ARTICLE
Since 1987 [1], about 60 cases of porphyria cutanea tarda (PCT) associated
with human immunodeficiency virus (HIV) have been reported [2-14]. This
association does not appear simply coincidental, but the respective roles
of HIV and toxic hepatic factors (particularly hepatitis C) in PCT remain
unclear. We report 10 new cases of HIV-positive patients with PCT; we
analyse the toxic hepatic factors in these patients.
Patients and methods
In a retrospective study, we made enquires at 8 hospitals in north eastern
France: Besançon, Strasbourg, Reims, Nancy, Dijon, Mulhouse, Colmar
and Thionville. We found 10 cases of PCT associated with HIV infection:
5 cases in Besançon, 3 in Strasbourg and 2 in Reims (prevalence:
10/1990: 0.005). The demographic features of these patients are presented
in Table I.
Diagnosis of PCT was assessed by cutaneous signs, high levels of urinary
porphyrins and histological examination of bullous lesions on the hands.
Evidence of alcoholism and prescribed drug consumption was established
during the initial interview.
Tests were done for: AST, ALT, gamma GT, ferritin, HCV antibodies (ELISA),
RNA-HCV (PCR), HBs antigenemia, HBV antibodies (HBs, HBc, HBe).
Results
All patients were men: 3 were IV drug abusers, 4 were homo/bisexual
men, 1 heterosexual man. The route of HIV transmission were unknown for
two patients. Seven of the ten had HIV-related symptoms: stage B (5),
stage C (2) according to the CDC classification, 1993; and 7 of the 10
had a CD4+ lymphocyte count below 200/mm3.
When PCT was diagnosed, their average age was 38 years (29-54) and the
presence of HIV infection had been established for 4.8 years (0.33-9)
in 9/10 patients.
By June 1997, 3 had died and 2 out of 8 were at stage C; 9 of the 10
patients had the characteristic cutaneous signs of PCT on the face, hands
and forearms (Figs. 1
to 4): blisters and erosions (9/10), hyperpigmentation
(10/10), photosensitivity (10/10), scars (9/10), milia (5/10), malar hypertrichosis
(4/10). One patient had only hyperpigmentation on the face and hands,
but he also had a very high level of uroporphyrins. Histological examination
showed a subepidermal blister, and direct immunofluorescence study revealed
perivascular deposition of immunoglobulins and complement. Urinary porphyrin
counts (uroporphyrins and coproporphyrins) were high in every patient.
For two patients, the level of coproporphyrins in the feces was determined
and was found to be positive. Because there was no family history of the
disease in the patients, levels of uroporphyrinogen decarboxylase (UPG-D)
were not determined. Hepatic data are presented in Table
II.
Alcohol abuse was present in 8 of the 10 patients; AST, ALT and gamma
GT were high in 9, 7 and 9 of the ten patients respectively; 5 of the
10 patients had HCV antibodies, and 4 of them had a positive HCV-PCR.
Of the 5 patients with HBV antibodies, none had positive HBs antigenemia.
All the patients took drugs which are on the list of those drugs contraindicated
for patients with hepatic porphyria (Centre français des porphyries,
Pr. Nordmann, Hospital Louis-Mourier, 92701 Colombes Cedex; ed Sept. 1996):
1 (6 patients) or 2 drugs (4 patients), among them: cotrimoxazole, sulfadoxine-pyrimethamine,
sulfadiazine, dapsone, fluconazole (Table
III).
Comment
Since Wissel's report of the first three cases in 1987 [1], the association
of PCT with HIV infection has become well known. About 60 cases have been
published so far. Here we report ten new cases which confirm some features
mentioned in the literature.
PCT is sporadic in most cases, but some familial cases have been reported
[1, 7]. Lestang et al. [15] reported two cases of familial PCT
using systematic assay of UPG-D, despite the stated absence of family
history. Mild cutaneous signs of PCT are possible in HIV-infected patients
[16].
In our patients, the mean age at onset of PCT (38 years) is lower than
for PCT in HIV-negative patients. Earlier onset of PCT is reported also
by Cribier et al. in patients with HCV infection [17]. Three out
of ten of our patients (37.5%) were IV drug abusers, whereas in the literature,
the figure is about 50% [18]. PCT can reveal HIV infection, although it
occurs at a late stage in HIV infection, B or C stage (CDC 1993), with
CD4+ T lymphocytes almost always below 200/mm3 [6].
