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- 1. Porphyrias
- 2. The Vampire disease Photosensitivity Psychosis Red Colored Urine Prominent Teeth Pains(neuropathy) and Muscular cramps Legend of Dracula
- 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
- 6. Mnemonics for Hereditary Porphyria All---------------Acute Intermittent Porphyria Congenital------Congenital erythropoetic Porphyria Porphyrias------Porphyria Cutanea Tarda Have------------Hereditary Coprophyria Variable---------Variegate Porphyria Presentation----Protoporhyria
- 7. Different types of porphyrias Type of porphyria Enzyme defect Characteristics Acute intermittent porphyria HEPATIC Uroporphyrinogen I synthase Abdominal pain, neuropsychiatric symptoms Porphyria cutanea tarda Uroporphyrinogen decarboxylase Photosensitivity Hereditary coproporphyria Coproporphyrinogen oxidase Abdominal pain, Photosensitivity , neuropsychiatric symptoms Variegate porphyria Protoporphyrinogen oxidase Abdominal pain, Photosensitivity , neuropsychiatric symptoms ERYTHROPOIETIC PORPHYRIA Congenital erythropoietic porphyria Uroporphyrinogen III cosynthase Photosensitivity , increased hemolysis Protoporphyria Ferrochelatase Photosensitivity
- 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).
- 10. • Diagnosis? • Which enzyme? • Why Precipitated by Drugs??
- 11. Acute Intermittent Porphyria 6P’s Porphobilinogen Deaminase deficiency Pain in Abdomen Psychological symptoms(Anxiety, Agitation, Hysteria,Hallucinations, Depression) Peripheral Neuropathy (Patchy numbness, Parasthesia) Pee abnormality(Dysuria, urinary retention/incontinence, dark urine) Precipitated by drugs (Barbiturates, OCPs, Sulpha Drugs) Hepatic porphyria
- 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.
- 41. Summary
- 43. Thank You
Editor's Notes
- #4: 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.
- #9: Female: Male ratio 5:1
- #32: 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.
- #34: 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.