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Overview of dermatologic problems following liver transplantation

Overview of dermatologic problems following liver transplantation
Literature review current through: May 2024.
This topic last updated: May 16, 2024.

INTRODUCTION — Liver transplantation recipients, like other solid organ transplantation recipients, have an increased risk of dermatologic problems due to their need for long-term immunosuppression, and they benefit from pre-and post-transplantation screenings. Management by a dermatologist and dermatologic care should be integrated into the comprehensive, multidisciplinary care of liver transplantation recipients [1,2].

Dermatologic conditions are common in liver transplantation recipients [3]. Cutaneous findings include aesthetic alterations, infections, precancerous lesions, and malignancies. The severity of skin alterations ranges from benign, unpleasant changes to life-threatening conditions [4-6]. In addition to skin cancer screening, diagnosis, and management, visits with a dermatologist serve to educate and improve the patient's sun-protection behavior.

Among all solid organ transplantations, liver transplantation requires the least amount of immunosuppression [7]. As a result, patients who have undergone liver transplantation tend to have fewer dermatologic complications compared with other solid organ transplantation recipients [8]. However, due to the large volume of the liver, patients undergoing liver transplantation receive more donor lymphocytes than kidney, heart, or lung transplantation recipients. Because of the immunosuppression, the transplanted lymphocytes proliferate and, rarely, trigger graft-versus-host disease [9,10].

This topic will provide an overview of dermatologic disorders following liver transplantation. A detailed discussion of skin cancer following solid organ transplantation and the general management of patients following liver transplantation are discussed separately. (See "Malignancy after solid organ transplantation" and "Prevention and management of skin cancer in solid organ transplant recipients" and "Liver transplantation in adults: Long-term management of transplant recipients".)

EFFECT OF TRANSPLANTATION ON PREEXISTING DERMATOLOGIC DISORDERS — Patients undergoing liver transplantation may have preexisting dermatologic disorders that are subsequently affected by transplantation. In many cases, the disorders improve either as a result of removal of the diseased liver or because of the immunosuppression patients receive [11].

Dermatologic manifestations of liver disease — In patients with dermatologic lesions related to cirrhosis or associated with specific forms of liver disease, transplantation often leads to improvement in the dermatologic findings (table 1).

Most of the nonspecific mucocutaneous lesions linked to cirrhosis, such as palmar erythema, spider nevi, and pruritus, disappear in the weeks following the liver transplantation [12], though skin pigmentation, clubbing, and fingernail changes [13] may take several months to regress. Dupuytren's contractures are usually irreversible (picture 1). (See "Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis", section on 'Physical examination'.)

Specific forms of liver disease may also be associated with dermatologic manifestations (table 1). Although the clinical courses of these disorders after liver transplantation have not been well described, the available data suggest that many of these conditions improve. Examples include:

Autoimmune hepatitis – Alopecia [14] and vitiligo (picture 2) [15].

Chronic cholestatic liver disease – Xanthomas and xanthelasmas (picture 3) [16] (see "Clinical manifestations, diagnosis, and prognosis of primary biliary cholangitis", section on 'Physical examination').

However, planar xanthomas have been reported in liver transplant recipients who develop cholangiopathy [17].

Hepatitis C virus infection – Cryoglobulinemia, porphyria cutanea tarda (picture 4), leukocytoclastic vasculitis (picture 5), and lichen planus (picture 6) [18].

Coexisting dermatologic disorders — Patients with liver disease may have dermatologic disorders that are not the result of their liver disease, such as psoriasis and atopic dermatitis. There may be shared risk factors for dermatologic disorders and liver disease (eg, alcohol use is a risk factor for both psoriasis and alcohol-associated liver disease [19,20]). In addition, the treatment of the dermatologic disorder could be associated with hepatotoxicity (eg, methotrexate [21,22]). In some cases, the immunosuppressive agents used following liver transplantation, such as glucocorticoids and calcineurin inhibitors, may also lead to improvement in dermatologic disorders. However, rapid tapering of immunosuppression could lead to exacerbations of dermatologic disorders. Management of psoriasis and other chronic dermatologic conditions is discussed separately. (See "Treatment of psoriasis in adults" and "Treatment of atopic dermatitis (eczema)".)

Previously treated skin cancer — Patients undergoing liver transplantation may have a history of treated skin cancer. While a history of treated skin cancer is not an absolute contraindication to transplantation, if a patient develops a recurrence of the cancer, a reduction in immunosuppression may be needed, increasing the risk of graft rejection [23]. (See "Prevention and management of skin cancer in solid organ transplant recipients" and "Liver transplantation in adults: Patient selection and pretransplantation evaluation", section on 'Contraindications'.)

DERMATOLOGIC COMPLICATIONS AFTER LIVER TRANSPLANTATION — New dermatologic lesions may develop following liver transplantation, often related to the patient's immunosuppression [24,25]. Dermatologic complications include cosmetic side effects of immunosuppressive therapy (table 2), skin infections (table 3 and table 4 and table 5), skin cancer (table 6), and graft-versus-host disease (table 7).

