heme metabolism, pathophysiology, classification References: Harrison's Principles of Internal Medicine Fitzpatrick textbook of Dermatology

1. Dr.Spandana Kanaparthi
Mediciti Institute Of Medical Sciences

2. The term porphyria - derived from
the Greek word "porphyra", meaning "purple pigment"
The porphyrias -group of disorders - defects in the
biosynthesis of heme

3.  Heme - iron porphyrin
 Heme biosynthesis - in most mammalian cells except
mature RBC - lack mitochondria
 85% of heme synthesis -in erythroid precursor cells
in the bone marrow and the majority of the
remainder in hepatocytes
 Examples - Hemoglobin, Myoglobin, Cytochrome C,
Catalase, Tryptophan pyrrolase

7. PORPHYRIAS

9.  Depending on the site of overproduction and accumulation, they
are classified as hepatic and erythropoietic porphyrias.
Hepatic porphyrias-adult life
1. Acute intermittent porphyria(AIP)
2. Hereditary coproporphyria(HC)
3. Variegate porphyria(VP)
4. ALA Dehydratase deficient
porphyria(ADP)/Plumboporphyria
5. Porphyria cutanea tarda(PCT)
AD
AR
Sporadic

10. Erythropoietic porphyrias: at birth/early childhood
1. Erythropoietic porphyria(EPP)
2. Congenital erythropoietic porphyria(CEP)
3. X-linked protoporphyria(XLP)
Hepatoerythropoietic porphyria(HEP)
AR
AR

11.  Also classified as acute and non-
acute(cutaneous):
 Acute-AIP,HC,VP, ADP
 Cutaneous- PCT, CEP, EPP, HEP

12.  If the enzymatic defects-in the initial steps-
early metabolic intermediates accumulate –
neurovisceral symptoms
 If the enzymatic defects - in the final steps-
sunlight-induced cutaneous lesions due to
porphyrin accumulation in the skin

14. Clinical presentation:

16.  HMB synthase activity less than 50%
 Precipitating factors-steroids, porphyrinogenic
drugs, alcohol, low calorie diet(hPGC 1α ),
hormones
 C/F:Neurovisceral symptoms
 Visceral symptoms:
 Abdominal pain
 Nausea, vomiting,
 Constipation, Abd. distension
 Hypertension and tachycardia

17. Barbiturates
Carabamazepine
Chloroquine
Dapsone
Diclofenac
Erythromycin
Sulfonul ureas
PORPHYRINOGENIC DRUGS
Ethyl alcohol
Phenytoin
Furosemide
Griseofulvin
OCPs
Rifampicin
Sodium Valproate

18.  Neuropsychiatric symptoms
o Motor- proximal muscles initially
o DTR decreased or absent
o Sensory-Paresthesias and loss of sensations
o Mental- Anxiety, insomnia, depression,
hallucinations, paranoia
o Seizures

19. oElectrolyte imbalance- hyponatremia
Infants(homozygous)-
developmental delay, bilateral cataract,
hepatosplenomegaly – die at an early
age.

20.  Diagnosis:
o Increased levels of plasma and urinary ALA
and PBG - elevated for longer period.
o Fecal porphyrins-Normal, unlike HC and VP.
o Enzyme assay and Mutation analysis

21. Treatment:
•IV Hemin 3-4mg/Kg(lyophilized hematin
/ heme albumin/ heme arginate) daily for
4 days.
•IV Glucose(Carb. loading)-300g/day.
•Narcotic analgesics for pain,
•Avoidance of precipitating
factors

23.  Complications:
o Renal failure
o Hepatocellular Ca.(Hepatic imaging yearly)
 D/D:
o Acute appendicitis
o Dysmenorrhoea
o Cholecystitis
o Peripheral neuropathy

24.  A rare acute hepatic porphyria.
 The symptomatic patients are homozygous
with <10% of ALAD activity.
 C/F:Neurovisceral symptoms with earlier
age of onset

25. Diagnosis:
 Elevated levels of plasma and urinary ALA and
urinary coproporphyrin III
Enzyme assay(ALAD activity less than 10%)
Gene mutation analysis
Prenatal diagnosis

26.  Differential Diagnosis
 Hereditary Tyrosinemia type I
 Lead intoxication
 Treatment:
 similar to that of AIP.
 Infants-hyperalimentation and periodic
blood transfusions(no response to IV hemin)

27.  COPRO oxidase <50%
 Neurovisceral and cutaneous
photosensitivity together or separately.
 C/F: Identical to those of AIP but less
severe.
 More common in women.
 Blistering skin lesions

28.  Diagnosis:
 COPRO III – in the urine and
feces(symptomatic)
 Urinary ALA and PBG levels during acute
attack but revert to normal more quickly.
 Mutation analysis
 Enzyme assay
 Treatment: Same as AIP.

