Hepatic Porphyrias (Acute Intermittent Porphyria, Variegate Porphyria, Porphyria Cutanea Tarda)

Ann IM 2005;142:439; Nejm 1991;324:1432

Cause:AIP and VP always genetic, VP is autosomal dominant (Nejm 1978;298:358); PCT may be either genetic (type II and III) or sporadic (type I)

Pathophys: Generally excess porphyrins cause skin sensitization; and excess ALA and porphobilinogen (PBG) cause neurologic damage. Impaired mitochondrial enzyme systems: succinyl CoA + glycine (with ALA synthetase, the rate-limiting enzyme) ALA PBG UroPG I-III CoproPG III ProtoPG III ProtoPorph heme (pathways—Nejm 1970;283:955). In AIP, drug/diet induces ALA synthetase increase and deficiency of UroPG synthetase (PBG deaminase), causing increased ALA and PBG, in turn causing demyelination and perhaps pain. In VP, decreased conversion PPG PP (Nejm 1980;302:765). In PCT, decreased conversion UPG CPG in rbc (Nejm 1978;299:1095) and liver (Nejm 1982;306:766); skin damage from UV and/or traumatic activation of complement (Nejm 1981;304:213)

Acute intermittent porphyria (AIP): more women than men. Variegate porphyria (VP): increased in South African Caucasians and in alcoholics (Nejm 1978;298:358). Porphyria cutanea tarda (PCT): increased in cirrhotics and hepatoma pts

Sx: Precipitated by barbiturates, sulfas, griseofulvin, alcohol (even in mouthwashes) (Nejm 1975;292:1115), estrogens and pregnancy, infections, weight reduction (Nejm 1967;277:350)

AIP: onset age 20-40 yr, abdominal colic, vomiting, constipation, urine becomes brown on standing after voiding; no skin involvement at all

VP: onset age 11-30 yr, abdominal colic, rash like PCT

PCT: dermal sensitivity w bullae and scars, hyperpigmentation, red urine, photosensitivity (see Table 3.3 for diff dx)

Si: AIP alone: hypertension, tachycardia, low-grade fevers

AIP and VP: peripheral motor and sensory neuropathy, psychoses, and neuroses

PCT: rashes, hirsutism, scarring, vitiligo, milia, esp on hands

AIP: 25% 5-yr mortality after 1st attack; worse in younger patients

AIP: respiratory paralysis, infections

VP and PCT: r/o scleroderma; congenital erythropoietic porphyria (Nejm 1986;314:1029); protoporphyria (Nejm 1991;324:1432); naprosyn, tetracycline, or nalidixic acid photosensitization or similar skin changes seen with hemodialysis and in all of which urine tests will be neg

Lab:

Hem:in PCT: Hgb, Fe, and TIBC increased often

Urine:in AIP and VP: red-brown on standing (pyrroles condense to porphyrins); single-void rapid semi-quantitative PBG level elevated and, if positive, get other tests for precursors (ALA porphyrin and PBG), plus plasma porphyrins, fecal porphyrins, and rbc PBG deaminase levels. 24-h urine PBG level >2 × normal during acute attack; urine porphyrins between attacks less helpful

• in PCT: PBG tests negative; chromatography shows increased UPG and CPG in urine

Rx:

Prevent attacks of AIP and VP by avoiding multiple precipitating drugs, weight loss, infections, and drugs; test relatives; warn about pregnancy and oral contraceptives. In VP and PCT, avoid skin changes with protective clothing

for PCT, phlebotomize 500 cc q 2 wk; unknown mechanism perhaps via hepatic Fe metabolism (Nejm 1968;279:1301). Chloroquine 250-500 mg qd × 5-8 d, exacerbates, then long remissions (Jama 1980;223:515)

of AIP/VP attacks: iv 10% glucose. Hemin (Panhematin) iv inhibits ALA synthetase