CLIN. CHEM. 39/6, 1334-1340 (1993)
Childhood Porphyrias: Implications and Treatments
Neil R.
ock,3
Denise
A. O’Reilly,’
Giovanni ft. Zoanetti,’
In describingthe clinical, biochemical, and family findings
in five children with porphyria, we examine initial treat-
ments and, where appropriate, the effectiveness of longterm therapy. We note that porphyria diagnosis, particularly in childhood, relies heavily on specialist laboratory
investigations.Because disease expression in some porphyrias requires exposure to precipitating factors, it may
be prevented or delayed by their avoidance.
Terms: pediatric chemistiy
heritable disorders
feces
porphobilinogen
p9-carotene
etythrocytes . enzyme actIvity . oppij.phyri
photosensitivity
skin disorders
Indexing
urine
.
.
‘
.
.
.
‘
.
One of the first inherited
metabolic
disorders to be
recognized as such was a porphyria, namely, congenital
erythropoietic
porphyria,
or Gunther disease. Now,
nearly 100 years later, if concurrent or dual porphyrias
are included, 15 different types of porphyria have been
described. Most are inherited as Mendelian
autosomal
dominant
traits, but some are recessive and others
acquired. The acute porphyrias
are of the most importance, because attacks of these may be life-threatening.
During an attack, patients accumulate
in their tissues
and excrete in their urine a massive
excess of the
neurotoxic porphyrin precursors, 5-aminolevulinic
acid
(ALA) and porphobilinogen
(PBG).4 The nonacute perphyrias
are largely dermatological
conditions, with
signs and symptoms confined to areas exposed to sunlight; concomitant liver disease occurs in some patients.
Skin photosensitivity
is due to the interaction of light
with circulating porphyrins present in cutaneous
tissues. A few porphyrias combine the clinical features of
acute and cutaneous porphyria.
Patients may have overt, subclinical, or latent disease; manifestation
ofporphyria
is usually delayed until
after puberty. This had led, until recently, to the belief
that porphyria was essentially
an adult disease. It is
now much more widely appreciated
that it is not the
disease but merely the diagnosis that is so rare in
childhood. Indeed, the much lower incidence of overt
Evelyn F. Robertson,’
and CoHn J. Parker
porphyria in susceptible
children
may simply reflect
lack of exposure to one of the necessary precipitating
agents, such as drugs (including ethanol), toxins, viruses, fasting, and hormonal factors.
We have performed porphyrin analyses at the Adelaide Children’s Hospital over the past 13 years. For a
pediatric institution to be the State Reference Centre for
porphyrin, analyses must be as rare as the disease itseIf
however, during the 13 years, -1700 adults and 400
children
have been screened. Of these, 7% (107 with
porphyria cutanea tarda; PCT) and 5% (9 with erythropoietic protoporphyria
EPP), respectively, have tested
positive. In the following case reports, we describe a few
of the childhood porphyrias
we have encountered and
provide details on the long-term success or otherwise of
respective
treatments.
Materialsand Methods
Blood was collected into a heparinized container and
an aliquot was centrifuged for assay of the plasma.
Leukocytes were isolated by standard procedures (1).
Urine
specimens, collected over 24-h periods and (or)
random (untimed) collections,
both without preservative,
were
kept
in the
dark
and
refrigerated
between
collections.
Feces were collected into a darkened
fecal
pot. Blood and leukocytes were stored at 70 #{176}C
until
analysis;
plasma,
urine, and feces were stored at
-
-20 #{176}C.
Specimens were protected from light at all
times.
ALA and PBG in the urine collections were measured
by the methods of Mauzerall and Granick (2) with
standard kits from Bio-Rad Labs. (Richmond, CA). Total
porphyrins in blood and plasma, urine, and feces were
quantified by the methods of ChisOlm and Brown (3),
Poulos
and LOCkWOOd (4), and Lockwood et al. (5),
respectively. Plasma was scanned spectrofluorometrically by use of a technique reported
previously (6).
Individual porphyrins in urine and feces were measured
by fluorescence detection after high-performance
liquid
chromatography of the free acid forms of the porphyrins
(7).
Department
of Chemical Patho1o,
and 2 Skin Clinic, Melaide Children’s
Hopita1,
72 King William Rd., North Melaide
5006, South Australia,
Australia.
3 Corresponding
author.