The following questions may be helpful to estimate a patient's risk for dermatologic complications following liver transplantation:

Were there pretransplantation dermatologic problems?

Is the patient's skin sensitive to light?

What is the patient's typical exposure to sunlight?

What is the patient's exposure to animals?

Are serologies for herpes simplex I, herpes simplex II, herpes virus 8, hepatitis C virus, or syphilis positive?

What is the degree of immunosuppression?

What is the length of the follow-up since the liver transplantation?

Cosmetic problems and side effects of immunosuppressive therapy — Many of the immunosuppressive drugs used in the transplantation setting have been associated with mucocutaneous complications, such as acne, cushingoid appearance, and gingival hyperplasia (table 2). The complexity of immunosuppressive regimens often makes it difficult to identify a specific drug as the cause of a dermatologic complication.

Dermatologic infections — Dermatologic infections after liver transplantation can be challenging [5]. Dermatologic infections may be due to bacteria [26] (table 3), mycobacteria (table 3), viruses (table 4), or fungi (table 5), and often involve several infectious agents, such as skin coinfection with herpes virus and cytomegalovirus. Another frequently seen problem is the development of warts due to papillomavirus infection. (See "Infection in the solid organ transplant recipient".)

In the transplantation setting, some of these skin lesions lose their characteristic macroscopic appearance, making the diagnosis more difficult than in the nontransplantation setting. As a result, systematic microbiologic and histologic tests should not be delayed. Common bacterial and viral infections predominate early (less than three months) after transplantation, while rarer bacteria and opportunistic agents, such as fungi (picture 7), are seen later [27-30].

Skin cancer — Skin cancers, including squamous cell carcinoma (the most common form) (picture 8), basal cell carcinoma (picture 9), melanoma (picture 10) [31,32] and Merkel cell carcinoma (picture 11 and picture 12 and picture 13), are important dermatologic complications of liver transplantation (table 6) [33-40]. Skin cancer is more commonly seen in patients who have undergone liver transplantation than in patients with other immunosuppressed states [7]. Additionally, squamous cell carcinomas tend to be more aggressive in organ transplant recipients compared with the general population [41]. The relatively high incidence of skin cancer is principally due to the effects of three factors:

Immunosuppression (table 8 and table 9)

Exposure to sunlight

Infection with human papilloma virus

The diagnosis and management of skin cancer following solid organ transplantation are discussed in detail elsewhere. (See "Epidemiology and risk factors for skin cancer in solid organ transplant recipients" and "Prevention and management of skin cancer in solid organ transplant recipients" and "Malignancy after solid organ transplantation" and "Liver transplantation in adults: Long-term management of transplant recipients", section on 'De novo malignancy'.)

Miscellaneous — A variety of uncommon skin disorders may also be seen following liver transplantation (table 7) [4,42-53]. These include:

Graft-versus-host disease (picture 14 and picture 15) because the donor liver contains a large number of lymphocytes (see "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease", section on 'Skin')

Cutaneous calcinosis

Erythema elevatum diutinum (picture 16 and picture 17) (see "Erythema elevatum diutinum")

Photosensitivity due to pseudoporphyria, transitory porphyrinemia (picture 18)

Porokeratosis (picture 19 and picture 20) (see "Porokeratosis", section on 'Clinical presentation')

Immune thrombocytopenia (also called idiopathic thrombocytopenic purpura) (picture 21) (see "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis")

Granuloma annulare (picture 22) (see "Granuloma annulare: Epidemiology, clinical manifestations, and diagnosis", section on 'Clinical features')

Alopecia has been reported in 2.7 percent of pediatric liver transplantation recipients [54]

Malakoplakia as a complication of cutaneous septic vasculitis [55]

Urticaria due to immunoglobulin E (IgE)-mediated food allergy may develop after liver transplantation [11]

PREVENTION AND MANAGEMENT — Prevention of dermatologic complications following liver transplantation focuses primarily on skin cancer prevention. After liver transplantation, patients should protect themselves from sunlight. We recommend patients wear sun protective clothing and use sunscreens with a sun protection factor (SPF) of 30 or higher, though data are lacking with regard to the minimal SPF patients should use. It is important that the sunscreen chosen protects against the entire spectrum of ultraviolet radiation (UVA and UVB). The sunscreen should be applied 30 minutes before sun exposure and should be reapplied at least every two hours. (See "Selection of sunscreen and sun-protective measures" and "Prevention and management of skin cancer in solid organ transplant recipients", section on 'Sun protection'.)

Chemoprevention for squamous cell carcinoma (SCC) of the skin is discussed separately. (See "Prevention and management of skin cancer in solid organ transplant recipients", section on 'Chemoprevention for squamous cell carcinoma'.)

