Acute hepatic porphyria syndrome with porphobilinogen synthase defect

On the basis of metabolite and enzyme studies a new type of acute hepatic porphyria with porphobilinogen synthase defect and repeated intermittent acute manifestations, abdominal colics, tachycardia and hypertension, and a persistent neurological syndrome was found in two young male patients. The main characteristic features are the following:

• 1.1. High urinary δ-aminolevulinic acid excretion( ⪢ 1 mmol/24hr), slight increase of porphobilinogen (up to 25 μmol/24 hr) and high increase of porphyrins (up to 22 μmol/24 hr) with coproporphyrin dominance.
• 2.2. Normal fecal and liver porphyrins.
• 3.3. Slight increase of erythrocyte protoporphyrin.
• 4.4. Decrease of porphobilinogen synthase activity in erythrocytes in both cases below 1% of healthy and not lead-exposed persons; normal activities of uroporphyrinogen synthase and decarboxylase in erythrocytes.
• 5.5. Low-normal lead concentrations in blood and low-normal lead excretion in urine in both cases; normal lead content in bone.
• 6.6. Normal plasma and urinary amino acids.
• 7.7. Irrelevant hepatological (liver biopsy), general clinical chemical and hematological findings.
• 8.8. Diminished activity of porphobilinogen synthase in nearly all family members of both patients. From these investigations it can be concluded that there is no exogeneous, “toxic” cause of this porphyria. Porphobilinogen synthase in lead poisoning is not diminished to such an extent as demonstrated here; in contrast to lead intoxication, porphobilinogen synthase activity cannot be activated or reactivated by thiols. All clinical and pathobiochemical data point at a new enzymatic type of endogeneous acute hepatic porphyria with intermittent acute manifestations, clinically analogous to so-called acute intermittent porphyria. Porphyrin precursors and porphyrin excretion both reflects the enzymatic defect and the regulatory consequences starting with the induction of δ-aminolevulinic acid synthase.

     

The incidence of chronic hepatic porphyria in an italian family

A genetic predisposition to develop porphyria cutanea tarda (PCT) was found in an Italian family. This predisposition in connection with an aggravating factor of alcohol or exposure to tetrachlorodibenzo-p-dioxin gave rise to two PCT cases in the family consisting of 66 persons.     

Hereditary porphobilinogen synthase deficiency in human associated with acute hepatic porphyria

Summary Deficient porphobilinogen-synthase (PBG-S) of a previously reported patient with PBG-S defect porphyria (red cell PBG-S activity 2% of the physiological level) has been characterized in erythrocytes after DEAE cellulose chromatography, ultrafiltration and polyacrylamide gel electrophoresis: Residual specific activity of 2.5%, increase of K_m, but identical fractionation, concentration and electrophoretic mobility of the enzyme protein compared to controls. These results provide evidence for a structural mutation of the gene specifying the enzyme PBG-S connected with a homozygous state of this new enzymatic type of hereditary acute porphyria.     

Impairment of latent inhibition in OXYS rats with hereditary syndrome of premature aging

The effect of latent inhibition has been tested in OXYS (strain selected for accelerated aging) and Wistar (control) rats at the age of 4 months using a conditioned passive avoidance reaction. The OXYS rats displayed a higher level of anxiety in the elevated plus-maze as compared to Wistar strain. The experimental procedure consisted of preexposure stage (presentation of non-reinforced environmental stimulus), conditioning (presentation of a preexposed stimulus paired with shock), and testing the effect of latent inhibition. The effect of latent inhibition was revealed only in Wistar rats, in which the latency of transition to the dark compartment of the experimental chamber was reduced. Contrastingly, in OXYS rats the conditioned performance was not inhibited. It is suggested that aging-associated factors such as the low rate of habituation to experimental situation at the preexposure stage and the high general anxiety level of OXYS rats can interfere with inhibition of the attention to irrelevant information.     

Development of chronic hepatic porphyria (porphyria cutanea tarda) with inherited uroporphyrinogen decarboxylase deficiency under exposure to dioxin

• 1.1. Exposure to dioxin triggered a clinically manifest chronic hepatic porphyria (porphyria cutanea tarda) in two patients (brother and sister) with hereditary uroporphyrinogen decarboxylase deficiency.
• 2.2. The patients showed a decrease of erythrocyte uroporphyrinogen decarboxylase activity to ~ 50% of controls even in reinvestigations after three years, whereas clinical symptoms and porphyrinuria had improved considerably. Only a subclinical phase of chronic hepatic porphyria persisted. Subnormal uroporphyrinogen decarboxylase activity could be determined in altogether nine family members.
• 3.3. The remission of porphyria cutanea tarda into a subclinical phase occurred after chloroquine therapy. Subclinical phases of chronic hepatic porphyria (type A) in other family members remitted without special therapy.
• 4.4. Among the 60 persons dioxin-exposed by the Seveso accident, a secondary coproporphyrinuria was found in 22% of examined patients with transition to a subclinical chronic hepatic porphyria in 5 cases. The changes had subsided completely after one year. A persistence of the transition state in 3 cases is probably due to alcohol influence. None of these cases developed a porphyria cutanea tarda.
• 5.5. The investigations showed that a hereditary disposition is necessary for biochemical and clinical expression of chronic hepatic porphyria after a unique dioxin exposure. This is not given in the sporadic cases: after a unique dioxin exposure they indeed develop a symptomatic disturbance of porphyrin metabolism but not a clinically relevant chronic hepatic porphyria.
• 6.6. We conclude that a unique acute exposure to dioxin can trigger the chronic hepatic porphyria disease process in persons with an underlying genetic abnormality of uroporphyrinogen decarboxylase.