8/6/2019 12.7.07 AIP Golden

1/16

8/6/2019 12.7.07 AIP Golden

2/16

The Porphyrias

Group of inheritedor acquireddisorders of hemeproduction

8 enzymes inheme biosyntheticpathway

First and the last 2are mitochondrial,

while the other fiveare in the cytosol.

8/6/2019 12.7.07 AIP Golden

3/16

Heme Production

The two major cell

types that are active

in heme synthesis

are hepatocytes and

bone marrowerythroblasts

85% of total

synthesis occurs in

erythroid cells

80% of liverproduction is used for

cytochromes

8/6/2019 12.7.07 AIP Golden

4/16

8/6/2019 12.7.07 AIP Golden

5/16

EnzymaticDeficiencies

All of the heme pathwayintermediates are

potentially toxic.

Their overproductioncauses the characteristicneurovisceral and/orphotosensitizingsymptoms.

8/6/2019 12.7.07 AIP Golden

6/16

Acute intermittent porphyria

The prevalence of AIP in the United States is thought to be510 per 100 000. It is more common in northern European countries, such as

Sweden (60100 per 100 000), Britain and Ireland.

Acute intermittent porphyria PBGD gene mutation isinherited in an autosomal dominant fashion. The enzyme activity is 50% of normal in those who inherit

the genetic trait.

There is no difference in PBGD activity between patients

and latent gene carriers. An inherited deficiency of PBGD is not in itself sufficient to

cause clinical expression of AIP; the great majority ( 90%)of individuals who inherit a deficiency of PBGD neverdevelop porphyric symptoms.

More than 200 mutations of the PBGD gene have beendescribed to date in AIP.

8/6/2019 12.7.07 AIP Golden

7/16

Affects women more than men, with a ratio of 2:1.

Most patients become symptomatic at age 18-40 years.

Attacks occurring before puberty or after age 40years are unusual unless a major provocation

Most patients are completely free of symptomsbetween attacks.

Course of the neurological manifestations is highlyvariable.

Acute attacks of porphyria may resolve quiterapidly.

Sudden death may occur, presumably due tocardiac arrhythmia.

Acute intermittent porphyria

8/6/2019 12.7.07 AIP Golden

8/16

Most patients are completely free of symptomsbetween attacks

Attacks involve neuro-visceral symptoms but no skinmanifestations: The sequence of events in attacks usually is (1) abdominal pain,

(2) psychiatric symptoms, such as hysteria, and (3) peripheralneuropathies, mainly motor neuropathies.

Gastroenterological Symptoms most common: Constipation (4884%), colicky abdominal pain (occurring in 85

95% cases), vomiting (4388%), diarrhea (512%)

The abdominal pain is severe and lasts for several days. Severeabdomen pain of short (

8/6/2019 12.7.07 AIP Golden

9/16

Patients often experience peripheralneuropathies (4260%) that are predominantlymotor and can mimic Guillain-Barr syndrome.The weakness usually starts in the lower limbsand ascends, but neuropathies can beobserved in any nerve distribution. Diffuse pain, especially in the upper body, can be

observed (5052%).

Patients may develop fever(937%),

hypertension (3654%) and tachycardia (2880%).

Patients can have a wide variety of psychiatricsymptoms (4058%). Depression is very common.

Symptoms

8/6/2019 12.7.07 AIP Golden

10/16

Mechanism

The exact mechanism underlying these complaints is not yetwell 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 thecentral nervous system (Whetsell et al, 1984)

Decreased heme synthesis in the liver results in decreased

activity of hepatic tryptophan pyrrolase (T

P), a heme-dependent enzyme, possibly resulting in increased levels ofserotonin

8/6/2019 12.7.07 AIP Golden

11/16

Precipitants Drugs: most common precipitate of acute attacks :

Barbiturates and sulphonamides being mostcommon

Reduced energy intake: even brief periods ofstarvation during dieting, postoperative periods, orconcurrent illness.

Tobacco smoke: polycyclic aromatic hydrocarbons,are known inducers of hepatic cytochrome P450enzymes and heme synthesis.

An association between cigarette smoking and

repeated attacks of porphyria was found in asurvey of 144 patients with AIP in Britain (Lip etal, 1991).

Infections, surgery and stress.

8/6/2019 12.7.07 AIP Golden

12/16

Diagnosis Demonstration of porphyrin precursors, such as ALA

and/or PBG, is essential for the diagnosis of acuteporphyrias.

Porphyrin analysis is necessary for the diagnosis ofporphyrias with cutaneous photosensitivity.

PBG usually is not included in a urine porphyrinscreen and must be ordered specially

Molecular diagnostic testing:

Detection of PBGD mutations in AIP provides95% sensitivity and around 100% specificity

Possible to screen asymptomatic gene carriers.

Less Useful in acute attacks

8/6/2019 12.7.07 AIP Golden

13/16

Urinary ALA and PBG are

always markedly increased

in symptomatic patients

with AIP and even in someasymptomatic individuals

with the inherited enzyme

deficiency

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.

Diagnosis

8/6/2019 12.7.07 AIP Golden

14/16

T

reatment

Recognition and avoidance of precipitating events is

the first key part of treatment. Management of acute attack is essentially the same

for AIP, ADP, HCP and VP.

IV administration of glucose is given to providea minimum of 400 g/day.

People experiencing severe attacks, especially

those with severe neurologic symptoms, shouldbe treated with hematin in a dose of 4 mg/kg/dfor 4 days (shown to decrease urinary excretionof ALA and PBG, acute attacks, and perhaps theseverity of neuropathy).

8/6/2019 12.7.07 AIP Golden

15/16

T

reatment

Haemolytic anaemia in erythropoietic porphyrias

may be treated by blood transfusion. Cutaneous photosensitivity may be treated by:

Photoprotection, e.g. with broad-bandsunscreens and/or protective clothing

Strict avoidance of sunlight exposure

Change day-night-rhythmoral

EEP- B-carotene

PCT- phlebotomy or oral chloroquine

Most patients (60-80%) who have an acute attackof porphyria never have another one

8/6/2019 12.7.07 AIP Golden

16/16

Vampires and

werewolves

Cutaneous Porphyrias have been suggested as an explanation for the

origin of vampire and werewolf legends, based upon a number ofsimilarities between the condition and the folklore that was firstspeculated upon by biochemist David Dolphin in 1985. His ruminationsgave rise to a popular urban legend which accepts this association asfactual, though it is historically and factually baseless.