Acute intermittent porphyria (AIP) is caused by a deficient activity of the enzyme porphobilinogen deaminase (PBGD). It is inherited in an autosomal dominant pattern and is characterized by acute neurovisceral attacks after puberty. Attacks are often triggered by drugs, hormones, fasting, or other stressors and cause abdominal pain, neuropathy, and sometimes mental symptoms. Diagnosis is confirmed by elevated urinary porphobilinogen and erythrocyte PBGD enzyme activity testing. Treatment of attacks involves intravenous heme and supportive care. Lifelong management focuses on identifying and avoiding triggers to prevent recurrent attacks.

1. ACUTE INTERMITTENT
PORPHYRIA (AIP)
(PYRROLOPORPHYRIA)
Dr.Padmesh.V

2.  Deficient activity of the housekeeping form of PBG
deaminase (PBGD). (This enzyme is also known as
hydroxymethylbilane (HMB) synthase;
The prior term uroporphyrinogen I synthase is
obsolete.

3.  Autosomal dominant.
 PBGD deficiency can be documented in fetus by
measuring enzyme activity in amniotic fluid cells, or
more reliably by finding a PBGD mutation in these
cells.
 More than 300 PBGD mutations, including:
 Missense mutations
 Nonsense mutations
 Splicing mutations
 Insertions, and
 Deletions.

4.  Pathology and Pathogenesis
 Induction of rate-limiting hepatic enzyme ALAS1
Acute exacerbations.
 AIP remains latent (or asymptomatic) in most of those
who are heterozygous carriers of PBGD mutations, and
this is almost always the case before puberty.
 In those with no history of acute symptoms, porphyrin
precursor excretion is usually normal. (suggesting that
half-normal hepatic PBGD activity is sufficient and
hepatic ALAS1 activity is not increased.)

5.  Pathology and Pathogenesis
 Many nongenetic factors (eg: drugs) that lead to clinical
expression of AIP have the capacity to induce hepatic
ALAS1 and CYPs.
 Under conditions in which heme synthesis is increased
in the liver, half-normal PBGD activity may become
limiting, and ALA, PBG, and other heme pathway
intermediates may accumulate.
 In addition, heme synthesis becomes impaired and
heme-mediated repression of hepatic ALAS1 is less
effective.

6.  Pathology and Pathogenesis
 Latency of AIP before puberty: suggests that endocrine
factors, especially adult levels of steroid hormones, are
important for clinical expression.
 Symptoms more common in women: a role for female
hormones.
 Premenstrual attacks: probably due to endogenous
progesterone.
 Acute porphyrias are sometimes exacerbated by exogenous
steroids, including oral contraceptive preparations
containing progestins.

7.  Drugs that are UNSAFE in Prophyria:
 Sulfonamide antibiotics
 Barbiturates
 Phenytoin
 Carbamazepine
 Clonazepam
 Valproic acid
 Griseofulvin
 Ketoconazole
Metoclopramide
Rifampin
Pyrazinamide
Diclofenac
Progesterone
Danazol
Alcohol
ACE inhibitors (esp enalapril)
Calcium channel blockers
(esp nifedipine)

8.  Other predisposing factors:
 Nutritional factors: reduced intake of calories and
carbohydrates.
(Increased carbohydrate intake may ameliorate attacks)
 Chemicals in cigarette smoke can induce hepatic CYPs
and heme synthesis.
 Metabolic stress

9.  Mechanism of neural damage in acute porphyrias:
 Poorly understood.
 Decreased nitrous oxide production by nitrous oxide
synthase (a hemoprotein) Vasospasm  cerebral
manifestations.
 Most favored hypothesis: 1 or more heme
precursors, or perhaps a derivative, are neurotoxic.

10.  Clinical Manifestations
 Neurovisceral manifestations: Any time after puberty.
(rarely before)
 Acute attacks: Constellation of nonspecific symptoms
(may become severe and life-threatening)
 Abdominal pain in 85-95% of cases.
 Nausea, vomiting, constipation are common, and
increased bowel sounds and diarrhea may occur.
 Bladder dysfunction-- hesitancy and dysuria.

