Porphyrias

Porphyrias are difficult to diagnose . Here it is comprehensively explained to aid making diagnosis of porphyrias easier for the benefit of medical students and practitioners.

1. Dr.S.Sethupathy,M.D,Ph.D.,
Professor and HOD
Dept. of Biochemistry
RMMC,AU

2. Agroupofraredisorderscausedbydeficienciesof
enzymesofthehemebiosyntheticpathway
Affectedindividualshaveanaccumulationofheme
precursors(porphyrins),whicharetoxicathigh
concentrations
Attacksofthediseasearetriggeredbycertaindrugs,
chemicals,andfoods,andalsobyexposuretosun
Treatmentinvolvesadministrationofhemin,which
providesnegativefeedbackforthehemebiosynthetic
pathway,andtherefore,preventsaccumulationofheme
precursors

3. Some symptoms of porphyrias have led people
to believe that these diseases provide some
basis for vampire legends:
Extreme sensitivity to sunlight
Anemia
But -Porphyrias do not cause a craving for
blood.
Drinking blood would not help a victim of
porphyria
Porphyria is a rare, but frightening condition:
hard to diagnose and there is no cure.
 Facial Hair growth-wolf like

5. Porphyria is a group of syndromes, largely
hereditary
Due to defective enzymes involved in heme
synthesis
Manifest clinically in an acute or a chronic
manner
Signs and symptoms predominantly
cutaneous, neurovisceral or neurologic,
psychiatric, or combination of those


7. PORPHYRIAS
GLYCINE+ SuccinylCoA
d-aminolevulinic acid(ALA)
Porphobilinogen(PBG)
hydroxymethylbilane
uroporphyrinogen III
coprophyrinogen III
Protoporphyrinogen IX
protoporphyrin IX
Heme
ALA synthase
ALA dehydratase
PBG deaminase
Uroporphyrinogen III
cosynthase
Uroporphyrinogen
decarboxylase
Coproporphyrinogen
oxidase
Protoporphyrinogen
oxidase
Ferrochelatase
ALA-dehydratase
Deficiency porphyria
Acute intermittent
porphyria
Congenital erythropoietic
porphyria
Prophyria
cutanea tarda
Herediatary
coproporphyria
Variegate
porphyria
Erythropoietic
protoporphyria
Mitochondria
9q34
11q23
10q26
1q34
9
1q14
18q21.3
3p21/Xp11.21

8. COORDINATED REGULATION OF HEME
AND GLOBIN SYNTHESIS:
Heme:
Inhibition of the synthaseand stimulation of globinsynthesis
are the most important aspects in balancing hemoglobin
production.
diminishes the transport of d-ALA synthase from
cytoplasm to mitochondria after synthesis of the enzyme.
represses the production of d-ALA synthase by regulating
gene transcription.
inhibits activity of pre-existing d-ALA synthase
stimulates globin synthesis to ensure that levels of free
heme remain low in concentration.

10. Porphyrias with acute presentation:
Acute intermittent porphyria
ALA dehydratase deficiency porphyria (Doss
porphyria)
Hereditary coproporphyria
Variegate porphyria
The chronic porphyrias :
Congenital erythropoieticporphyria
Erythropoietic porphyria
Porphyriacutanea tarda

11. Acute porphyrias : features of attacks
Abdominal pain -The most common
Muscle weakness
Focal neurologic deficits (eg, tetraparesis)
Limb pain
Psychiatric symptoms (eg, psychosis, anxiety)
Discolored urine (turns red or dark on
exposure to light)
The chronic porphyrias : dermatologic diseases
May involve the liver and nervous system
Cutaneous signs result from photosensitivity
(eg, skin fragility and blisteringin porphyria
cutanea tarda).

