Porphyria in animals

Porphyrins are found to be widely, although erratically, distributed throughout the animal kingdom. It would indeed have been surprising had it been otherwise since the tetrapyrrole ring system is a key material used in hemoproteins and essential for all biologic oxidative metabolism in the fabric of life. Those anaerobes, which possess no cytochromes or other hemoproteins, may be regarded as degenerate forms in which this biosynthetic ability has been lost. The porphyrins are stable chemical materials that have been detected in fossil shells from the post-Pleistocine and upper-Eocene deposits and are thus many millions of years old.^1,2 In the lower phyla, the black slug, Arion, contains great quantities of uroporphyrin. Among the higher forms of animal life, the group of birds known as the Turacos or plantain-eaters are unique in having utilized the copper complex of uroporphyrin III, called turacin,³ for the deep red areas of pigmentation in their flight feathers (Fig. 1) although there seems to be nothing otherwise unusual about the porphyrin metabolism of these birds.⁴ Other birds also have porphyrins in their feathers and down^5–7 and porphyrins are used in the coloration of eggs. Among the mammals, a few genera appear normally to produce much more porphyrin than others and these belong to the family of rodents. The rat excretes a relatively large quantity of protoporphyrin, which arises by synthesis in Harder's glands.⁸     

Bovine papillomaviruses

Bovine papillomaviruses have a major contribution to make in unravelling the mechanisms of oncogenesis by this group. Most papillomaviruses can exert their biologic effect only in vivo, but several of the bovine types transform fibroblasts in culture; the altered cells have measurable attributes such as anchorage independence, density inhibition, and tumorigenicity in nude mice. Another important feature is that subgenomic fractions of DNA can be transfected into cells and elicit transformation. It is, therefore, possible to undertake quantitative molecular biologic and genetic studies in a way which is impossible with most papillomaviruses. Large amounts of virus can be obtained from bovine tumors. The six currently characterized viruses have all been cloned by recombinant techniques, and are the subject of intensive comparative research in many laboratories.     

Hematologic and hepatic manifestations of the cutaneous porphyrias

This chapter has dealt with five photocutaneous forms of human porphyria. The forms are a diverse group of disorders with many different hematologic, hepatologic, and neurologic manifestations. In essence, most photocutaneous porphyrias occurring in childhood will relate to congenital erythropoietic porphyria or protoporphyria. The nature of the skin lesions and a study of the heme precursor profile in red cells, plasma, urine, and feces should easily distinguish these two conditions. CEP is a disease wherein photomutilation is a dominant concern and aggressive new approaches of therapy also have been discussed. In protoporphyria, the dermatologic problem is less severe and the dermatologist should be aware that a subset of patients could develop active liver disease that may lead to fatal cirrhosis. Novel approaches of therapy have been briefly alluded to. With regard to postpubertal photocutaneous porphyria, the classic porphyria cutanea tarda syndrome is associated with liver disease, usually alcoholic with siderosis, and the treatment by phlebotomy to reduce hepatic iron is highly effective. The potential danger of liver carcinoma has been discussed. In subsets of porphyria cutanea tarda, this can be an endemic disease relating to environmental factors, ie, ingestion of polyhalogenated hydrocarbons. The biochemical diagnosis can be attained by fairly straight-forward solvent extraction analyses of urine and feces, showing the dominance of uroporphyrin excretion in the urine and coproporphyrin in the feces. Chromatographic techniques in plasma, bile, and feces reveal a PCT-specific porphyrin: isocoproporphyrin. Rare subtypes with hematologic manifestations, ie, hepatoerythropoietic porphyria and CEP, indicate the wide spectra of disorders that might be associated with a spontaneous deficiency of uroporphyrinogen decarboxylase activity. These latter syndromes are, however, rare. Two hereditary hepatic porphyrias, ie, autosomal dominantly inherited VP and HCP, have been briefly discussed. The hepatic lesion is metabolic, not morphologic, and its expression by the liver relates to its adaptive response to induction of microsomal hemoproteins by a variety of exogeneous and endogeneous compounds, eg, drugs and hormones. Photocutaneous lesions of HCP and VP are identical to PCT, the latter having no neurologic sequelae. In the former two, however, exposure of persons to drugs, such as the hydantoins and barbiturates, can lead to potentially fatal acute porphyric attacks.(ABSTRACT TRUNCATED AT 400 WORDS)     

