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Klinisk Biokemi i Norden · 3 2013
Doktorgradsavhandling:
Diagnosing and monitoring the porphyrias
Aasne K. Aarsand
Institutt for Samfunnsmedisinske Fag, Universitetet i Bergen og Laboratorium
for Klinisk Biokjemi, Haukeland Universitetssykehus, Bergen
Porphyrias are a heterogeneous
group of rare, mainly inherited
metabolic disorders characterised
by excessive production and excre-
tion of haem precursors, that are
caused by abnormal function of
the enzymes in the haem biosyn-
thetic pathway (Table 1) (1). In
symptomatic patients, the diagnoses depend on the
identification of specific patterns of increased haem
precursors in urine, faeces and blood (2). The accuracy
of the diagnoses thus directly influences the quality of
patient care. Notwithstanding, many studies concer-
ning porphyria diagnostics are mainly descriptive in
their approach, and high-quality diagnostic perfor-
mance data is scarce. In most European countries,
the full range of porphyria diagnostics is performed
by specialised laboratories (3). The overall aim of this
thesis was to increase the knowledge on the diagnostic
and monitoring performance of porphyria-related
markers and on the diagnostic efficiency of European
specialist porphyria laboratories.
The use of urinary δ-aminolevulinic acid (ALA)
and porphobilinogen (PBG) for monitoring
patients with acute intermittent porphyria
Acute intermittent porphyria (AIP) is characterised
by life-threatening acute attacks with abdominal pain
and neurovisceral symptoms most typically induced
by many commonly used drugs or hormonal chan-
ges. Experts in the field agree that patients invariably
present with increased concentrations of urinary ALA
and PBG when in acute attacks, and this is used diag-
nostically. There is, however, no consensus on or clear
evidence for what urinary concentrations, or changes
in concentrations, are required to diagnose an acute
attack, and most AIP patients have markedly increased
ALA and PBG concentrations also in remission (4,5).
In study I, we therefore assessed the biological varia-
tion of urinary ALA and PBG in order to improve on
the evaluation of serial test results for these markers
(6). Samples were collected by a standardised protocol
once weekly for ten weeks (short-term study period)
for both asymptomatic AIP patients (n = 15) and
healthy individuals (n = 15), extended to two years
for the AIP patients (long-term study period; in total
7 samples). The included AIP patients had either
been in remission for at least two years (n = 9) or had
never experienced acute symptoms (n = 6). Clinical
data were collected with all samples. Examination for
outliers and assessment of homogeneity of variances
were carried out prior to data analysis. Biological and
within-series analytical coefficients of variation were
estimated by analysis of variance with the statisti-
cal model for repeated balanced sub-sampling. The
within-subject biological variations of urinary PBG
and ALA per millimole creatinine were 16% - 20%
for both study groups in the short-term setting and
for PBG 25% in the long-term setting. Based on these
estimates and presuming that pre-analytical variation
is negligible, reference change values (RCV) for uri-
nary ALA and PBG were 50% (short-term one-sided
setting, 97.5% level of confidence). Our study thus
shows that substantial variations in ALA and PBG con-
centrations are apparent in asymptomatic patients and
that RCVs must be applied for the evaluation of serial
test results in patients with potential acute symptoms
or in patients using porphyrinogenic drugs.
Diagnostic strategies for the differentiation of
familial and sporadic porphyria cutanea tarda
Porphyria cutanea tarda (PCT) can be familial, caused
by mutations in the
uroporphyrinogen
decarboxylase
(
UROD
) gene, or sporadic (Table 1). Measurement of
UROD activity in erythrocytes has traditionally been
used to differentiate between the two types. In study II,
