The patient, a 49-year-old man, presented with blistering on sun-exposed areas like his face and hands over the past year. Physical examination showed brown pigmented lesions and scarring on his hands and face. Laboratory tests found elevated levels of porphyrins and porphobilinogen in his urine. Serum also showed red fluorescence under UV light. Enzyme testing confirmed a deficiency of uroporphyrinogen decarboxylase. The diagnosis is porphyria cutanea tarda (PCT), which results from a buildup of porphyrin precursors due to the enzyme deficiency, making the skin photosensitive and causing blisters to form on exposure to sunlight.
3. King George III had a particularly severe form
of porphyria..
4. Porphyrias
• Porphyrias are the metabolic disorders of heme
synthesis, characterized by the increased
excretion of porphyrins or porphyrin
precurcors.
• Porphyrias are either inherited or acquired.
The most common acquired form of porphyria is due to
lead poisoning.
• Lead can inactivate ferrochelatase and ALA
dehydratase by combining with essential thiol
groups.
5. Classification of porphyrias
• Erythropoietic (bone marrow):
• Enzyme deficiency occurs in the erythrocytes.
• Hepatic:
• Enzyme defect lies in the liver.
Erythropoietic Hepatic
Porphyrias
8. Case
A 35-year-old woman presented to emergency
with severe abdominal pain, nausea, vomiting
and diarrhoea. GIT Evaluation was
unremarkable for intestinal infection. She
gradually improved and was discharged after 2
weeks.
After 3 years, she presented to a psychiatric
OPD with acute mental changes, hallucinations.
However, she was transferred to the emergency
department due to severe abdominal pain and
grand mal seizures.
9. Case 1 contd…
On examination, Her vitals were stable. She was
disoriented to time, place and person but had no focal
neurological signs.
MRI showed sub cortical abnormalities, and the spinal
fluid was normal.
After cholecystectomy for a distended gallbladder, she
was discharged Later on she continued to have mental
illness and developed muscle weakness.
Her condition worsened and progressed to quadriparesis,
respiratory failure due to aspiration pneumonia.
Urinary porphobilinogen (PBG) was reported as 52 mg/day
(reference range 0-4).
12. • Enzyme defect: Uroporphyrinogen I synthase
• Characteristic features:
• Increased excretion of porphobilinogen & γ-ALA.
• Urine gets darkened on exposure to air due to
conversion of porphobilinogen to porphobilin &
porphyrin.
• It usually expressed after puberty.
13. Symptoms
• Abdominal pain, vomiting & cardiovascular
abnormalities.
• Neuropsychiatric distrubances- due reduced
activity of tryptophan pyrrolase (caused by
depleted heme levels) resulting in the
accumulation of tryptophan & 5-
hydroxytryptamine.
14. • Symptoms are more severe after
administration of drugs (e.g. barbiturates)
• It induce the synthesis of cytochrome P450.
• This is due to the increased activity of ALA
synthase causing accumulation of PBG & ALA.
• These patients are not photosensitive.
• It is treated by administration of hematin, it
inhibits ALA sytnthase & accumulation of
porphobilinogen.
15. Porphyria cutanea tarda
• Thisis also known as cutaneous hepatic
porphyria & is the most common porphyria.
• It associated with liver damage caused by
alcohol overconsumption or iron overload.
• Enzyme deficiency:
• Uroporphyrinogen decarboxylase.
16. Characteristic features
• lncreased excretion of uroporphyrins (l & lll) &
rarely porphobilinogen.
• Cutaneous photosensitivity is the most
important clinical manifestation of these
patients.
• Skin fragility, scarring, sclerodermoid skin
changes, blistering skin lesions that develop
on sun-exposed skin
• Liver exhibits fluorescence due to high
concentration of accumulated porphyrins.
17. Pathogenesis of PCT
• PCT is usually an acquired liver disease caused
by exogenous factors, chief among which are
excess alcohol intake, iron overload, chronic
hepatitis C, oestrogen therapy and cigarette
smoking
• excessive alcohol intake and chronic hepatitis C
infection decrease hepcidin production by
hepatocytes.
• The decrease in hepcidin leads to increased iron
absorption from the gut.
