver disease remains unclear. There is controversy over whether bile salts contribute to itch. The release of undefined putative pruritogens from the liver in the presence of cholestasis has been proposed as an alternative mechanism. Endogenous opioids and steroid metabolites also seem to be part of the complex process that leads to the development of cholestatic pruritus [35].

Treatment, where possible, is for the underlying cause – for example, drug withdrawal in drug-induced cholestasis, surgery for mechanical biliary obstruction, interferon and ribavirin for chronic HCV infection, etc. Diverse treatment regimens for cholestatic pruritus have been proposed: among them is a stepwise escalation scheme, starting with bile salt-chelating resins, followed in turn by rifampicin then opioid antagonists (e.g. naltrexone), then sertraline and, finally, consideration of other more experimental approaches [34]. UVB phototherapy can be effective [12], but ongoing treatment is generally required. Other treatments that have been used with success include albumin dialysis and plasmapheresis. The problem will normally respond to liver transplantation where this is indicated.

Skin pigment changes in liver disease [12]

A yellowish hue of the sclerae, mucous membranes and skin due to hyperbilirubinaemia is called icterus (jaundice). Green-coloured sweat [33] and green discoloration of the gingivae may accompany jaundice. Melanosis cutis due to excess epidermal melanin is found. A muddy grey pigmentation occurs in chronic liver disease of any cause. It may be blotchy or diffuse, and may be exaggerated in the areolar as well as in the perioral and periorbital areas (resembling melasma); in other cases it may resemble freckling and it can also localize to the palmar creases. Spotty hypomelanosis may occur on the back, buttocks and extremities, often in relation to spider angiomas.

vascular changes [12,13]

Spider telangiectases. These are a characteristic feature in patients with severe chronic liver disease (Figure 152.5) and are found in one-third of patients with liver cirrhosis. Hyperoestrogenaemia (which also accounts for the loss of secondary male-pattern hair, gynaecomastia and testicular atrophy) seems to be an important factor for the development of theses vascular changes.

Image described by caption.

Figure 152.5 Multiple spider telangiectases in 53-year-old woman with alcoholic liver disease.

Palmar erythema. Palmar erythema refers to a bright red discolora­tion of the palms, which is most pronounced on the hypothenar eminences and may also affect the soles of the feet. None of these vascular features are specific for liver disease. Diffusely scattered tiny telangiectatic vessels are referred to as ‘paper-money’ skin. Increased peripheral blood flow with dilatation of digital pulp arteriovenous anastomoses is thought to be the cause of finger clubbing.

Bleeding. Purpura, petechiae, ecchymoses and mucosal bleeding (epistaxis, gingival bleeding) may occur due to coagulation defects in patients with liver disease. In progressive liver disease with portal hypertension, collateral blood flow creates visible coiled varicose veins on the abdominal wall. When these are in a pattern radiating from the umbilicus, the appearance is termed ‘caput Medusae’.

hair and nail changes [12, 13]

The body hair is often thinned or partially lost, and males tend to develop a female pubic hair pattern, which may be associated with gynecomastia and testicular atrophy.

Various nail changes have been reported in association with chronic liver disease (see Chapter 95). They include a diffuse white colour with an invisible lunula, a proximal white colour with distal pink or brownish colour (Terry's nails) or paired white bands (Muehrke's bands). Altered digital blood flow, soft-tissue overgrowth and hypoalbuminaemia may all contribute. Nail plate changes include clubbing and its milder variant, the ‘watch-glass’ deformity; flattened nails or koilonychia as well as brittle nails may also occur. These are all non-specific findings that are also found in association with internal diseases of other organ systems.

Porphyria cutanea tarda

Chronic liver disease is involved in the skin changes of porphyria cutanea tarda (Figure 152.6). Lesions consist of bullae, scarring and hyperpigmentation of sun-exposed skin areas and hypertrichosis of the face. This is discussed in more detail in Chapter 60.

Image described by caption.

Figure 152.6 Porphyria cutanea tarda of the hand.

Other cutaneous lesions associated with liver disease

Lichen planus has been reported in a number of diseases with abnormal immune function. The association of erosive oral lesions in PBC and chronic active hepatitis may be related to a common immunological pathogenesis. There is uncertainty as to whether there is an association between HCV infection and lichen planus [37].