Drug therapy in the acute porphyrias

The thrust of this chapter will be on drug therapy in the acute porphyrias. Specifically, avoidance of those drugs that might precipitate an acute neurologic episode or “acute attack” will be discussed. In the realm of the dermatologist, this will apply to patients with one of two disorders: variegate porphyria (South African genetic porphyria, VP) and hereditary coproporphyria (HC). The third of the acute porphyrias, acute intermittent porphyria (AIP), is not associated with skin lesions and such patients are accordingly unlikely to consult a dermatologist. In this chapter, we shall neither deal with the important topic of drug therapy during an acute attack nor precipitation or treatment by drugs of the purely cutaneous porphyrias; these subjects will be addressed elsewhere in this volume.     

Cutaneous artifactual disease. A review, amplified by personal experience

Cutaneous artifactual disease is part of the general syndrome of contrived disease. While classical examples are easy to recognize, it can present in unusual ways. Difficulties in recognition include the unusual doctor-patient relationship, the doctor's fear of missing organic disease, and the reality of the disease to the patient's family and the family doctor. The diagnosis depends upon finding lesions whose morphology is consistent and an emotionally immature patient, whose personality shows, or has shown, hysterical and masochistic traits. Lesions "arrive" fully developed. Once there they begin to heal, so that a continuous supply of new ones is necessary if the illness is to continue. High intelligence is compatible with the diagnosis, but a mature personality is not. The differential diagnosis is extensive. Investigations prove negative or equivocal; in the latter case, the investigator is led even further into unfamiliar territory. It is suggested that the essence of management is to keep in contact with the patient.     

Secondary intention healing: an alternative to surgical repair

The choices of wound management are limited to either surgical repair or healing by secondary intention. Use of secondary intention healing is the oldest method, antedating the practice of medicine, but its use has declined since surgical techniques have been developed, refined, and popularized. Now secondary intention healing is used mostly for small superficial surgical wounds, lacerations, abrasions, chronic ulcers, and for wounds created by destructive methods such as electrodessication, cryosurgery, or chemical cautery. These applications are known well to dermatologists, but are less often used by other surgeons except when wounds have persisted after surgical repair, become infected, or result from necrosis of flaps or grafts.Even among dermatologic surgeons the interest in plastic and reconstructive techniques has overshadowed the importance and advantages of secondary intention healing. In the past several decades, only a small number of reports has appeared discussing the use of secondary intention healing for wounds that are traditionally managed by surgical repair.^1–10 These reports “rediscovered” the often amazing cosmetic results that follow secondary intention healing. There remains a reluctance to use this method to its fullest advantage. This is partly due to fear that open wounds heal inordinately slowly with complications of pain, bleeding, infection, and horrible scarring, and partly due to the conceit that our surgical skills are superior to Mother Nature's own way. There is an immediate gratification that occurs after the successful repair of a large wound. This feeling is difficult to sacrifice, especially if the results of secondary intention healing cannot be predicted. This chapter will review the advantages of secondary intention healing and provide a set of guidelines that will enable one to predict the cosmetic results of wounds allowed to heal by this method.     

Effect of topically applied agents on healing wounds

In 1978, we published a new method for evaluating epidermal wound healing.¹ Our model was similar to that used by Winter.² Both models employed partial thickness wounds in domestic outbred swine. Winter evaluated wound healing by determining the percentage of the wound which was resurfaced by epidermis. The percentage of the surface re-epithelialized was determined by examining 100 histologic sections from each wound. The sections studied were at 50 μm intervals so that 20% of the wound area was studied.     