11.  Clinical Manifestations
 Other common manifestations:
 Mental symptoms
 pain in the extremities, head, neck, or chest
 muscle weakness
 sensory loss

12.  Clinical Manifestations
 Tachycardia, the most common physical sign (80%)
 Often accompanied by hypertension, restlessness,
tremors, and excess sweating. (Sympathetic
overactivity & increased catecholamines. )
 Because all these manifestations are neurologic
rather than inflammatory, there is no abdominal
tenderness/ fever/ leukocytosis.

13.  Clinical Manifestations
 Porphyric neuropathy is primarily motor (result from
axonal degeneration rather than demyelinization).
 Motor weakness most commonly begins in proximal
muscles of the upper extremities and then progresses to
the lower extremities and the periphery. It is usually
symmetric, but occasionally asymmetric or focal.
 Sensory involvement: pain in extremities (muscle or
bone pain), numbness, paresthesias, and dysesthesias.
 Paresis may occur early, but more often a late
manifestation in an attack that is not treated.

14.  Clinical Manifestations
 Common central nervous system manifestations
include seizures, anxiety, insomnia, depression,
disorientation, hallucinations, and paranoia.
 Initially tendon reflexes little affected or hyperactive 
become decreased or absent.
 Cranial nerves, most commonly X andVII, may be
affected, and blindness from involvement of the optic
nerves or occipital lobes has been reported.
 Hyponatremia is common during acute attacks.
Inappropriate antidiuretic hormone (ADH)
secretion is often the most likely mechanism.

15.  Clinical Manifestations
 Attack resolves rapidly, unless treatment is delayed.
 Abdominal pain may resolve within few hours and
paresis within few days.
 Even severe motor neuropathy can improve over
months or several years, but may leave some residual
weakness.
 Progression of neuropathy to respiratory and bulbar
paralysis and death is uncommon with appropriate
treatment and removal of harmful drugs.
 Sudden death from cardiac arrhythmia.

16.  Lab findings:
 Fundamental step: Urine Porphobilinogen (increased)
 Levels of ALA and PBG are increased.
 Erythrocyte PBGD activity is approximately half-normal in most
patients (70-80%) with AIP.

17.  Lab findings:
 An increased urinary PBG establishes that a patient has 1 of the 3
most common acute porphyrias .
 Measurement of urinaryALA is less sensitive than PBG and also
less specific but will detect ADP, the fourth type of acute
porphyria.
 Erythrocyte PBGD activity is decreased in most AIP patients and
helps confirm the diagnosis in a patient with high PBG.
A normal enzyme activity in erythrocytes does not exclude AIP.

18.  Complications
 Risk of advanced liver disease and hepatocellular
carcinoma is increased during adult life.
 Risk of chronic hypertension and impaired renal
function, with evidence of interstitial nephritis, is
increased in AIP.

19.  Treatment
 Hemin
 Intravenous hemin + symptomatic + supportive
measures is the treatment of choice.
 There is a favorable response to early treatment with
hemin, and less response if treatment is delayed.

20.  Treatment
 Hemin
 Intravenous hemin + symptomatic + supportive
measures is the treatment of choice.
 Favorable response to early treatment with hemin, and
less response if treatment is delayed.
 Stabilization of lyophilized hematin by reconstitution
with 30% human albumin can prevent local adverse
effects.
 3-4 mg/kg daily for 4 days

21.  Treatment
 Others:
 Hospitalization
 Discontinue exacerbating drugs/agents
 IV Fluids
 Narcotic analgesics for pain
 Ondansetron
 Chloral hydrate or low doses short-acting
benzodiazepines for restlessness or insomnia.
 β-Adrenergic blocking agents for tachycardia and
hypertension.
 IV 10% dextrose
 Treatment of seizures

22.  Prognosis
 In those presenting with acute symptoms, recurrent
attacks were most likely within the next 1-3 yr.
 Improved outlook with early detection and
treatment.

23.  Prevention :
 Identify inciting factors and remove.
 A well-balanced diet that is somewhat high in
carbohydrate (60-70% of total calories)
 CorrectAnemia.
 Hormonal therapy
 Hemin once or twice weekly can prevent
frequent, noncyclic attacks.

24.  Genetic Counseling
 If the child is found to have inherited the mutation,
counsel to avoid potentially harmful drugs.
 Counseling that the great majority of those who
inherit a PBGD mutation never develop symptoms,
and the prognosis of those who do is favorable.

25. www.slideshare.net/Dr_Padmesh
dnbpediatricstheory.blogspot.com/
oscepediatrics.blogspot.com/