• In the liver, iron loading and increased oxidative
stress leads to the formation of non-porphyrin
inhibitor(s) of uroporphyrinogen decarboxylase and
to oxidation of porphyrinogens to porphyrins
18. Treatment of PCT
• The treatment of choice of active PCT is iron
reduction by phlebotomy
• Maintenance of a mildly iron-reduced state
without anaemia.
• Low-dose antimalarials (cinchona alkaloids) are
also useful as additional therapy or as alternative
therapy for active PCT in those without
haemochromatosis or chronic hepatitis C
20. Hereditary coproporphyria
• Enzyme defect:
• Coproporphyrinogen oxidase.
• Coproporphyrinogen lll & other intermediates
(ALA and PBC) of heme synthesis prior to the
blockade are excreted in urine & feces.
• The patients are photosensitive.
21. Symptoms
• Symptoms are similar to acute intermittent
porphyria
• Abdominal pain, vomiting & cardiovascular
abnormalities.
22. • Neuropsychiatric distrubances- due reduced
activity of tryptophan pyrrolase (caused by
depleted heme levels) resulting in the
accumulation of tryptophan & 5-
hydroxytryptamine.
• It is treated by administration of hematin, it
inhibits ALA stnthase & accumulation of
porphobilinogen.
23. Variegate porphyria
• Enzyme defect: Protoporphyrinogen oxidase
• Due to this blockade, protoporphyrin lX required for
the ultimate synthesis of heme is not produced.
• Almost all the intermediates (porphobilinogen,
coproporphyrin, uroporphyrin, protoporphyrin etc.) of
heme synthesis accumulate in the body & are excreted
in urine and feces.
• The urine of these patients is coloured & they exhibit
photosensitivity
24. Erythropoietic porphyria
Congenital erythropoietic porphyria:
• Enzyme defect:
• Uroporphyrinogen III cosynthase.
• Also caused by an imbalance between the
activities of uroporphyrinogen I synthase and
uroporphyrinogen lll cosynthase
25. Characteristic features
• It is a rare congenital disorder.
• Mostly contained in erythropoietic tissues
(bone)
• Individuals excrete uroporphyrinogen I &
coproporphyrinogen I which oxidize
respectively to uroporphyrin I &
coproporphyrin I.
26. • The patients are photosensitive (itching &
burning of skin when exposed to light).
• Skin pain or burning in sunlight
• Erythema, swelling.
• Erosions in light exposed areas-mainly in
face & hands.
• Scarring - shallow circular or linear.
• Waxy thickening of the skin.
• Increased hemolysis.
28. Erythropoietic Protoporphyria
• Enzyme defect:
• Ferrochelatase.
• Protoporphyrin IX accumulates in tissues & is
excreted into urine & feces.
• Reticulocytes (young RBC) & skin biopsy exhibit
red flourorescence.
29. Acquired or toxic porphyria
• It occur due to toxicity of several compounds.
• Exposure of the body to heavy metals (e.g.
lead), toxic compounds (hexachlorobenzene)
and drugs (e.g. griseofulvin) inhibits many
enzymes in heme synthesis.
• These includes ALA dehydratase,
uroporphyrin I synthase & ferrochelatase.
30. Diagnosis of Porphyria
Urinary δ ALA and PBG- Chemical
Methods
Porphyrin Isomers: HPLC/TLC
Definite Diagnosis:
Specific Enzyme Deficiency/Gene Defect.
31. Porphyrins are colored & fluoresce
Porphyrinogens are colorless,
Porphyrins are colored.
The sharp absorption band near 400 nm, a distinguishing feature shared
by all porphyrins, is termed the Soret band
Porphyrins dissolved in strong mineral acids or in organic solvents and
illuminated by ultraviolet light emit a strong red fluorescence
Cancer Phototherapy: Since tumors often take up more porphyrins than
do normal tissues,
Hematoporphyrin or related compounds are administered to a patient
with an appropriate tumor. The tumor is then exposed to an argon laser
to excite the porphyrins, producing cytotoxic effects.