4 Nonstandard
abbreviations: ALA, 5-aminolevulinic acid; PBG,
porphobilinogen;
PJT, porphyria
cutanea
tarda
EPP, erythropoietic protoporphyria;
PBGD, porphobilinogen
deaminase;
000X,
coproporphyrinogen
oxidase; HC, hereditary
coproporphyria
and
AlP, acute intermittent
porphyria.
Received June 8, 1992; accepted November 10, 1992.
1
1334
CLINICAL CHEMISTRY, Vol. 39, No. 6. 1993
ErythrOCyte
PBG deaminase (PBGD; hydroxymethylbilane synthase, EC 4.3.1.8) and uroporphyrinogen
decarboxylase (EC 4.1.1.37) were assayed by the method of
Piepkorn et al. (8) and McManus et al. (9), respectively.
Leukocyte protoporphyrinogen
oxidase (EC 1.3.3.4) and
coproporphyrinogen
oxidase (COOX; EC 1.3.3.3) activity were determined by the method of Li et al. (10) and
Guo et al. (1 ), respectively, with modifications
to COOX
was free of blisters
measurement
as outlined by Blake et al. (11 ). Enzyme
activity was determined on two or more different blood
collections taken several weeks apart. Reference ranges
for enzyme activity were established from determina-
Treatment with chloroquine has continued with no
of chloroquine
tOXiCity.
Despite the absence of
cutaneous symptoms and a significant improvement in
porphyrin concentrations,
the concentrations
of urinary
porphyrin
and particularly uroporphyrin
have renamed somewhat high. This has led to a strengthening
of the therapeutic regime to 20 mg twice a week in
August 1990 and to 25 mg twice a week since February
1991. Throughout chloroquine therapy, the patient’s
liver-function
test results have remained normal except
for a persistently above-normal
activity of alanine aminotransferase
(242 UIL in February 1991; reference
range 30-120).
Subsequent investigations revealed that the patient’s
parents
were healthy and nonconsanguinous
with no
cutaneous symptoms. Porphyrin
studies of the child’s
mother showed normal results for porphyrins, porphyru
precursors, and porphyrin-related
enzymes. The father refused testing. Two years later, the girl’s paternal
uncle presented with a recent history of photosensitivit3’, which had manifested after a job change that
brought him into contact with several aromatic hydrocarbons. His clinical and biochemical
picture indicated
PCT; with an erythrocyte uroporphyrinogen
decarboxylase activity -40% of normal, he too was shown to have
the classic familial type II condition.
evidence
tions made on at least 30 healthy children, ages 2 to 15
and on the same number ofnormal
adult subjects.
years,
PatIent 1
A 4-year-old girl from a rural community presented in
November 1986 with a 2-year history of blistering
and
fragile skin on the back of the hands, nose, cheeks, and
occasionally
feet. Symptoms
were worse in summer. A
red color of the urine had been observed
for several
months. There was no itching and burning and, at the
time, no family history of similar disease. The patient
had complained of central abdominal pain once or twice
a week and, on occasions, particularly when tired,
became pallid and sweaty. She had a history of pesticide
exposure but no organochloro
compounds were detected
in the blood. There was no hepatic disorder and no
masses or visceromegaly.
Porphyrin
investigations
revealed a very high plasma
concentration
of total porphyrin. The concentration of
erythrocyte porphyrin was normal. Urinary uro- (prodominantly
isomer I) and heptacarboxylic
porphyrin
were much increased, oxoisocoproporphyrin
was present, and the hexacarboxylic and pentacarboxylic
perphyrins were moderately increased. Concentrations of
porphyrin precursors, ALA and PBG, were normal.
There was increased focal excretion of isocopro- and
hept.acarboxylic
porphyrins, with normal fecal concentrations of copro- and protoporphyrin. ErythrOCyte uroporphyrinogen decarboxylase activity was -50% of normal (Table 1). Porphyrin concentrations are shown in
Table 2. These results were diagnostic of familial (type
II) PCT and excluded other types of porphyria.
In addition to advising protection from sun exposure,
treatment
was commenced in March 1988 with oral
chioroquine,
12.5 mg twice a week. Despite an inimediate and dramatic increase in urinary porphyrin excretion, which persisted over several months, the young
girl showed an improvement
in her well-being and a
reduction of the frequency of blistering lesions on the
back ofthe hands and face; however, there were residual
milia in these areas. She also had persistent skin fragility secondary to trauma, particularly
noticeable on
her legs. When reviewed in December 1988, the patient
1 . Porphyrin
Table
and erosions and the scars had faded
considerably; since then, she has been asymptomatic.