29.  Results from deficient activity of PROTO
oxidase.
 Presents with neurologic symptoms,
photosensitivity or both.
 C/F:Acute attacks- similar to those of AIP.
 Blistering skin lesions- similar to those of
PCT.

30.  Diagnosis:
 Urinary ALA and PBG-return to normal
 Persistant in fecal protoporphrin and
COPRO III and urinary COPRO III
 plasma porphyrins(esp. In cutaneous
lesions)
 Fluorescence spectroscopy
 Enzyme assay & mutation analysis

31.  Treatment:
 IV Hemin
 Avoid sun exposure

34.  The most common
 Sporadic/familial
 Hepatic URO decarboxylase (with ≤20% )

35. C/F: Blistering skin lesions-rupture and
crust-atrophy, scarring
Numerous milia ,
 Hypertrichosis-light & porphyrins
Hyperpigmentation

37. Other skin changes:
Heliotrope rash
Sclerodermoid plaques

38.  Diagnosis:
o Plasma/urinary/fecal Porphyrins
o Urinary ALA and PBG-normal
o Fluorometric studies
o Isocoproporphyrins in feces
 Treatment:
o Phlebotomy- 450ml/1-2 wks
o Antimalarials- 125mg chloroquine twice
weekly for abt 6-12 months

39.  Second most common porphyria in adults.
 The most common EP in children.
 C/F:
 Non-blistering photosensitivity
 Urticarial lesions
 Small, atrophic pitted scars

40. Pseudorhagades
Old knuckes/premature aging
Biliary fibrosis

41. DIAGNOSIS
Elevated levels of erythrocyte
protoporphyrin(free)
Fluorescence microscopy-red fluorescence
Enzyme assay
Mutation analysis

42.  Treatment:
 Avoid sunlight exposure
 Oral beta carotene
 Cholestyramine
 Plasmapheresis and IV hemin

43.  Gunther’s disease
 C/F:
• Bullae and vesicles
• Hypo/hyperpigmentation
• Hypertrichosis
• Secondary infections
• Brown teeth
• Hemolysis---- Anemia

45.  Diagnosis:
 URO & COPRO
 COPRO I in feces
 Enzyme assay
 Mutation analysis
 Treatment:
 Blood transfusions for anemia

46.  Systemic UROD -Early childhood
 Dark red urine- first sign
 Asso. with ocular manifestation
 C/F:
 Photosensitivity
 Hyperpigmentation
 Hypertrichosis
 Scleroderma like scarring

47.  Diagnosis:
 Increased fecal conc. of coproporphyrin
 Elevated RBC Zn-protoporphyrin levels
 Increased uro and coproporphyrin(RBC ,
Urine)
 Treatment:
 Photoprotection

49.  Defects in the erythroid gene ALAS
 Decreased activity—X linked sideroblastic
anemia.
 Increased activity- X-linked form of EPP,
known as X-linked protoporphyria (XLP).
 (Free PROTO= Zn-PROTO)

50.  XLSA- C/F:Males, during infancy
 Refractory hereditary anemia, pallor,
weakness
 Diagnosis: Bonemarrow- Hypercellular with
shift to left
 Prussian blue-sideroblasts
 Urinary ALA/PBG & Urinary and fecal
porphyrins – Normal

51.  Mutation Analysis
 Treatment:
 Pyridoxine
 Blood transfusion

52. •NEUROVISCERAL SYMPTOMS
• URINARY ALA & PBG
ALA
N PBG
ALA
PBG
porphyrins AIP HC VC
Urinary Copr III U & C Copr III
plasma N/
fecal N Copr III Copro &
Proto
ALAD
Urinary Porph
(Copr III )

53. CUTANEOUS LESIONS
Blistering Non-blistering
Plasma porphyrins
Porph PCT/HEP HC/VP CEP
Urine Uro/hep.co2 C-III U-I
C-I
Fecal Isocopr C-III
C, P
Copr I
RBC U-I
C-I
Plasma porphyrins
Porph EPP XLP
Urine N N
Fecal Proto N
RBC Proto
(F)
P(Z=F)