The International Dermatology Journal Club was initiated to take advantage of the new dialog of the connected dermatologic community world-wide. The members of this group consist of 16 dermatologists with diverse background and training, each bringing a unique perspective to these discussions. As the group presents and discusses articles, those comments are archived and will appear here in this column. Discussion is limited to members.
These archives are part of the proceedings portion of the Journal. As such, there is some editorial filtering, but the material has not been subject to the peer-review process. This section of the Journal also contains material which is open to additions until release of the next issue. This format is one attempt to make the the Journal reflect the immediacy of the Internet and to make it more interactive with the readers.
Arthur Huntley M.D.
"Mutations of keratinocyte transglutaminase in lamellar ichthyosis", by Huber et al (There are 10 authors), Science vol 267, 525-528, with an interesting editorial by Dennis Roop on pg 474.
The abstract is as follows:
Lamellar ichthyosis is a severe congentital skin disorder characterized by generalized large scales and variable redness.
Affected individuals in three families exhibited drastically reduced keratinocyte translutaminase activity. In two of these
families, expression of TGK transcripts was diminsihed or abnormal and no TGK protein was detected. Homozygous or compond
herozygous mutations of the TGK gene were identified in all families. These data suggest that defects in transglutaminase
cause lamellar ichthysosis and that intact cross-linkage of cornified cell envelopes is required for epidermal tissue homeostasis.
Basically, what these authors did was to find three families with lamellar ichthyosis, identify that the gene common to the affected individuals was transglutaminase (a calcium-sensitive enzyme that takes part in the crosslinking of cornified envelopes), grow the keratinocytes in culture, sequence the transglutaminase gene in these cells, and determine that affected individuals had various mutations in transglutaminase.
What I thought was important about this article:
Thea Mauro, M.D.
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Comments of Paul Bleicher M.D., Ph.D.
This paper is quite interesting as another example of the identification of the genetic defect in particular diseases. Unfortunately, at this time there is a long leap from this to a drug therapy for the disease. However, rapid progress is being made in this arena. The example you cited, sickle cell, is actually now being treated by a "non-specific" stimulator of gene transcription (to increase the fetal hemoglobin content (hydroxyurea). In addition, several other non-specific and more specific therapies are being tested, based directly on our understanding of the gene defect.
In the case of a keratinocyte transglutaminase mutation in lamellar icthyoses, the problem is difficult to translate directly to therapy. A "brute force" gene-directed approach seems unlikely without a direct skin graft to all involved skin. However, retroviral vectors could be used in an applied lotion on a regular basis (similar therapies are being suggested for an inhaled retroviral dnase in cystic fibrosis). In addition, liposomes containing the non-mutant form of the enzyme could be applied topically (if the barrier problem could be overcome and IF the mutation is not "dominant negative". A "dominant negative" mutation inactivates normal forms of the molecule.) Certainly, identification of the gene defect can contribute a great deal to diagnosis (not really a problem here) and in utero identification of affected fetuses.
I selected this article because of the recent interest in using traditional chinese herbal medication for atopic dermatitis.
Chaparral Ingestion: The Broad Spectrum of Liver Injury Caused by Herbal Medications: Gordon DW et al JAMA 1995:273:489-90
This is a case report of a 60 year old patient who developed acute on chronic liver failure from Chaparral, a herbal preparation made from desert shrub used for its antioxidant properties. The patient developed liver failure followed by renal failure necessitating liver and kidney transplant.
The patient complained of RHC pain, anorexia and jaundice. Liver function tests showed markedly raised bilirubin, liver enzymes, moderately elevated alkaline phosphatase and prolonged prothrombin time. Investigations for antibodies to hepatitis A and C, hepatitis B core antigen were negative. Antinuclear and antimitochrondrial antibodies were negative. Laparotomy showed ascites and a nodular liver. Biopsy showed acute hepatitis with areas of lobular collapse and nodular regeneration, mixed portal inflammation and marked bile ductular proliferation.
The Patient was not on any other drugs except for diltiazem, atenolol, aspirin and nitroglycerins and occasional acetaminophen. There was no history of transfusion or alcohol use. She had been taking Chaparral capsule 1 to 2 a day for 10 months plus a glass of herbal tea made from nettle and chickweed.
Three weeks before admission, the patient developed a "flu-liked syndrome" and increased her chaparral intake to 6 capsules per day. Jaundice developed 2 weeks later with encephalopathy and renal failure (from acute tubular necrosis). The patient underwent orthotopic liver transplantation and cadeveric renal transplantation. She made a slow recovery and after 1.5 years follow-up, her liver function tests remained normal.