PatIent 2
This 15-year-old prepubertal boy has already been
reported (12). He presented in March 1989 with abdominal pain, vomiting, disturbed consciousness, hypertension, dehydration, tachycardia,
and malnutrition.
He
had suffered convulsions
since infancy and was being
treated with carbamazepine, sodium valproate, and phenytoin; the drug concentrations had always been within
the therapeutic range. On admission, his weight was 19
kg. There was no photosensitivity. Because the passage
of rose-colored urine and the patient’s clinical manifestations
raised the possibility of an acute porphyria,
specimens were collected for porphyrin analyses.
Results
from these
investigations
are given
in Tables
1 and 2. They show greatly increased excretion of ALA
and PBG in the urine, together with increased concentrations
of porphyrins, particularly two- and heptacarboxylic porphyrins.
Total erythrocyte
porphyrin
was
Enzyme Data
for Each PatIent
Patient
Refsrsnos
s_
InaI
I
2
3
4
5
Erythrocytes
Uroporphyrinogen decarboxylase, U/L at 37 #{176}C
1.6-3.0
0.8
1.8
1 .9
2.1
3.5
Porphobilinogen
deaminase,U/Lat 45
1 .2-3.6
1 .4
2.0
0.7
1 .4
1.6
#{176}C
Leukocytes
Coproporphytinogenoxidase.at 37 ‘C
Protoporphynnogen oxidase, at 37 C
a Units are picomoles
of protopcrphyrn
per milligram of leukocyte protein.
produced
3#{149}#{216}_55a
0.037-0.071
_
b
per minute per milligram of Ieukoc4e
protein;
b
_
_
_
1.1
0.045
0.071
-
0.047
unitsare
nanomoles
of pmtoporphyvln
produced
per minute
CUNICAL CHEMISTRY, Vol. 39, No. 6, 1993
1335
Table2.
Urinary, and Fecal Porphyrin Concentrations
Blood,
Patient 1
Reference
5-
Intsrval
PatISnt2
-
Last
dat:
mviewsd:
Nov. 1999 Aug.1991
Patient3
ust
dM
PatIents
-
at
Last
Diegnoats
st
revIsvud:
date:
reviewed:
data:
rsvIsd:
Dec.1991 Nov.1991 Apr. 1992 Jan. 1978 Nov. 1991 Nov. 1991 Apr. 1992
Nviewsd:
Mw.1
Patient4
Diegnosie
ds:
EIyThrOCyteS
Total porphytin, moV1
0.4-1.7
0.5
0.9
1.3
1.5
1.1
0.9
21
103
0.7
0.5
9
4
5
-
221
6
8
20
27
Pfssma
Totai porphytin, nmol/L
<10
95
21
101
<43
230
9
40
37
17
719
7
4
7400
11
97
Urine
moVL
AL
PBG, in,ol/L
Totai porphylin,
22
20
<25
2
6
<300
2910
PorphyrlrVcreatinine,
<35
323
86
2387
34
6
36
4
Uroporphytin,nmol/L.
<40
2182
581
6919
29
<1
-
302
63
247
4
<1
-
<1
61
36
-
lola
-
91
.-
HeptacaJbOX1IC
nmoVl..
<6
porphytin,
795
-
20
131
33
4
3
17
1
<1
<1
127
190’
116b
233
270
211
135
7&
59
199k’
l28
157
211
106
-
6
2
5
207
124
37
29
8
nmoVL
Coproporphyiln.
nmoVL
<150
138
74a
ja
Feces
Total porphy,ln, irno1/kg
dry wt
Coproporphyrin,moVkg
<2#{244}0
<
239
96
43
20
33
24a
135
55
8
180
3f
dry wt
Protoporphyrin,
moUkg
<180
-
58
-
<0.01
-
12
7
dry wt
Isocopro-/copropcrphyrin
<0.02c
0.13
0.50
0.01
<0.01
-
<0.01
<0.01
ratio
Age, years
lIrstappearance of
aAt diagnosis
At
2
15
NA
3
4
15
6
4
Familial(type II)
VSJISntAJP
1atem AlP
NA
3
EPP
Latent
HC
PCT
III <40% of total coproporphyiln
isomer III>40% of total coproporphyiln
a Isomer
b
For porphyrias other than vailegate
NA, not applicable.