Current wound management: a symposium

As is evident in each of the preceding chapters, this is an exciting time for the dermatologist interested in wound healing. New information is available from the cell biologist about which chemicals released during the inflammatory response to wounding are important in healing. New wound dressing materials from industry provide a means of i ncreasing the speed of wound healing while reducing wound pain and tenderness. Guidelines have been determined for predicting the cosmetic result of wounds after secondary intention healing. The near future promises many more advanced techniques for wound management, such as skin autografts and electromagnetic devices to stimulate and speed healing.Nevertheless, today physicians are charged with the very practical matter of treating patients' wounds. We must apply the results of research, using newer information and advanced materials, in a sound manner to enhance wound healing. To document the current state-of-the-art in wound care so that our readers are aware of current practices, I have asked five prominent dermatologic surgeons to describe their methods of treating wounds. These physician represent several different geographic areas of the United States and both clinical and full-time faculty. Each of the five was asked to write short answers to the same set of questions. Their essentially unedited answers are presented.The dermatologic surgeons participating in this symposium are STEVEN MANDY. M.D., University of Miami School of Medicine, Miami. Florida; SHELDON V. POLLACK, M.D., Duke University Medical Center, Durham. North Carolina; SAMUEL J. STEGMAN, M.D., University of California Medical Center, San Francisco, California; NEIL SWANSON, M.D., University of Michigan School of Medicine, Ann Arbor, Michigan; and JOHN A. ZITELLI, M.D., University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.     

Detection of papillomavirus common antigens in lesions of skin and mucosa

HPV infections are associated with many proliferative lesions of cutaneous and mucosal squamous epithelium. PV genus-specific (common) antigens can be detected by immunocytochemical techniques in approximately 50% of lesions (warts and papillomas) without dysplastic changes. Dysplastic lesions of squamous epithelium are less likely to be permissive for viral expression: squamous neoplasias are rarely, if ever, productively infected. Almost any tissue that has been processed for pathology or exfoliative cytologie preparations can be reliably stained for the presence of papillomavirus common antigens. A positive staining reaction is interpreted as meaning that the lesion is associated with HPV infection and that it has a potential for being contagious.     

Postoperative cutaneous wound infections

Postoperative infectious complications are a frequent cause of morbidity and mortality in the surgical patient. These septic events usually involve the urinary or respiratory tracts or occur in the operative wound. The overall incidence of postoperative wound infection was 7.5% in a much-quoted national study reported nearly two decades ago.¹ The incidence varied from surgeon to surgeon, from hospital to hospital, and from one surgical procedure to another. The lowest infection rate (< 2%) followed clean operations, such as elective orthopedic procedures or herniorrhaphy, in which the possible sources of wound contamination were solely airbone or exogenous. Clean-contaminated operations that resulted in additional exposure of the operative site to the endogenous microflora had higher rates of infection (10 to 20%).Some surgeons have been relatively nonchalant about uncomplicated wound sepsis, thinking that it rarely influenced the patient's physical or psychological well-being or markedly altered the duration or cost of hospitalization; however, Green and Wenzel² reported that the average hospital stay doubled and the costs of hospitalization were thus increased when postoperative wound infection developed after any of six commonly performed operations.The economic, physical, and psychological impact of postoperative wound sepsis mandates the use of preventive methods,³ of which the most critical are proper operative technique and sound judgment—e.g., in the choice of operation—on the part of a responsible surgeon and his team. In addition, well controlled prospective, blinded clinical studies have defined the circumstances in which antibiotic prophylaxis is of benefit, as well as the situations in which the risks of prophylaxis outweigh the expected benefit,⁴ and have led to authoritative recommendations concerning the indications for antibiotic prophylaxis in the surgical patient.^5,6For the dermatologist who may be called upon to assist in repair of postoperative cutaneous wound infection, we review the factors that can lead to this complication.     