32. Acute Treatment
•Opioids: Pain
Phenothiazines: Nausea and psychiatric
manifestations
•Propranolol: Tachycardia and hypertension
•Chloral hydrate or benzodiazepines: Insomnia
•Levetiracetam: Seizures
•Hematin: Given IV 1 to 4 mg/kg once daily for 3
to 14 days
33. •Phlebotomy is helpful in porphyrias with
photosensitivity(PCT)
•Givosiran, an RNA interference therapy, inhibits hepatic delta-
aminolevulinic acid synthase 1 (ALAS1) expression.
•The FDA has granted marketing approval to use afamelanotide,
a chemical analogue of alpha-melanocyte stimulating hormone,
to increase pain-free light exposure in adult patients with a
history of phototoxic reactions from erythropoietic
protoporphyria (EPP)
34. Chronic Treatment
•It is advisable to carry a medical bracelet with the
name of the porphyria and for specific avoidance
of substances that may trigger porphyria in
medical emergency or hospital admissions for
other reasons.
Consume sufficient carbohydrates.
•Avoid alcohol and other triggers, including rapid
weight loss or emotional/physical stress.
35. Prevention
•Use zinc oxide sunscreens.
• Attacks can be prevented by avoiding triggers
• Screen for hemachromatosis in PCT, as
increasing liver iron triggers this disease.
• Screen for hepatocellular carcinoma with liver
ultrasound (alpha-fetoprotein is not usually
increased).
37. Case 2
49 yr old man presented to skin OPD with
complaints of blistering on sun-exposed areas
for the last year.
Dark coloured urine. Blisters were particularly
prominent on his face and hands and usually
healed leaving behind scarring.
Physical examination: showed that both dorsal
regions of his hands had brown pigmented skin
lesions, his face also had multiple scars.
• Porphyrin levels (24 hr urine) was 832 ug/24
hr, porphobilinogen level was 1.65mg/24 hr
38. • Patients serum showed a red fluorescence
to UV light and excreation of discoloured
urine.
• Specific enzyme assay confirmed the
deficiency of uroporphyrinogen
decarboxylase.
39. • What is the diagnosis
• Why did the patient develop blistering on the
sun-exposed areas
40. • PCT
• PCT occurs due to the deficiency of UROD.
This leads to accumulation of uro
porohyrinogen and the partially carboxylated
intermediates hepta, hexa, penta-
carboxylate porphyrinogens which are auto-
oxidized to the corresponding porphyrins.
These porphyrins get excited on exposure to
sunlight, leading to lysosomal damage and
blistering of skin.
George III had a particularly severe form of porphyria. His first attack occurred in 1765, four years after his marriage to Queen Charlotte. Further signs of the disease showed up in 1788-1789. From 1811 to the time of his death in 1820 the royal patient became progressively insane and blind. He was nursed in isolation, and kept in straight jackets and behind bars in his private apartments at Windsor Castle.
His mental state was frightening. There were times when he would talk so much and so quickly that he would begin to foam at the mouth, needing to be restrained. He went through violent phases, one particularly bad one was directed at his son, who would later succeed him a full decade before his death. And there were times when he thought that he was already dead, and he would have conversations with relatives that had long since passed on and with the angels he believed surrounded him in heaven.
Female: Male ratio 5:1
The conjugated double bonds in the pyrrole rings and linking methylene groups of porphyrins (absent in the porphyrinogens) are responsible for their characteristic absorption and fluorescence spectra.
Porphyrins dissolved in strong mineral acids or in organic solvents and illuminated by ultraviolet light emit a strong red fluorescence, a property often used to detect small amounts of free porphyrins
The photodynamic properties of porphyrins have suggested their possible use in the treatment of certain types of cancer, a procedure called cancer phototherapy. Since tumors often take up more porphyrins than do normal tissues, hematoporphyrin or related compounds are administered to a patient with an appropriate tumor. The tumor is then exposed to an argon laser to excite the porphyrins, producing cytotoxic effects.
In a recent randomized trial in patients with acute hepatic porphyria (AHP) who had recurrent attacks, givosiran resulted in reductions in induced ALAS mRNA levels and nearly normalized levels of the neurotoxic intermediates delta ALA and porphobilinogen. Givosiran also led to fewer days of hemin use and better daily scores for pain than placebo and is now approved for use as a monthly subcutaneous injection in adults with AHP.