C
porphyria and porphyria cutanea
tarda.
normal, but the concentration of porphyrin in plasma
was increased.
There was no porphyrin abnormality
in
a fecal specimen collected 10 days after admission. The
patient had normal activities
of erythrocyte
PBGD and
protoporphyrinogen
oxidase. Porphyrin studies of the child’s parents
showed normal results and
there was no family history of porphyria, although a
maternal
uncle had died at age 14 years after treatleukocyte
ment with a general
anesthetic
for a minor surgical
procedure.
With acute porphyria
established,
we sought to deter-
mine the particular type of porphyria.
The patient’s
normal leukocyte
protoporphyrinogen
oxidase actiVity
and plasma fluorescence
characteristics
(6) ruled out
variegate porphyria. The biochemical
findings also axcluded hereditary
coproporphyria (HC), a rare inherited
disorder distinguished
by a marked increase in urinary
and focal excretion of coproporphyrin,
mostly isomer ifi
(7), which, with a coproporphyrin ifi value <40% of total
coproporphyrin,
did not match the pattern of abnormal
porphyrins found in this particular
case. Further, the
pattern was dearly different from that described in a
family
with decreased
5-aininolevulinate
1338 CUNICAL CHEMISTRY, Vol. 39, No. 6, 1993
dehydratase
(EC 4.2.1.24)
aCtiVity
(13). Urine and focal analyses
the subject had a pattern typical of acute
intermittent
porphyria (AlP), in no way differing from
results for other patients with this type ofporphyria (14).
Despite the normal actiVity
of PBGD then and the
unavailabffity
of the COOX assay, the clinical and biochemical picture identified this as a case ofvariant
AlP,
a subtype of AlP reported earlier (15-18), in which the
enzyme defect is expressed
in the liver but not in the
peripheral blood cells. Precipitation
of this porphyria
attack was probably a consequence of the patient’s anticonvulsant medication, an acute vomiting disease, and
the patient’s profound emaciation.
The disease resolved spontaneously after the withdrawal of carbamazepine and sodium valproate and the
commencement
ofparenteral
nutrition with subsequent
carbohydrate
loading.
After about 9 weeks, he was
discharged back to his previous hospital, the porphyrin
pattern having returned to normal values several weeks
before. The only biochemical abnormality
remaining
was the mildly increased activities of liver enzymes.
Treatment from discharge to the present has included
phenytoin and clobazam combined with continuing
di-
showed
that
etary management,
i.e., a high calorie intake of carbohydrate and protein, with limited fats. Concentrations
of porphyrin
and porphyrin precursors
have remained
normal postpuberty,
and there has been no further
exacerbation
of his acute porphyria condition.
PatIent 4
A 4-year-old girl with a normal medical history until
the previous summer complained in January 1978 of
episodic itching and burning of the skin on the face,
hands, and feet immediately
on exposure to sunlight. So
intense was the burning sensation that the young girl
would often immerse her feet in ice and, on many
Patient3
occasions,
slept with her feet in ice-cold water. The
The porphyrin precursor, PBG, was grossly increased
symptoms
were always accompanied by edema and
at postmortem
examination
of the 70-year-old paternal
erythema
of
the exposed areas. Vesicles, petechiae, and
grandmother
of patient 3. An acute porphyria was
some residual scarring had also occurred, but much less
diagnosed on the basis of the increased concentration of
frequently.
Symptoms
had abated gradually during the
PBG, qualitatively determined by a referring laboratory
winter
months. There were reports of several clinically
using a simple screening test. Her four clinically well
affected relatives.
grandchildren
were subsequently investigated by the
Laboratory data showed a 10-fold increase in erythsame referring laboratory and results for urine, blood,
rocyte and plasma concentrations
of protoporphyrin.
and fecal porphyrin tests were all reported to be normal.
ErythrOCyte Zn protoporphyrin
content was normal.
As was the case with the grandmother, no tests for
There were no other biochemical alterations; blood copenzyme insufficiency
were performed.
roporphyrin,
urinary porphyrin
precursors,
and urine
As a precautionary
measure,
before administering
and fecal porphyrins were all normal. The results were
anesthesia
for a minor surgical procedure to the 6-yeardiagnostic
ofEPP. A 1-year-old brother was later shown
old granddaughter (patient 3), blood, urine, and feces
to have a latent form of protoporphyria.
were again collected and sent to our laboratory
for more
The patient was treated with 30 mg of 3-carotene
comprehensive
porphyrin investigations.
