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clinica/
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An International Journal
Oustri-Verlag Or. Karl Feistle
MOnchen-Oeisenhofen
Clinical Nephrology,
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Case
Report
@2006 Oustri-Verlag Or. K. FeisUe
ISSN 0301-0430
Key words
Henoch-Sch6nlein
purpura - drug reactionparacetamol - renal
disease
Vol. 66 - No. 2/2006 (131-134)
Henoch-Sch6nlein purpuraassociated with
acetaminophen and codeine
D. Santoro1, M. Stella2 and S. Castellino1
1Unit of Nephrology and Dialysis, San Vincenzo Hospital, Taormina ASL 5,
2Unit of Pathology Cervello Hospital, Palermo, Italy
Abstract. Wereport a case of a relapse of
Henoch-Schonlein Purpura (HSP) associated
with intake of paracetamol (also known as
acetaminophene) and codeine. A 69-year-old
man presented with fever, gross hematuria,
acute renal failure, palpable purpuric skin
rash over the legs, feet and arms, arthralgias
and abdominal discomfort. 1 week before he
had started therapy with co-efferalgan (association of paracetamol and codeine) for cervical arthrosis. Blood test revealed increase in
serumcreatinine levels (2.6 mg/dl), CRP(375
mg/dl), with no thrombocytopenia or hypocomplementemia. Co-efferalgan was discontinued. Gross hematuria resolved in 2 days,
purpuric rash disappeared in IO days, renal
function retumed to normal after 2 weeks and
abdominal pain and arthralgias improved on
the folIowing 2 - 3 weeks. An objective causality assessment in accordance with the
Naranjo algorithm, revealed that the adverse
drug reaction was probable between
paracetamoUcodeine and Henoch-Schonlein
purpura. To our knowledge, and based on a
medline search (up to 2005), we believe that
this could be considered the first case of
Henoch-Schonlein purpura, associated with
intake of paracetamol and codein. Although
this event could be considered rare, clinicians
should to be aware of possible associations
between HUS and the intake of paracetamol
amI/orcodeine to provide an early therapeutic
intervention and a close monitoring.
Introduction
Received
January 25, 2006;
accepted in revised form
March 14,2006
Correspondence to
D. Santoro, MD
Unit of Nephrology and
Dialysis, San Vincenzo
Hospital,
Taormina ASL 5, Italy
[email protected]
Henoch-Schonlein Purpura is a systemic
vasculitis characterizedclinicalIyby palpable
purpura, arthritis with renal and gastrointestinal involvement and, histologicalIy, by immunodeposition of IgA-containing immune
complexes in the skin or kidney. Such disease
is more common in children with an incidence of 15/20 cases/lOO.OOOchildrenlper
year [Nielsen 1988]. In adults, the incidence
of renal involvementranges from 45 - 85% of
cases [Coppo et al. 1999]. There is some debate regarding the different clinical course
between adults and children. Indeed, a study
showed that clinical presentation, renal lesions and long-term outcome were the same
among adult and pediatric patients with HSP
and renal involvement [Coppo et al. 1999],
while, another study, which observed retrospectively 250 adults on an average of 14.8
years, showed that clinical presentation in
adults was more severe and the outcome was
poorerthan in children [PilIeboutet al. 2002].
Pathogenesis is stilI unknown, however,
an infection involving the mucosal system of
the upper respiratory tract has been reported
as a likely cause of the ilIness [Miura et al.
1992]. Another possible cause is the association with drug ingestion [Borras-Blasco et al.
2003]. Here, we presenta case ofan adultpatient who developed a drug-related HenochSchonlein purpura.
Case report
In August 2004, a 69-year-old man was
adrnitted to our hospital with microscopic
hematuria, proteinuria and acuterenal failure.
2 months before admission he was diagnosed with purpuric rash with an unconfirmed association with drug ingestion (ketorolac-trometarnine).The patient stated he had
taken several drugs, and the onset of purpuric
rash had occurred a few days after ingesting
ketorolac. At that time, urine analysis showed
microscopic hematuria with normal renal
function. The purpuric rash did not disappear
on withdrawal of ketorolac. On admission,
physical examination revealed persistence of
multiple confluentpurpuric lesion on the legs,
132
Santoro, Stella and Castelli no
Table 1. List of HSP drug-related.
No.
Reference
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
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Zilliox AP
Valero Prieto I
Gamboa F
Escudero A
Prajapati C
Alberich RS
Michail S
Goncalves R
Bosch X
Goldberg EI
Goad JA
Pons R
ChoiSJ
Borras-Blasco J
Borras-Blasco J
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abdominal pain with nausea and arthralgias. (1.5 g/day of acetaminophen and 90 mg/day
The patient had lost 5 kg in a month. Labor- of codeine phosphate). After l week, the paatory results were creatinine 1.3mg/dl, hema- tient presented with gross hematuria, arthraltocrit 33%, whiteblood cell count 12,1l0/mm3 gias in the knees, wrists and elbows, and ex(N 82%), platelet count 356,000/mm3, 24- tensive bilaterally petechial hemorrhages on
hourproteinuria0.86g. Urinesedimentshowed the arms and legs. On admission, temperature
microscopic hematuria (80% dysmorphic was 39.5 °C and blood pressure was norerythrocytes). C-reactive protein level was mal. Laboratory testing revealed creatinine
46 mg/l. Serum IgA, IgG, IgM were normal. 2.7 mg/dl, hematocrit 30.5%, white blood cell
Serum complement was normal. Cryoglobu- count 13,51O/mm3(N 87%), platelet count
lins, antinuclear antibodies, antineutrophilic 257,000/mm3, 24-hour proteinuria 0.95 g.
