A Post-cure Complication
Article Outline
Presentation
Long-term drug therapy for hepatitis C virus (HCV) infection would prove to have persistent effects—both desirable and undesirable. A 29-year-old woman with chronic hepatitis C, genotype 4, was to embark on a treatment regimen of oral ribavirin, 1000 mg, once daily and subcutaneous injections of pegylated interferon alfa-2b, 80 μg, once a week. At her initial physical examination, she had a body mass index of 26 (25-29 indicates overweight). Laboratory results showed that her alanine transaminase level, at 88 IU/mL, was well above the normal reference value (<31 IU/mL). Her albumin level and prothrombin time were within the normal range. She had no other relevant medical or family history.
In the first month, the patient reported anorexia, asthenia, and a weight loss of 8.8 lb (4 kg). Therapy continued, and just before the 48-week treatment period ended, she developed signs of bilateral lipoatrophy at the interferon injection site on her abdomen (Figures 1 and 2).
Figure 1.
This is the way the patient's abdomen looked at the end of the 1-year treatment period.
Figure 2.
Another view is seen here.
Assessment
The loss of subcutaneous fat at the patient's injection site was examined by specialists in the dermatology department. They confirmed a diagnosis of bilateral lipoatrophy. Six months after interferon treatment ended, a sustained antiviral response to therapy was verified with a negative HCV-RNA test.
Diagnosis
Lipoatrophy is usually secondary to an inflammatory process. In this case, it was attributed to the patient's 1-year course of interferon alfa-2b. Sometimes, differentiation between the cutaneous manifestations of hepatitis C infection and interferon therapy is not possible. A temporal relationship between the beginning of therapy and the appearance of the lesion is needed if the effect is to be ascribed to the drug.
Hepatitis C infection is a common cause of morbidity and mortality, affecting 3% of the world's population. In industrialized countries, chronic hepatitis C causes 40% of cirrhosis cases and 60% of hepatocellular carcinoma cases. It also is the leading indication for liver transplants, accounting for 30% of the surgeries. Currently, the standard regimen for chronic hepatitis C infection is subcutaneous pegylated interferon and oral ribavirin, a combination intended to produce a sustained antiviral response.1
Interferon therapy has been associated with a number of cutaneous complications. The most common dermatologic side effect, occurring in 15-20% of cases, is localized inflammatory skin lesions at the injection site. Progression to ulceration and necrosis, though infrequent, has been described.2, 3 The pathogenesis of progression is unknown, but a local immune-mediated inflammatory process might be involved.
Alopecia is one of the most frequently occurring cutaneous secondary reactions to interferon treatment, with a prevalence of around 10%-20%. Although the condition is generally mild, a more severe type, alopecia universalis, has been reported in a few patients. However, it was reversible once therapy was stopped.
Other complications of the skin and mucous membranes include oral pigmentation, trichomegaly, nail pigmentation, aphthous ulcers, and urticaria. It has been shown that patients with previous dermatologic diseases, such as psoriasis, seborrheic keratosis, or lichen planus, may suffer an exacerbation.4 Overall, hospital admission is rarely required for most cutaneous and mucous membrane reactions to therapy.
Lipoatrophy secondary to subcutaneous injections has been described in conjunction with several drugs, including insulin, corticosteroids, vasopressin, antibiotics, human growth hormone, iron dextran, diphtheria-pertussis-tetanus vaccine, antihistamines, and glatiramer acetate, a treatment for multiple sclerosis.5 Localized lipoatrophy also has been reported during treatment with interferon beta-1a and interferon beta-1b in patients with multiple sclerosis.6 Until now, however, lipoatrophy has not been reported in patients with hepatitis C or in patients treated with interferon alfa. Although different pathogenic mechanisms have been proposed for each of these drugs, lipoatrophy most probably is the shared late or residual stage of a previous drug-induced localized panniculitis.
In some studies with glatiramer acetate, for example, biopsy of the depressed areas showed “fibrosis of the dermis and subcutis with reduction in the size of the fat lobules and minimal mononuclear infiltrates.”7 It is likely that the drug has a direct toxic effect on the adipocytes, inducing a local inflammatory response that is followed by a hypersensitivity reaction and residual lipoatrophy.
The mechanism whereby lipoatrophy lesions appear at the site of pegylated interferon injections remains to be clarified. Hypothetical explanations include stimulation of local adhesion molecules, proinflammatory chemokine expression, and a direct chemotactic effect on immune cells by interferon.8 Why this complication seems to occur more frequently among patients with multiple sclerosis than those with hepatitis C infection is unknown.
A further point to consider is the possible pathogenic role of the polyethylene glycol molecule. Polyethylene glycol is often used as an additive in products such as topical drugs and cosmetics, and the literature refers to several cases of unwanted cutaneous side effects caused by this additive; particularly, contact dermatitis.9
Management
The patient's disfigurement persisted for several months. She was referred to a plastic surgeon for treatment that subsequently achieved good results. To our knowledge, this is the first published case of lipoatrophy after subcutaneous injection of pegylated interferon alfa in a patient with hepatitis C infection.
References
- . Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49:1335–1374
- Cutaneous ulceration induced by interferon alfa. Ann Pharmacother. 2004;38:173–174
- Cutaneous necrosis after injection of polyethylene glycol-modified interferon alfa. J Am Acad Dermatol. 2005;53:62–66
- . Exacerbation of lichen planus during interferon alfa-2a therapy for chronic active hepatitis C. Gastroenterology. 1993;104:903–905
- Localized panniculitis secondary to subcutaneous glatiramer acetate injections for the treatment of multiple sclerosis: a clinicopathologic and immunohistochemical study. J Am Acad Dermatol. 2006;55:968–974
- . Lipoatrophy: a non-reversible complication of subcutaneous interferon beta-1a treatment of multiple sclerosis. J Neurol. 2006;253:377–378
- Localized lipoatrophy after prolonged treatment with copolymer 1. J Neurol. 2000;247:220–221
- Subcutaneous interferon beta injections in patients with multiple sclerosis initiate inflammatory skin reactions by local chemokine induction. J Neuroimmunol. 2005;168:175–192
- . Skin reaction in antiviral therapy for chronic hepatitis C: a role for polyethylene glycol interferon?. Acta Derm Venereol. 2004;84:120–123
Parwathi “Uma” Paniker, MD, Section Editor
Conflict of Interest: The authors have no conflict of interest.
Funding: We had no funding sources.
Authorship: All authors had access to the data and participated in the preparation of the manuscript.
PII: S0002-9343(09)01080-8
doi:10.1016/j.amjmed.2009.12.009
© 2010 Elsevier Inc. All rights reserved.