Records from
twice a day and a topical sunscreen.
Throughout her
childhood, /3-carotene therapy has been shown to proan operation under general anesthesia 3 years before
had noted the patient was “slow to wake up,” with “3#{189} vide very significant symptomatic amelioration and an
increased tolerance to sun exposure, even though her
hours in recovery.” The considerably reduced
PBGD
erythrocyte protoporphyrin
concentration has remained
activity with normal concentrations for porphyrin, PBG,
very
high.
Plasma
(3-carotene
concentrations
were
and ALA were consistent with this patient’s being an
maintained
between
8
and
13
mo1/L
during
this
period
asymptomatic gene carrier for AlP (Tables 1 and 2). We
(reference
range 0.2-2.3; plasma concentration at initial
included
with our porphyrin
report a list of drugs,
diagnosis
1.1
mo1IL). Apart from a distinct yellowing of
unsafe and safe for use in acute porphyria.
Subsequent
the
skin
and
despite
the fact that carotene is a provitablood and urine collections from two of the other three
mm A, no vitamin A side effects have been observed.
asymptomatic
grandchildren, ages 7 and 11 years, have
Vitamin A concentrations have remained within the
since shown a similar decrease in PBGD activity with
normal range.
normal ALA, PBG, and urine porphyrin excretion patIn the past 3 years the patient has chosen to discontorus. The fourth grandchild, age 3 years, has normal
tinue therapy with 3-carotene. Moderate to severe cuPBGD activity.
taneous photosensitivity
has returned,
together with
The operation proceeded uneventfully with a change
abdominal pain. Causes such as gallstones and a dual
from the standard anesthetic regime of halothane to
porphyria have been ruled out. Results of liver-function
isoflurane
with nitrous oxide and the avoidance of
tests remain normal, despite a recent erythrocyte total
steroidal relaxants. Moreover, the patient’s asthma
porphyrin measurement
of 103 pmoI/L (reference range
medication
was changed from theophylline
(unsafe
0.4-1.7) and a corresponding
plasma a-carotene
of 0.5
drug) to salbutamol
and sodium
cromoglycate
(safe
mol/L. Other porphyrin tests, including
urine coprodrugs) for the long term.
porphyrin
and the ratio of its isomers, give normal
The three children with reduced enzyme activities
results.
The younger brother continues to be free of
have been advised to avoid drugs with established
cutaneous symptoms, despite a recent erythrocyte total
porphyrinogenic
properties.
Because
of the occasional
porphyrin
concentration of 16.4 pmol/L.
overlap between
the normal and abnormal
reference
intervals for PBGD activity (19, 20), our previous recPatient5
ognition of variant AlP in a patient with a quite high
enzyme activity, and a report that described low erythMedical and biochemical evaluation was sought in
rocyte PBGD activity in one member of a large kindred
November
1991 for an 8-year-old boy with a family
with variant AlP (21 ), thus raising the possibility of
history of HC. The child had no clinical symptoms of
variant
and classical AlP coexisting within the one
porphyria. An older sister had died at age 5 years after an
family, we could not give unequivocal
assurance
that
unknown febrile illness. A regional referring laboratory
the youngest child would not develop the diseasehad found no porphyrin abnormality
in the young boy.
although extra precautions were not recommended. NeiOur investigations
revealed
slightly
increased
conther parent has yet submitted samples for testing.
centrations of coproporphyrin
in the urine and feces,
CLINICAL CHEMISTRY, Vol. 39, No. 6, 1993
1337
III; all other porphyrin
including ALA and PBG, were normal.
Significantly,
the fecal coproporphyrin
ffl:coproporphyrin I (CIII:CI) isomer ratio, recently cited as a new test
for diagnosing latent HC (11 ), was 9.1 (HC >2, reference range < 1.3). A leukocyte COOX determination
showing diminished
activity confirmed the diagnosis of
HC.
HC combines the clinical features of both cutaneous
and, even more importantly, acute porphyria. Consequently, like patient 3, this patient, through his parents, will be encouraged to maintain a regular diet and
warned about the dangers of certain drugs, including
alcohol, in an effort to prevent clinically overt disease.
