Porphyrias are a group of rare hereditary disorders caused by enzyme deficiencies in the heme biosynthetic pathway, leading to toxic accumulation of heme precursors and various symptoms including photosensitivity, abdominal pain, and neurological issues. Treatments involve management of symptoms, administration of hemin, and avoidance of triggers such as certain medications and foods. Though symptoms can be severe and the condition often misunderstood, porphyrias do not lead to a craving for blood, contrary to common myths.

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

2. A group of rare disorders caused by deficiencies of
enzymes of the heme biosynthetic pathway
Affected individuals have an accumulation of heme
precursors (porphyrins), which are toxic at high
concentrations
Attacks of the disease are triggered by certain drugs,
chemicals, and foods, and also by exposure to sun
 Treatment involves administration of hemin, which
provides negative feedback for the heme biosynthetic
pathway, and therefore, prevents accumulation of heme
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 synthase and stimulation of globin synthesis
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 erythropoietic porphyria
 Erythropoietic porphyria
 Porphyria cutanea 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 blistering in 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.  Attacks involve neuro-visceral symptoms but no skin
manifestations:
◦ (1) abdominal pain, (2) psychiatric symptoms, such as
hysteria, and (3) peripheral neuropathies, mainly
motor neuropathies.
 Gastroenterological Symptoms most common:
◦ Constipation ,colicky abdominal pain,vomiting,
diarrhea
 Patients may have CNS signs consisting of seizures,
mental status changes, cortical blindness, and coma.
 Patients often experience peripheral neuropathies -
mainly motor and mimic Guillain-Barré syndrome.
 Patients may develop fever, hypertension and
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, autosomal dominant
 Deficiency in uroporphyrinogen decarboxylase
 It is involved in the conversion of uroporphyrinogen III
to coproporphyrinogen III
 Uroporphyrinogen appears in urine
 Patients are photosensitive (cutaneous photosensitivity)-
photoactive molecules absorb energy in the visible violet
spectrum
 Accumulation of porphyrinogens results in their
conversion to porphyrins by light
 Porphyrins react with molecular oxygen to form oxygen
radicals
 Oxygen radicals can cause severe damage to the skin

21.  The most common initial symptoms of porphyria
cutanea tarda are cutaneous fragility and blistering of
the hands, forearms, and, sometimes, the face.
 thin or fragile skin.
 Increased hair growth, usually on the face.
 crusting and scarring of the skin.
 redness, swelling, or itching of the skin
 Hyperpigmentation in the face
 Indurated, waxy, yellowish plaques develop over the
chest and the back but are most prominent in the
preauricular and nuchal areas.

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.  Clinical picture:
◦ 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 porphyrin fluorescence
spectrum—626 nm is diagnostic
24 hour urine porphyrin levels:
coproprophyrin = or > uroporphyrin
Urine ALA and porphobillinogen (PBG)
levels increased during attacks
Fecal prophyrin levels: 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 increased porphobilinogen (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 & protoporphyrin analysis
 Fecal protoporphyrin always 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 cutanea tarda.

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