Immunopathology in pemphigus

The introduction of immunofluorescence (IF) techniques in dermatology has led to major advances in the understanding and in the diagnosis of pemphigus. These IF methods have allowed us to detect the serum autoantibodies reactive with an intercellular substance (ICS) of skin, mucosa, and bound immunoglobulin (IgG) in the ICS of skin lesions.¹ These studies provided the initial evidence that pemphigus is an autoimmune disease that affects the skin.     

Lupus erythematosus in neonates, children, and adolescents

Neonatal LE should be suspected in any infant with an erythematous or scaling dermatitis, especially if it is distributed on the head and neck or if there is a history of photosensitivity. It should also be suspected in any infant with congenital heart block. A biopsy, though helpful, is not necessary since the diagnostic abnormality is the presence of anti-Ro(SSA) antibodies in infant's serum. When the disease is diagnosed, the infant can be effectively treated with a mild topical steroid and sun avoidance, with or without sunscreens, until the age of 12 months when the autoantibodies have presumably degraded. The child then should be observed periodically through adulthood for the onset of SLE. Mothers of infants with neonatal LE need to be checked for the presence of anti-Ro antibodies and SLE, Sjögren's syndrome, or thyroiditis. The recurrence of neonatal LE in some, but not all, future pregnancies must be anticipated. As more of these infants are followed into adulthood, we will learn how often neonatal LE is a marker for adult-onset SLE.     

Mixed connective tissue disease

Mixed connective tissue disease (MCTD) was first described by Gordon Sharp,¹ in 1972, as a distinct connective tissue disorder characterized by overlapping features of systemic lupus erythematosus (SLE), progressive systemic sclerosis (PSS), and dermato/polymyositis (DP/PM). This can be distinguished from other overlap syndromes of the connective tissue diseases by the presence of high titers of an antinuclear antibody with specificity for ribonuclear protein (RNP).^1,2 Initial reports described the following additional characteristics of MCTD patients: a good therapeutic response to systemic corticosteroid therapy, a very low incidence of significant renal involvement, and a better prognosis than for SLE or PSS.^1–4 Currentopinion is divided, but in general MCTD is considered to be an overlapping clinical expression in the evolution of a more classic connective tissue disease, usually PSS. The prognosis is less favorable than once thought, particularly when the MCTD is dominated by features of PSS.^5–8     

Regression of flat warts and common warts

Wart (human papilloma) is such a common disease that even a child can make a diagnosis at a glance. Furthermore, from our long experience, we are aware that warts often disappear in a short period of time, spontaneously or after various magical rituals that are prevalent in different parts of the world. In Japan, we can find some shrines or temples in every district where ardent worshipers make pilgrimages in search of quick answers to their prayers to cure their warts.

Evaluation of clinical effectiveness of a new therapeutic modality is most difficult because of its high incidence of spontaneous wart resolution. The lesion can be cured even by hypnosis.

Recently, the phenomenon of spontaneous regression of warts was reviewed from the viewpoint of tumor immunology. We now know that in the body, tumors may be rejected by an immune “surveillance” mechanism analogous to resistance to microbial pathogens. Various modalities of immunization procedure or enhancement of host immunity can induce partial or complete resolution of established tumors in both experimental animals and humans. Even malignant tumors, such as melanoma or choriocarcinoma, may disappear spontaneously. Wart is one of the most common tumors in humans and probably the tumor that most commonly shows the phenomenon of spontaneous regression.

Advances in molecular biology and biotechnology have disclosed that, as there are various clinical types of wart, there are many distinct HPV types and that the distinct HPV types are associated with distinct cutaneous and mucosal papillomas.¹ Analogous to animals with the Shope papillomavirus or bovine papillomavirus infections, it is known that some human papillomavirus lesions may undergo malignant transformation.^2,3