Six months later, he remains asymptomatic.
Two
younger brothers have normal results for HC enzyme
activity and fecal CIII:CI isomer ratios.
particularly
coproporphyrin
measurements,
Discussion
A deficiency in enzyme activity was established
only
after the analysis (in duplicate) of at least two different
blood specimens collected several weeks apart. This was
done to counter any effect on enzyme activity from viral
and bacterial infections (22-24). Also, a complete drug
history was gathered and a toxicology screen performed
to allow drug therapy, particularly anticonvulsant therapy, to be excluded as the cause of abnormal enzyme
activity (25). In establishing a reference range for each
enzyme, we determined that the mean enzyme activity,
as well as the lower and upper range limit, was relatively constant and unrelated to age and sex.
Because patient 1 has familial PCT, we anticipate
that long-term chioroquine therapy will be necessary.
This contrasts with one of the few reported cases of the
sporadic
(type
I) condition in childhood (26). In that
report,
a girl, 2 years old at initial diagnosis, has
apparently attained permanent remission 20 years later
by adhering to a vitamin-rich diet and avoiding potentially porphyrinogenic
substances (A. Kansky, personal
communication).
Chloroquine
acts by releasing tissue-bound hepatic
porphyrinogens
and facilitating their excretion in urine
(27); it has also been shown to inhibit porphyrin synthesis (28). Phlebotomy
is also effective
therapy
for
PCT, but is not recommended for use in children (29). In
an attempt to treat PCT in this young child while
avoiding the acute hepatotoxic effects ofchloroquine,
we
initiated a very low-dose regime of 12.5 mg orally twice
weekly. Previously, treatment of four children
with a
daily dose of 250 mg of chloroquine
orally for 7 days
brought about unacceptably high concentrations of liver
enzymes
and urinary
porphyrin
(29
).
Chloroquine
intro-
duced at 75 mg twice a week to treat familial PCT (type
II) in a 7-year-old child (30) was accompanied by an
immediate gross worsening of the patient’s symptoms.
The dose was subsequently reduced, then withheld until
a successful introduction at a dose of 75 mg and then 100
mg every 10 days (M. Rogers, personal communication).
Interestingly, in all of these reports, urinary porphyrin
concentrations have fallen well below pretreatment val1338
CLINICAL CHEMISTRY, Vol. 39, No. 6, 1993
ues and the patients
relatively
phyrin
high residual
have become asymptomatic,
concentrations
of urinary
but
per-
still remain.
In investigating patient 1, we identified another miportant
distinguishing
aspect of the familial and the
sporadic condition. Our 18 patients, of all ages, who
have tested positive for familial PCT have always had
normal y-glutainyltransferase
activities at diagnosis;
contrast this with our 87 patients with sporadic PCT,
whose plasma y-glutamyltransferase values have never
been <3.5 times the upper normal range at initial
diagnosis. The determination ofthis liver enzyme is less
technically demanding than the assay of uroporphyrinogen decarboxylase
and is very useful in checking the
familial or sporadic status of a PCT condition.
Patients 2, 3, and 5 ifiustrate the considerable variation that exists in the clinical expression of the enzymatic defect in porphyrias with autosomal dominant
inheritance. Further, patients 2 and 3 dramatically
contrast
in showing expression of the acute porphyria,
despite a normal enzyme activity in one instance, and
the absence of any clinical manifestation,
despite unequivocal enzyme deficiency, in the other. These patients
provide
further evidence that the detection of
latent forms of the porphyrias requires special techniques and is best carried out by reference laboratories.
When latent cases are detected, patients can be advised
about the precautions necessary to avoid attacks. Procipitating factors in susceptible patients include drugs,
hormones (especially estrogens),
starvation
or dieting,
and infections. Some women have regular premenstrual
attacks and pregnancy may provoke an exacerbation.
Early diagnosis of the disorder and recognition of the
precipitants ensure appropriate treatment should an
attack
occur.
Specific therapies of acute hepatic porphyrias include
the use of high carbohydrate
intake and infusion with
hematin.
The regulatory effects of hematin on heme
in the liver are multiple
and involve
not
only inhibition of the synthesis of ALA synthase (EC
2.3.1.37)
but also inhibition ofthe enzyme transfer and
importantly
inhibition
ofits own catalytic activity (31).