Pyoderma gangrenosum has also been reported in chronic active hepatitis [38]. The Gianotti–Crosti syndrome has been linked to hepatitis. Skin changes simulating classic glucagonoma syndrome have been reported in cirrhosis and termed the pseudoglucagonoma syndrome [1].

Acquired zinc deficiency may occur in chronic liver disease, especially alcoholic liver disease, and is thought to be due to a combination of increased urinary excretion and decreased dietary intake [39].

Drugs and the liver

Examples of drug-related links between the skin and the liver are given in Table 152.2.

Table 152.2 Drug-related links between the skin and the liver.

Mechanism Examples
Drugs whose hepatic metabolism is altered by liver disease or by other drugs that are also metabolized in the liver Ciclosporin
Drugs that may cause hepatitis or other liver damage Azathioprine, methotrexate
Drugs for the treatment or prevention of liver disease causing cutaneous side effects Penicillamine (elastosis perforans serpiginosa), thimerosal or other preservatives in hepatitis vaccines (local reactions)
Drugs that cause liver changes with secondary cutaneous signs Oestrogens (porphyria cutanea tarda)
Drugs that may cause concurrent hepatitis and rash Phenytoin and other anticonvulsants

References

  1. Shah KR, Boland CR, Patel M, et al. Cutaneous manifestations of gastrointestinal disease: part I. J Am Acad Dermatol 2013;68:189.e1–21; quiz 210.
  2. Thrash B, Patel M, Shah KR, et al. Cutaneous manifestations of gastrointestinal disease: part II. J Am Acad Dermatol 2013;68:211.e1–33; quiz 244–6.
  3. Abenavoli L, Proietti I, Vonghia L, et al. Intestinal malabsorption and skin diseases. Dig Dis 2008;26:167–74.
  4. Lin CC, Liu KL, Lin JT, et al. Education and imaging. Gastrointestinal: Sister Mary Joseph nodule. J Gastroenterol Hepatol 2008;23:1462.
  5. Hernando-Harder AC, Booken N, Goerdt S, et al. Helicobacter pylori infection and dermatologic diseases. Eur J Dermatol 2009;19:431–44.
  6. Huang BL, Chandra S, Shih DQ. Skin manifestations of inflammatory bowel disease. Front Physiol 2012;3:13.
  7. Freeman HJ. Long-term natural history and complications of collagenous colitis. Can J Gastroenterol 2012;26:627–30.
  8. Abenavoli L, Proietti I, Leggio L, et al. Cutaneous manifestations in celiac disease. World J Gastroenterol 2006;12:843–52.
  9. Eriksson P, Jacobs C, Johansson K-E. Remission of arthritis after esophagectomy in three patients with severe achalasia. Dis Esophagus 2013;26:226–30.
  10. Tucker SC, Chalmers RJG, Andrew SM, Odom NJ. Pustular vasculitis secondary to achalasia of the cardia. Br J Dermatol 2000;142:373–4.
  11. Schneider T, Moos V, Loddenkemper C, et al. Whipple's disease: new aspects of pathogenesis and treatment. Lancet Infect Dis 2008;8:179–90.
  12. Ghosn SH, Kibbi AG. Cutaneous manifestations of liver diseases. Clin Dermatol 2008;26:274–82.
  13. Hazin R, Abu-Rajab Tamimi TI, et al. Recognizing and treating cutaneous signs of liver disease. Cleve Clin J Med 2009;76:599–606.
  14. Geyer AS, Rosenburg DS, Herlong HF, Provost TT. Hepatitis. In: Provost TT, Flynn JA, eds. Cutaneous Medicine: Cutaneous Manifestations of Systemic Disease. Hamilton, Ontario: Decker, 2001:452–63.
  15. Glikson M, Galune E, Oren R, et al. Relapsing hepatitis A: review of 14 cases and literature survey. Medicine 1992;71:14–23.
  16. Criado PR, de Oliveira Ramos R, Vasconcellos C, et al. Two case reports of cutaneous adverse reactions following hepatitis B vaccine: lichen planus and granuloma annulare. J Eur Acad Dermatol Venereol 2004;18:603–6.