cytoplasmic antibodies (cytoplasmicpattem), Urine sediment showed macroscopic hemaantineutrophiliccytoplasmic antibodies (peri- turia (severe dysmorphic erythrocytes). C-renuclear pattem) were all normal or negative. active protein level was 375 mg/l. Serum IgA,
Serologic tests for hepatitis B and C were IgG, IgM were normal. Serum complement
negative. Colon endoscopy showed aspecific was normal. Antinuclear antibodies were necolitis, colon biopsy revealed a mild chro- gative. Antineutrophilic cytoplasmic antibonic inflammatory infiltrate. Abdominal ultra- dies (cytoplasmic pattem), antineutrophilic
sound disclosednormalkidneys.Renalbiopsy cytoplasmic antibodies (perinuclear pattem)
confirmed a diagnosis of IgA nephropathy and anti-DNAantibodies were negative. Crywith increased and hypercellular mesangial oglobulins were negative. Co-efferalgan was
areas and mesangial deposition ofIgA and C3 discontinued. Gross hematuria and the purpuon immunofluorescence. In addition, there ric rash disappeared and renal function
returned to normal after 2 weeks. On the last
were cellular crescents in 3 glomeruli.
In sucha clinicalsetting,the immunecom- examination, 9 months later; serum creatinine
plex process is indicative of Henoch-Schon- was 0.9mg/dlandproteinuriawas 0.125g/24h.
leinpurpura nephritis. The patient was treated
with boluses of methylprednisone (750 mg)
for 3 days followedby a combination of pred- Discussion
nisone (0.5 mg/kg/day) and cyclophosphaThe involvement of renal disease in HSP
mide (125mg/day). 1year later,due to cervical
arthrosis,he started therapy with coefferalgan may vary [Cameron 1984].Most patients may .
Henoch-Schonlein
133
purpura drug-related
have renal disease characterizedby hematuria
and proteinuria, with slightly elevated serum
creatinine. However, in some patients, nephritic syndrome and/or acute renal failure
may occur [BIanco et al. 1997]. Clinical remission is not common in patients with HSP
and, as Pillebout observed, it was achieved in
only 20% out of250 adult patients [Pillehout
et al. 2002]. Factors associated with a poor
prognosis, like high degree of proteinuria, renal failure, high percentage of sclerotic glomeruli, fibrinoid necrosis and interstitial fibrosis were mildly present in our patient.
Several drugs are associated with onset of
HSP. In Table l, HSPs associated with drugs
ingestion are listed. Sincemost drugs are antibiotics, we could also deduce that infection
may play a role in the pathogenesis ofHSP in
these cases. Other drugs include antihypertensive such as enalapril or losartan, metoclopramide, ranitidine, streptokinase, acetylsalicylic acid, acenocoumarol and thalidomide.
In 1987, a case of HSP associated with
Co-dydramol (acetaminophen plus dihydrocodeine tartrate) ingestion was reported [Naranjo et al. 1981]. From a careful reading of
this case report we deduced that the diagnosis
of HSP could be questioned. Indeed, the
symptoms ofthe patient, in Richards and colleagues' case report, were characterized by
purpuric rash on the feet, legs, abdomen and
arms, joint pains and ankle and foot edema,
without carrying out immunofluorescence
studies [Richards and Linley 1987].
IgA immunodeposition, either in the skin
or kidney, is necessary for HSP diagnosis
[Cameron 1984]. In addition to IgA immunodeposition,their patient didn't show any clear
sign ofrenal involvement, since there was no
evidence of hematuria, proteinuria or renal
failure, and the only evidence of renal disease
was the presence of edema. Considering all
these factors, other diagnoses could have
been made such as hypersensivity vasculitis,
mixed essential cryoglobulinemia, microscopie polyangiitis, acutepost-streptococcal glomerulonephritis and endovascular infection
[Michel et al. 1992, Richards and Linley
1987].
The different renal involvement in the
2 episodes is relevant. Indeed, in the first episode, renal failure was mild and only microhematuria was observed, whilst the relapse
was characterizedby rapidly progressive glo-
merulonephritis with gross hematuria. In the
last episode, the evolution towards end-stage
renal disease was arrested due to discontinuation of drug (acetaminophen/codeine) intake.
The occurrence of HSP was probably related to the consumption of acetaminophen
and codeine for many reasons, even if another
pathogenetic mechanism cannot be ruled out.
First of all, there was a close temporal relationship between drug ingestion and onset of
symptoms. Moreover, co-efferalgan (acetaminophen and codeine) was the only drug
added before the onset of cutaneous, renai
andjoint symptoms, and when its intake was
interrupted, the patient's generaI condition
improved. For this reason, in accordance with
our data and on the basis ofthe Naranjo algorithm, adverse drug reaction could be
considered possible [Habib et al. 1993].
It has to be mentioned that our patient had
taken acetaminophen several times in the
past, whilst he denied he had taken codeine in
the past. Therefore, we deduced that codeine
intake, or the combination ofboth molecules,
may be responsible for adverse drug reaction.
Drug rechallenge was not attempted for ethical reasons, since, with the available data, adverse drug reaction could be considered possible.
For this reason, we believe that our patient
may represent the first clear evidence of a
possible relation between HSP and acetaminophen/codeine consumption.
Clinicians should be aware ofpossible associations between HSP and acetaminophen
and/or codeine consumption in order to provide prompt therapeutic intervention, including drug intake discontinuation.
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