Hematin may also repress the synthesis of the mRNA
for ALA synthase (32). The effect of hematin on heme
formation in erythroid cells may also be suppression of
ALA synthase activity (33), although recent evidence
suggests that its principal role is to regulate the transport of iron into reticulocytes (34). Like hematin,
the
“glucose effect” results mainly in suppression of the
induction of hepatic ALA synthase (35), and the mechanisms of mediation are multifactorial
and imbedded in
the highly complex regulation of heme synthesis (36).
Its regulatory role remains highly controversial,
with
concerns beyond the stated carbohydrate
repression of
enzyme induction to RNA synthesis, transport of ALA
synthase, and glucocorticoid activity as well as the role
of cAMP and cGMP (37-39).
Although
total focal coproporphyrin excretion was
only slightly increased in patient 5, this increase is
significant
because, apart from descriptions of homozybiosynthesis
gnus HC in children (40-42), whose deficiency of COOX
is severe (< 10% ofnormal values), only one other case of
increased focal coproporphyrin
has been reported in a
child: a prepubertal
12-year-old member of an HC family (43). At the age of8, patient 5 is the youngest subject
with heterozygous HC yet described to have abnormal
concentrations
of fecal coproporphyrin.
Interestingly,
this first fecal porphyrin measurement was made while
he was undergoing
treatment with the antibiotic Bad-
rim (trimethoprim and sulfamethoxazole; both drugs
that exhibit porphyrinogenicity). Subsequent total fecal
coproporphyrin measurements have been normal, although the CIII:CI ratio has remained increased.
The mechanism by which 3-carotene is effective in
EPP is unknown, although perhaps it absorbs 400-nm
photons or quenches free radicals and singlet oxygen
(44). Increased
tolerance to sunlight was reported
within weeks of patient 4’s commencing therapy with
3-carotene.
Treatment continued to be effective during
her several years of compliance with the medication.
The obvious clinical carotenemia
that developed was
well tolerated and there were no other side effects.
Despite the fact that in practical terms 6 pg of -carotene is converted to 1 tg of vitamin A, plasma concentrations ofvitamin A remained within the normal range
during
treatment.
This suests
that EPP patients
could safely continue with fe-carotene therapy during
pregnancy
without
vitamin A toxicity and its associated
fetal teratogenicity.
Because of her perception that treatment was no
longer effective, patient 4 has recently decided to discontinue therapy with (3-carotene. This has coincided
with a return of photosensitivity,
although much less
prominent than when symptoms first developed in childhood-a
surprising
result considering the very high
concentrations
of erythrocyte
and plasma porphyrin.
This apparent lack of correlation between blood porphyrim concentrations
and severity of symptoms has been
noted previously (44) and may suggest that endogenous
compensatory mechanisms for the cutaneous photosensitivity are involved; with the frequent improvement in
symptoms after age 10-11 and the decrease in photosensitivity noted during pregnancy in some EPP patients, it
is interesting to speculate that hormonal factors may be
involved.
If hormones
do play a positive role in EPP, it
is in stark contrast to their action as precipitants in the
acute porphyrias.
Fortunately,
this EPP patient has not
yet developed liver disease, despite having several prodictive factors for doing so (45, 46): e.g., very high and
increasing erythrocyte porphyrin, high plasma porphyrin, and relatively low normal fecal protoporphyrin
concentrations.
Importantly,
urinary
coproporphyrin
concentrations and its isomer 1:111ratios,
increased are said to serve as a sensitive
the hepatic complication of protoporphyria,
mal in patient 4. She will continue to be
monitored for hepatobiliary disease.
which when
indicator for
remain norvery closely
In conclusion, descriptions of porphyrias in children
are rare and usually limited to single reports with no
follow-up. In outlining the cases above, we have demonstrated the value of providing a comprehensive porphyun service within a pediatric institution. Surely such
institutions
are able not only to recognise the existence
of overt childhood porphyrias, but also to screen for
latent and subclinical carriers. Further,
through
the
ease of monitoring a child’s progress several years after
initial diagnosis and their better compliance
with thorapy relative to adults, young patients can be given a
prognosis based on historical information, not speculation. The low level ofdllnical expression despite reduced
enzyme activities is a striking feature of juvenile perphyrias in our experience.
Early biochemical diagnosis
with the avoidance of porphyrinogenic factors is very
effective treatment.
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