Author's Comments
Chaparral is prepared by grinding leaves of an evergreen desert shrub (creosote bush or greasewood). Chaparral has been recommended
as a free radical scavenger to retard aging as well as for various skin conditions. The active ingredient is a potent antioxidant,
nordihydroguaiaretic acid (NDGA). NDGA is a potent and selective inhibitor of lipoxygenase pathways, although in higher concentrations
it also inhibits cyclo-oxygenase pathways as well as cytochrome P-450 activity in rats. NDGA could possibly cause a shift
favouring proinflammatory mediators and potentiate hepatotoxicity. There were 3 previously reported cases of chaparral hepatotoxity
with hepatitis-like syndrome. Author did not analyse the patient's uningested chaparral capsules for impurities that might
have contributed to her liver injury. It was likely that the patient developed subclinical hepatotoxicity from chronic use
of chaparral. She increased her dose of chaparral, acute liver injury may have superimposed on chronic liver disease resulting
in fulminant hepatic failure.
Physicians should therefore question patient regarding their use of nontraditional medications and consider these as a potential cause of hepatic dysfunction.
Editorial Comments in the same issue of JAMA:
RS Koff, Dept of Medicine, MetroWest Medical Center, Framingham, Mass
Alternative, nontraditional, or unconventional medicine is widely used. Patients regard these preparations as harmless because they are derived from botanical products. However, these herbal products often do not have safety nor efficacy studies performed.
Some of these products are potent hepatotoxins. In up to 50% of patients with fulminant liver disease, viral infections cannot be confirmed to be the cause. Some of these cases might be due to unrecognized ingestion of hepatotoxic alternative herbal products.
Ingested plants, plant products, plant adulterants and contaminating substances have been known to cause hepatotoxicity e.g. Amanita phalloides, aflatoxin, pyrro?lizidine alkaloids. Many more are not recognized.
Public education is essential to counter the assumption that herbal preparations are invariably safe. Although there is no doubt that some herbs are safe, reducing the risk of herbal hepatotoxicity may require reducing the use of these products until more is learned about their composition and safety. There have been recent interest in the use of traditional Chinese herbal medication for treating atopic dermatitis. Several dermatologists have been making enquiries about the source of these herbs.
Dr Goh's comments:
Those intending to use herbal concoctions should bear in mind the risk of such botanical products. The constituents of many of these products vary according their source and time of harvest. The original study conducted by Sheehan and Atherton was carried out in a very stringent and scientific way where each batch of the concoction was tested by chemical analytical procedures to ensure consistency of constituents.
C L Goh
Institute of Dermatology, Singapore
National Skin Centre
Singapore
I did a bit of searching in non-derm journals and found a good review of Kaposi's sarcoma -- written from a slightly different standpoint than are the Archives, JAAD, etc.
Hermans, Clumeck, "Kaposi's Sarcoma in patients infected with Human Virus (sic) (HIV): An Overview" Cellular and Molecular Biology 41(3), 357-64, 1995.
This article begins with the cursory definitions of the forms of KS: Classic (indolent disease on the lower extremities of Mediterraneans and Ashkenazi Jews), Endemic (aggressive disease in young Central African males), Associated with Renal Transplant (tends to regress after discontinuation of immunosuppression), and AIDS-associated (mostly in homosexual caucasian males). The epidemiology, pathogenesis, and clinical/theraputic elements of the disease are briefly discussed, highlighting the most recent developments. A good portion of the information is not substantially different than that in a dermatology text -- but some of the newer developments are interesting.
Epidemiology -- The paper does a nice job of tying together the epidemiologic factors that suggest an infectious etiology for KS (although the novel herpesvirus recently found is mentioned only in passing). KS as the initial manifestation of AIDS has been decreasing over the past decade, as is the mean CD4 count at the time of KS incidence. No explanation other than the expanding number of AIDS-defining conditions is given. The question of the male predominance in KS is then addressed: Beta-Human Chorionic Gonadatropin has found to be inhibitory to KS cells in vitro, and case reports exist of spontaneous regression of tumors in females during pregnancy. The mechanism is not known, but may be related to B-HCG acting as a competitive inhibitor for PDGF.