14. More common in western countries-USA-5–10 per 100 000.
Northern European countries 60–100 per 100 000).
Acute intermittent porphyria -Porphobilinogen
deaminase (PBGD) gene mutation-A.D
Affects women more than men, with a ratio of 2:1.
Most patients symptomatic at age 18-40 years.
Attacks before puberty or after age 40 years are unusual
Most patients are free of symptoms between attacks.
Course of the neurological manifestations is highly variable.
Acute attacks of porphyria may resolve quite rapidly.
Sudden death may occur, presumably due to cardiac
arrhythmia.

15. Attacksinvolveneuro-visceralsymptomsbutnoskin
manifestations:
◦(1)abdominalpain,(2)psychiatricsymptoms,suchas
hysteria,and(3)peripheralneuropathies,mainly
motorneuropathies.
GastroenterologicalSymptomsmostcommon:
◦Constipation,colickyabdominalpain,vomiting,
diarrhea
PatientsmayhaveCNSsignsconsistingofseizures,
mentalstatuschanges,corticalblindness,andcoma.
Patientsoftenexperienceperipheralneuropathies-
mainlymotorandmimicGuillain-Barrésyndrome.
Patientsmaydevelopfever,hypertensionand
tachycardia
Symptoms

16. The exact mechanism underlying these complaints is not yet
well understood, various hypotheses have been put forward:
◦Excess amounts of PBG or ALA may cause neurotoxicity
(Meyer et al, 1998)
◦Increased ALA concentrations in the brain may inhibit
gamma-aminobutyric acid release (Mueller & Snyder, 1977;
Brennan & Cantrill, 1979)
◦Heme deficiency may result in degenerative changes in the
central nervous system (Whetsell et al, 1984)
◦Decreased heme synthesis in the liver results in decreased
activity of hepatic tryptophan pyrrolase (TP), a heme -
dependent enzyme, possibly resulting in increased levels of
serotonin

17. Drugs:Barbiturates and sulphonamides -
most common
Reduced energy intake: even brief periods
of starvation during dieting, postoperative
periods, or concurrent illness.
Tobacco smoke: polycyclic aromatic
hydrocarbons, are known inducers of
hepatic cytochrome P450 enzymes and
heme synthesis.
Infections, surgery and stress.

18. Demonstration of porphyrin precursors,
such as ALA and/or PBG, is essential for the
diagnosis of acute porphyrias.
Porphyrin analysis is necessary for the
diagnosis of porphyrias with cutaneous
photosensitivity.
◦PBG in urine must be ordered specially
Molecular diagnostic testing:
◦Detection of PBGD mutations in AIP
◦Possible to screen asymptomatic gene
carriers.
◦Less Useful in acute attacks
PBG in urine is oxidized
to porphobilin upon
standing, which gives a
dark-brown color to
urine, and often
referred to as ‘port-
wine reddish urine’.

19. It is caused by elevation of both water-soluble and lipid-
soluble porphyrin levels due to deficiency of
uroporphyrinogen III synthase enzyme.
Clinical features-phototoxic burning and blistering
Erythrodontia
Mutilation of light exposed areas
Hyperspleenism
Hemolytic anemia
Thrombocytopenia
Uroporphyrin &coproporphyrin
in urine
Coproporphyrin in stool

20. Most common porphyria, Hepatic, autosomaldominant
Deficiency in uroporphyrinogendecarboxylase
It is involved in the conversion of uroporphyrinogenIII
to coproporphyrinogenIII
Uroporphyrinogenappears in urine
Patients are photosensitive (cutaneousphotosensitivity)-
photoactive molecules absorb energy in the visible violet
spectrum
Accumulation of porphyrinogensresults in their
conversion to porphyrinsby light
Porphyrinsreact with molecular oxygen to form oxygen
radicals
Oxygen radicals can cause severe damage to the skin

21. The most common initial symptoms of porphyria
cutaneatardaare cutaneousfragility and blisteringof
the hands, forearms, and, sometimes, the face.
thin or fragileskin.
Increased hair growth, usually on the face.
crusting and scarring of theskin.
redness, swelling, or itching of theskin
Hyperpigmentationin the face
Indurated, waxy, yellowish plaques develop over the
chest and the back but are most prominent in the
preauricularand nuchalareas.