Because of recent therapeutic progress and the fact that early medical
care is encouraged, the diagnosis of HIV infection via PCT should
become rarer. A diagnosis of PCT however, should prompt investigation
for underlying HIV and HCV.
A possible specific role of HIV in the development of PCT and its mechanism
remains undetermined. Abnormalities in porphyrin metabolism can exist
in HIV infection despite the absence of clinical features of PCT: 36%
(23/64) of cases [19] to 58% (21/36) of cases [20, 21]. The most frequent
abnormality is the isolated increase of coproporphyrins (23%); uroporphyrins
were increased in only 11% (7/64) of the cases in the series of Mouly
[19], including only 6% (4/64) with a profile of PCT. In the series of
O'Connor [21], 12% of the patients (4/33) had urine and stool porphyrin
excretion patterns that were typical of PCT. Among their 121 HIV-positive
patients, Cribier et al. found no patients with a porphyrin-excretion
profile that evoked PCT [22].
There are abnormalities in porphyrin metabolism
associated with the HIV infection, but they rarely constitute a real profile
of PCT. Presence of hepatitis C suggests that HIV alone cannot provoke
the development of clinical manifestations of PCT.
The mechanism involved are unknown, but various hypotheses have been
proposed. Fuchs suggests that the increase of cytokines (particularly
tumor necrosis factor and interferon) inhibits hematopoiesis, stimulates
neopterin, and results in anemia [20]. Anemia stimulates the biosynthesis
of porphyrins by feed-back. This hypothesis is supported by the relationship
between urinary excretion of neopterin and porphyrins.
The glutathione deficiency described in HIV-positive patients inhibits
the activity of UPG-D [23]. Reynaud et al. suggest that HIV infection
may produce a relative, endogenous estrogen excess, which could then lead
to an alteration of porphyrin metabolism [11]. The usual factors known
to trigger PCT are causal, associated co-factors in HIV infection. Some
co-factors, such as HCV and HBV hepatitis, hepatotoxic drugs, alcoholism,
blood transfusions, CMV or MAC hepatitis [10], are more frequent in HIV
infection. Among these, HCV appears to be a major trigger of PCT because
of its high prevalence (50 to 90%) in PCT, the early age at onset of PCT
(before age 40) and the usual detection of HCV RNA (PCR) in blood [17,
24-26, 28-30]. Regression of the cutaneous changes under interferon-alpha
therapy occurred in two patients [17, 31]. Normalization of urinary porphyrin
level was reported in one of these patient [31].
In our series, the prevalence of HCV infection
was 50% (5/10 patients), including a positive PCR for 4 of them. Co-infection
with both HCV and HBV is frequent in PCT: 30% in a recent study [27].
However, HBV replication markers, necessary to demonstrate its causal
role in PCT [32], were negative, as in our series.
Hepatotoxic drugs also constitute an important co-factor in these patients,
who take a lot of prescribed drugs. The most frequently used are fluconazole,
which is prescribed for oropharyngeal and oesophageal candidiasis, and
sulfamides, used for prophylaxis and treatment of Pneumocystis carinii
pneumoniae and cerebral toxoplasmosis. Sulfamides are prescribed for
patients with a CD4+ T lymphocyte count of less than 200/mm3,
or AIDS patients. This could partially explain the usual occurrence of
PCT at a late stage of HIV infection. Lafeuillade has evoked the triggering
role of zidovudine [33]. The precise role of antiretroviral therapy has
not yet been well defined. It could represent an important factor in the
future, because of the earlier indication of antiretroviral "tritherapy".
Classic phlebotomy is more difficult in HIV-positive patients because
of frequent anemia, and the risk of contamination for the nurses. The
treatment of HCV hepatitis with interferon could decrease the cutaneous
features [17, 31]. Abstinence from alcohol is difficult to maintain, and
substitution of drugs is not always easy.
CONCLUSION Our
series of ten patients confirms the presence of toxic hepatic factors in
PCT of HIV-positive patients, and in particular factors such as hepatitis
C, alcoholism and/or hepatotoxic drug use observed in each patient.These
co-factors seem to be triggers for the appearance of PCT in HIV-positive
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