  17. Karakaş M, Durdu M, Tuncer I, et al. Gianotti-Crosti syndrome in a child following hepatitis B virus vaccination. J Dermatol 2007;34:117–20.
  18. Yasky AS, Eyal A, Kappel A, et al. Occupational contact dermatitis in a nurse due to thimerosal. Isr Med Assoc J 2011;13:254–5.
  19. Monti G, Saccardo F, Castelnovo L, et al. Prevalence of mixed cryoglobulinaemia syndrome and circulating cryoglobulins in a population-based survey: the Origgio study. Autoimmun Rev 2014;13:609–14.
  20. Rashtak S, Pittelkow MR. Skin involvement in systemic autoimmune diseases. Curr Dir Autoimmun 2008;10:344–58.
  21. Jakez-Ocampo J, Atisha-Fregoso Y, Llorente L. Systemic sclerosis associated with primary biliary cirrhosis (Reynolds' syndrome) in a pair of siblings. Clin Exp Rheumatol 2007;25:793.
  22. Shehade SA, Chalmers RJG, Prescott RJ. Predictable and unpredictable hazards of erythropoietic protoporphyria. Clin Exp Dermatol 1991;16:185–7.
  23. Lankisch PG, Weber-Dany B, Maisonneuve P, et al. Skin signs in acute pancreatitis: frequency and implications for prognosis. J Intern Med 2009;265:299–301.
  24. Dargin JM, Lowenstein RA. Ruptured abdominal aortic aneurysm presenting as painless testicular ecchymosis: the scrotal sign of Bryant revisited. J Emerg Med 2011;40:e45–8.
  25. Narváez J, Bianchi MM, Santo P, et al. Pancreatitis, panniculitis, and polyarthritis. Semin Arthritis Rheum 2010;39:417–23.
  26. Lee WS, Kim MY, Kim SW, et al. Fatal pancreatic panniculitis associated with acute pancreatitis: a case report. J Korean Med Sci 2007;22:914–17.
  27. Thayalasekaran S, Liddicoat H, Wood E. Thrombophlebitis migrans in a man with pancreatic adenocarcinoma: a case report. Cases J 2009;2:6610.
  28. Fine JD, Mellerio JE. Extracutaneous manifestations and complications of inherited epidermolysis bullosa: part I. Epithelial associated tissues. J Am Acad Dermatol 2009;61:367–84; quiz 385–6.
  29. Tian XP, Zhang X. Gastrointestinal complications of systemic sclerosis. World J Gastroenterol 2013;19:7062–8.
  30. Xu D, Yang H, Lai CC, et al. Clinical analysis of systemic lupus erythematosus with gastrointestinal manifestations. Lupus 2010;19:866–9.
  31. Fox LP, Lightdale CJ, Grossman ME. Lichen planus of the esophagus: what dermatologists need to know. J Am Acad Dermatol 2011;65:175–83.
  32. Nybaek H, Jemec GB. Skin problems in stoma patients. J Eur Acad Dermatol Venereol 2010;24:249–57.
  33. Sabbà C, Pompili M. Review article: the hepatic manifestations of hereditary haemorrhagic telangiectasia. Aliment Pharmacol Ther 2008;28:523–33.
  34. Ghent CN. Cholestatic pruritus. In: Bernhard JD. Itch: Mechanisms and Management of Pruritus. New York: McGraw-Hill, 1994:229–42.
  35. Imam MH, Gossard AA, Sinakos E, et al. Pathogenesis and management of pruritus in cholestatic liver disease. J Gastroenterol Hepatol 2012;27:1150–8.
  36. Allegue F, Hermo JA, Fachal C, Alfonsín N. Localised green pigmentation in a patient with hyperbilirubinemia. J Am Acad Dermatol 1996;35:108–9.
  37. Friedrich RE, Heiland M, El-Moawen A, et al. Oral lichen planus in patients with chronic liver diseases. Infection 2003;31:383–6.
  38. Byrne JP, Newitt M, Summerley R. Pyoderma gangrenosum associated with chronic active hepatitis. Arch Dermatol 1976;112:1297–301.
  39. Mohammad MK, Zhou Z, Cave M, et al. Zinc and liver disease. Nutr Clin Pract 2012;27:8–20.