Pathogenesis -- The pathogenesis of KS is still unclear, with epidemiologic data suggestive of an infectious etiology, but some in vitro experiments able to establish KS cultures from a cellular responce to inflammatory cytokines. These agents (Il-1, Il6, PDGF, TGFB, GM-CSF and others) have been shown in vivo to enhance KS growth, and raise the question of non-infectious etiology in patients with multiple (e.g. sexually-transmitted) infections. Interestingly, the paper cites a case report in which GM-CSF administered to an AIDS patient caused growth of his KS lesions.
Clinical/Theraputic -- The paper cites median survival of 17 months after diagnosis of AIDS-associated KS, which has not been changing over the past 10 years. The authors make no attempt to reconcile this with the previously stated declining CD4 counts at the time of diagnosis. Unfortunately, after a review of the existing treatments, the authors conclude that no promising new treatments have been recently introduced.
I think that the value of this article is not in the presentation of any one "new" piece of information, but rather in viewing (and reviewing) Kaposi's sarcoma in AIDS patients in a different light. Some of the recent developments in the understanding of this disease are presented -- the discussion of the potential use of B-HCG is especially interesting. I don't think that this article will change the way that we treat Kaposi's, but it did provide a useful review. I would be especially interested to hear from anyone involved in the trials of theraputic B-HCG.
The journal "Hautarzt" is the publication of the German Dermatologic Society. In Hautarzt 46: 144-153 (1995) appeared the review: Possibilities and Limitations of Cell Markers Reactive on Paraffin-Embedded Tissues for the Diagnosis of Primary Cutaneous Histiocytoses. by M. Fartasch, S. Goerdt and O.P. Hornstein
I will give a condensed overview; the reference - , figure- and table- numbers refer to the original article. It remains to be discussed, how well this kind of translated paper travels across language borders. The advantage of a review paper is, that tables and references are universally intelligible.
Summary:
Histiocytoses have been diagnosed traditionally by clinical exam, transmission electron microscopy and immunostaining on frozen sections. Several new markers for immunostaining on formalin fixed, paraffin embedded material have become available recently. Liechtenstein 1953 (40) was first in grouping the diseases Morbus Letterer-Siwe, Hand-Schueller-Christian disease and eosinophilic granuloma together as "histiocytoses X" with the X referring to the unknown pathogenesis. Since these cells resembled epidermal Langerhans Cells by electron microscopy (presence of Birbeck granules) (3) and by immunostaining (CD1a-expression) (46) the Histiocyte Society grouped these diseases as Langerhans Cell (LHC-) Histiocytoses (LHC-H) and set them apart from diseases with Monocyte/Macrophage proliferation: non-LHC-Histiocytoses (9,14). Table 1 lists the diseases which are subsumed under LHC and non-LHC histiocytoses.
Immunostaining of LHC-Histiocytoses on paraffin sections is possible via the following markers:
Niels Krejci-Papa
Jerry Eisner M.D.
Private Practice, Washington (state)
Haines Ely M.D.
Clinical Professor of Dermatology, UC Davis
Steven D. Emmet, M.D.
Clinical Associate Professor of Dermatology, UC San Diego
Hiroshi Fujiwara, M.D., PhD
Deptartment of Dermatology Niigata University, Niigata Japan
Niels Krejci-Papa M.D.
Dermatology Resident, University of Erlangen
Goh Chee Leok M.D.
Medical Director and Consultant Dermatologist of the National Skin Centre, Singapore(NSC). Clinical Associate Professor of
the National University of Singapore.
Edward C.P. Gomez, M.D., PhD
Professor Emeritus in the Department of Dermatology at UC Davis
L.J. Gregg, M.D.
Assistant Clinical Professor Dermatology and Medicine, OU Tulsa Medical College
Norman D. Guzick, M.D.
Clinical Assistant Professor of Dermatology & Family Practice at UT-Houston
SL Lamberg M.D.
Private Practice, Connecticut
Jeff Marmelzat M.D.
Private Practice, Los Angeles
Thea Mauro M.D.
Assistant Professor at the University of California, San Francisco
Chris Scholes M.D.
Dermatology Resident, Hahnemann University/Medical College of Pennsylvania
Kevin Smith M.D.
Private Practice, Ontario
Yoshiki Taniguchi M.D.
Lecturer, Department of Dermatology, Mie University School of Medicine
Dan Siegel M.D.
Associate Profesor of Clinical Dermatology
State University of New York at Stony Brook School of Medicine
Radoslaw Spiewak, M.D.
Institute of Agricultural Medicine, Lublin Poland
All contents copyright (C), 1995. Dermatology Online Journal University of California Davis