28. Inheritance:
AD ,Protoporphyrinogen oxidase gene (PPO)
Severe forms associated with hemochromatosis gene
Prenatal Diagnosis: DNA analysis
Incidence: Most common in South African whites 1:330
Elsewhere is 1:50,000 to 100,000 M=F
Age at Presentation:
Begins after puberty in second and third decade of life
Pathogenesis:
Acute attacks precipitated by:
Drugs: barbiturates, estrogen, griseofulvin, sulfonamides
Infection , Fever
Alcohol
Pregnancy
Decreased caloric intake
Increase Δ-aminolevulinic acid (ALA) synthetase with
attacks

29. Clinicalpicture:
◦Skin:
Identical to PCT with bullae, erosions, skin fragility,
scarring, hypertrichosis, hyperpigmentation on
photodistributed face, neck and dorsum of hands
◦Acute Attacks (i.e., Acute Intermittent Porphyria
and Hereditary Coproporphyria):
Gastrointestinal:
Colickly abdominal pain, nausea, vomiting, constipation
CNS:
Peripheral neuropathy with pain, weakness, paralysis
Confusional state, anxiety, depression, delerium
Seizures, coma
CV:
Tachycardia, hypertension

30. Laboratory Data:
Plasma porphyrinfluorescence
spectrum—626 nm is diagnostic
24 hour urine porphyrinlevels:
coproprophyrin= or > uroporphyrin
Urine ALA and porphobillinogen(PBG)
levels increased during attacks
Fecal prophyrinlevels: markedly
elevated, protoporphyrin>coproporphyrin

31. It is the most common childhood porphyria
due to deficiency of ferrochelatase . AD
It is usually evident by 2 years of age.
Clinical features -skin –pain and burning in
sunlight
Erythema, purpura, swelling
Erosions in exposed areas –face, hands
Scarring, waxy thickening of the skin

33. Complications-
Anemia, liver failure, gall stones
Investigations
Complete blood count
Quantitavive porphyrins in RBCs
Ferritin
LFT once in a year
USG/CT/MRI of liver
Liver biopsy

35. Delta-aminolevulinic acid dehydratase
(ALAD), also known as porphobilinogen
synthase
Deficiency causes ALAD deficiency porphyria
(ADP), an extremely rare cause of acute
porphyria.
Autosomal recessive
Only neurovisceral manifestations.
Confirmed by mutation analysis

37. Urine porphyrin for the diagnosis of acute
porphyria attacks
Test for increasedporphobilinogen(PBG) in a
single-void urine collected during an attack.
Significantly increased urine ALA and PBG in acute
intermittent (hepatic) porphyria, variegate
porphyria, and coproporphyria.
To assess for cutaneous porphyria, the plasma
porphyrin level measured using fluorescence
emission spectroscopy.
Whole blood for porphyrin analysis is used to
identify protoporphyria plasma porphyrins.

38. Stool studies: The ratio of fecal
coproporphyrin& protoporphyrinanalysis
Fecal protoporphyrinalways exceeds
coproporphyrin(P > C = V) in variegate
porphyria, whereas the reverse is true in
hereditary coproprophyria.
Erythrocyte uroporphyrinogen
decarboxylase activity is a reliable
diagnostic test for porphyria cutaneatarda.

39. Acute attacks-pain management
Stopping of drugs
IV glucose or oral glucose
Control of infections
IV fluids for dehydration
IV injections of Hemin

40. Avoiding exposure to sunlight
Phlebotomy
Hydroxy chloroquine or Chloroquine –
absorbs excess porphyrins
Afamelanotide, an α-melanocyte–
stimulating hormone analogue-permit
increased duration of sun exposure in
patients with erythropoietic protoporphyria.
Intake of carotenes regularly
Vitamin D