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CASE FILES: BIOCHEMISTRY
The porphyrias are a group of inherited disorders resulting from specific
enzymatic defects of the heme biosynthetic pathway. Figure 44-3 shows the
heme biosynthetic pathway and characteristics of porphyrias associated with
each step. A derangement in any of the involved enzymes can result in an over-
production or backlog of heme precursors prior to the deficient enzymatic
step. All of the intermediate compounds in this pathway are potentially toxic.
The disorders are divided into two broad groups, erythropoietic and hepatic
porphyrias, based on the primary source of precursor accumulation.
Furthermore, the porphyrias are also categorized based on the appearance of
distinctive acute or chronic symptoms. Pressure to overcome the metabolic
“roadblock” contributes to the rapid accumulation of precursors in acute
attacks. Early pathway intermediates, that is, ALA and PBG are associated
with acute neurovisceral symptoms, whereas later intermediates (which
undergo porphyrinogen-porphyrin conversions upon exposure to light) cause
skin photosensitivity through free-radial damage. The porphyrins can be
detected and identified by spectrofluorometry based on characteristic excita-
tion and emission wavelengths for each porphyrin. For example, serum uro-
porphyrin levels can be determined by detection at 615 nm after excitation at
Succinyl-CoA
4
Glycine
1
Aminolevulinic Acid
I
Porphobilinogen
1
Hydroxy mcthylbi lane
!
Uroporphyrinogen III
i
C'oproporphyrinogen III
I
Proloporphyri nogen IX
1
Protoporphryin IX
Heme
Disease Inheritance
Enzyme
Type
Manifestation
Symptoms
ADP
Autosomal
Recessive
2. ALA
Dehydrase
Hepatic
Urinary ALA
Neurovisceral
AIP
Autosomal
Dominant
3. PBG
Deaminase
Hepatic
Urinary ALA & PBG
Neurovisccral
CEP
Autosomal
Recessive
4. URO III
Synthase
Erythropoietic
Urinary & RBC URO I
and COPRO I
Photosensitivity
PCT.
HEP
Variable.
Autosomal
Recessive
5. URO
Decarboxylase
Hepatic/
Erythropoietic
Urinary URO- and
lieptaporphyrin:
Fecal isocoproporphyrtn
Photosensitix ity.
Hemolytic anemia
HCP
Autosomal
Dominant
6. COPRO
Oxidase
Hepatic
Urinary ALA. PBG.
coproporphryin
Neurovisceral.
Photosensimity
VP
Autosomal
Dominant
7. PROTO
Oxidase
Hepatic
Urinary ALA & PBG;
Fecal protoporphyrin
Neurovisceral.
Photosensitis ity
EPP
Autosomal
Dominant
8. Ferrochelatase Erythropoietic
RBC protoporphyrin.
Fecal protoporphyrin
Photosensitivity
Figure 44-3. Heme biosynthetic pathway and characteristics associated with
specific enzyme-deficiency porphyrias. ADP = ALA dehydratase deficiency
porphyria; AIP = acute intermittent porphyria; CEP = congenital erythropoi-
etic porphyria; PCT = porphyria cutanea tarda; HEP = hepatoerythropoietic
porphyria; HCP = hereditary coproporphyria; VP = variegate porphyria;
EPP = erythropoietic protoporphyria.
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