The skin of patients after transplantation should be examined completely and systematically, including the oral, genital, and anal areas [56]. Regular systematic examination of the skin is needed to discover and treat precancerous lesions, such as actinic keratosis (picture 23), verrucae (picture 24), and oral leukoplakia (picture 25). Any suspicious lesions should be examined by a dermatologist. (See "Prevention and management of skin cancer in solid organ transplant recipients", section on 'Post-transplantation surveillance' and "Prevention and management of skin cancer in solid organ transplant recipients", section on 'Follow-up'.)

The early recognition of cutaneous diseases after liver transplantation permits treatment during the mild stages and alerts the transplantation hepatologist that a reduction in the level of immunosuppression may be needed. A declining incidence of keratinocyte carcinoma has been observed following the implementation of routine, periodic dermatologic screening for organ transplant recipients [38,57,58].

Management of the cosmetic consequences of the immunosuppressive regimen, such as hypertrichosis and sebaceous hyperplasia (table 2), enhances the adherence of patients to treatment and their trust in the clinician. In some cases, changing the immunosuppressive regimen may improve dermatologic complications following solid organ transplantation. As an example, in renal transplantation recipients, conversion from calcineurin inhibitors (eg, cyclosporine) to tacrolimus has been shown to improve hypertrichosis [59]. Also, inhibitors of the mechanistic target of rapamycin (mTOR) kinase have been shown to slow down cutaneous carcinogenesis [60,61] compared with cyclosporine, but they can have multiple side effects such as impaired wound healing [62,63], rashes, and acne.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Liver transplantation".)

SUMMARY AND RECOMMENDATIONS

Effect of transplantation on pre-existing dermatologic conditions – Patients undergoing liver transplantation may have preexisting dermatologic disorders that are subsequently affected by transplantation. (See 'Effect of transplantation on preexisting dermatologic disorders' above.)

In patients with dermatologic lesions related to cirrhosis or associated with specific forms of liver disease, transplantation often leads to improvement in the dermatologic findings (table 1). Most of the nonspecific mucocutaneous lesions linked to liver cirrhosis, such as palmar erythema, spider nevi, and pruritus, disappear in the weeks following the liver transplantation, though skin pigmentation, clubbing, and fingernail changes may take several months to regress. Dupuytren's contractures are usually irreversible. (See 'Dermatologic manifestations of liver disease' above.)

Patients with liver disease may have dermatologic disorders that are not the result of their liver disease, such as psoriasis and atopic dermatitis. In some cases, the immunosuppressive agents used following liver transplantation, such as glucocorticoids and calcineurin inhibitors, may also lead to improvement in dermatologic disorders. However, rapid tapering of immunosuppression could lead to exacerbations of dermatologic disorders. (See 'Coexisting dermatologic disorders' above.)

Patients undergoing liver transplantation may have a history of treated skin cancer. While a history of treated skin cancer is not an absolute contraindication to transplantation, if a patient develops a recurrence, a reduction in immunosuppression may be needed, increasing the risk of graft rejection. (See 'Previously treated skin cancer' above.)

Dermatologic conditions related to liver transplantation – New dermatologic lesions may develop following liver transplantation, often related to the patient's immunosuppression. (See 'Dermatologic complications after liver transplantation' above.)

These include:

Side effects of immunosuppressive therapy, such as acne, hypertrichosis, cushingoid appearance, and immune thrombocytopenia (table 2). (See 'Cosmetic problems and side effects of immunosuppressive therapy' above.)

Skin infections due to bacteria, viruses, and/or fungi (table 3 and table 4 and table 5). The infections often involve several infectious agents. Common bacterial and viral infections predominate early (less than three months) after transplantation, while rarer bacteria and opportunistic agents, such as fungi, are seen later. (See 'Dermatologic infections' above.)

Skin cancer, particularly squamous cell carcinoma (table 6 and table 8). (See 'Skin cancer' above.)

Graft-versus-host disease (table 7). (See 'Miscellaneous' above.)

Prevention and management – Prevention of dermatologic complications following liver transplantation focuses primarily on skin cancer prevention. After liver transplantation, patients should protect themselves from sunlight with sun protective clothing and sunscreens with a sun protective factor (SPF) of 30 or higher. In addition, patients' skin should be examined completely and systematically, including the oral, genital, and anal areas. (See "Prevention and management of skin cancer in solid organ transplant recipients", section on 'Sun protection' and "Prevention and management of skin cancer in solid organ transplant recipients", section on 'Post-transplantation surveillance'.)

Early recognition of cutaneous diseases after liver transplantation permits treatment during the mild stages and alerts the transplantation hepatologist that a reduction in the level of immunosuppression may be needed. In some cases, changing the immunosuppressive regimen may improve dermatologic complications following solid organ transplantation.

ACKNOWLEDGMENTS — The authors and UpToDate thank Edmond Schmied, MD, and Patrick A Oberholzer, MD, who contributed to earlier versions of this topic review.

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