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Hematology Center
Acute Intermittent Porphyria

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CLINICAL FINDINGS
Expressed clinically almost invariably after puberty, & more commonly in women.
1. Abdominal pain (generalized or localized), is the most common symptom (often the initial sign of an acute attack).
2. Nausea, vomiting, constipation or diarrhea, abdominal distention & ileus.
3. Urinary retention, incontinence, & dysuria are also common,
4. Tachycardia, hypertension
5. Fever, sweating, restlessness & tremor (less frequent)
6. There are no cutaneous manifestations.
7. Peripheral neuropathy (very common). Muscle weakness (proximally in the legs but may involve the arms or the distal extremities). Motor neuropathy may also involve the cranial nerves, or lead to bulbar paralysis, respiratory impairment, & death. Sensory, patchy neuropathy may also occur.

Acute attacks of AIP may be accompanied by seizures.
The course of an acute attack of AIP is highly variable within a single individual as well as among patients, with attacks lasting from a few days to several months.

Psychiatric complaints may be the only feature of this diesease. They may include hysteria, anxiety, apathy or depression, phobias, psychosis, organic disorders, agitation, delirium, and altered consciousness, ranging from somnolence to coma. Some patients develop a psychosis similar to schizophrenia.

DIAGNOSIS
Variably increased amounts of ALA and PBG in the urine between attacks.
In the majority of cases, the onset of an acute attack is accompanied by marked increases in excretion of these precursors.
In severe cases, the urine may develop a port-wine color, due to a high concentration of porphobilin, an autooxidation product of PBG
Acute attacks may also be associated with elevations in the plasma concentrations of ALA, PBG, and porphyrins, which are normally undetectable.
Stool porphyrin concentrations are usually normal or only slightly elevated.
Despite the enzymatic block at the level of PBGD, overall hemoglobin and bilirubin production rates are normal, and patients with AIP are neither anemic nor jaundiced.

SCREENING TESTS
The Watson-Schwartz test - widely used in emergency situations as a screening test for urinary PBG. This test is positive about 50% of the time at urinary concentrations of PBG five times the upper limit of normal, and consistently positive at concentrations more than 10 to 20 times normal.

Screening methods that employ ion-exchange columns are more sensitive and specific than the Watson-Schwartz test.

Definitive testing When neurovisceral symptoms suggestive of a hepatic porphyria are present, urinary ALA, PBG, & porphyrin concentrations should be determined in an aliquot from a 24 hour urine collection.

  Aminolevulinic acid Normal excretion of ALA is less than 7 mg per 24 hours; in an attack of AIP, urinary ALA excretion is markedly elevated, with typical values being several, or sometimes more than 10 times the upper limit of normal.

  Porphobilinogen Normal excretion of PBG is less than 4 mg per 24 hours; in an attack of AIP, urinary PBG excretion is markedly elevated, with typical values being several, or sometimes more than 10 times the upper limit of normal. The increase in excretion of PBG is usually equal in magnitude to that of ALA.

  Erythrocyte enzyme assay If AIP is suspected, erythrocyte PBGD activity should be determined, since patients with type I and type III disease have approximately 50 percent enzyme activity compared with normal controls. In type II AIP (<5 percent of cases), PBGD deficiency is seen only in nonerythroid cells (ie, fibroblasts, lymphocytes, hepatocytes) (show table 2).

The decrease in enzyme activity is similar for latent gene carriers; thus, the same test should be run in families in which a proband is identified. The diagnosis of type I and III AIP (> 95 percent of all AIP patients) can be made by demonstrating decreased PBGD activity in erythrocytes [1]. The distinction between latent status and clinically expressed AIP requires demonstration of elevated urinary excretion of PBG and ALA in the latter.

The diagnosis of type II AIP (<5 percent of all AIP patients) is made either by demonstrating PBGD deficiency in nonerythroid cells (eg, lymphocytes or fibroblasts), or via DNA hybridization using allele-specific oligonucleotides specific for the mutation. If a mutation is identified in a given pedigree, it offers full specificity and sensitivity, and can be used as the sole diagnostic method in the family under study [