++
This hepatic porphyria is an autosomal dominant condition resulting
from the half-normal level of HMB synthase (also termed PBG deaminase)
activity.1,9 The disease is widespread but is especially
common in Scandinavia and Great Britain. The enzyme deficiency can
be demonstrated in most heterozygous individuals, but clinical expression
is highly variable. Activation of the disease is related to ecogenic
factors, such as drugs, diet, and steroid hormones, which can precipitate
the manifestations. Attacks can be prevented by avoiding known precipitating
factors. Rare cases of homozygous AIP have been reported in children.10
++
Most heterozygotes remain clinically asymptomatic (latent) unless
exposed to factors that increase porphyrin production. Endogenous and
exogenous gonadal steroids, porphyrinogenic drugs, alcohol ingestion,
and low-calorie diets (usually instituted for weight loss) are common
precipitating factors. Table 167-3 lists
the major drugs that are harmful in AIP (and in hereditary coproporphyria [HCP] and variegate
porphyria [VP]) and some drugs and anesthetic
agents known to be safe. More extensive lists of drugs considered
harmful or safe are available at the Drug Database for Acute Porphyrias
(www.drugs-porphyria.com) and at www.porphyriafoundation.com
and www.porphyria-europe.com, but information is incomplete for
many drugs. Attacks also can be provoked by infections and by surgery.
++
++
Because the neurovisceral symptoms rarely occur before puberty
and are often nonspecific, a high index of suspicion is required
to make the diagnosis. The disease can be disabling but is rarely
fatal. Abdominal pain, the most common symptom, is usually steady
and poorly localized but may be cramping. Ileus, abdominal distention,
and decreased bowel sounds are common. However, increased bowel
sounds and diarrhea may occur. Abdominal tenderness, fever, and leukocytosis
are usually absent or mild, because the symptoms are neurological
rather than inflammatory. Nausea; vomiting; constipation; tachycardia;
hypertension; mental symptoms; muscle weakness; sensory loss; dysuria;
urinary retention; and pain in the limbs, head, neck, or chest are
characteristic. Tachycardia, hypertension, restlessness, tremors,
and excess sweating are due to sympathetic overactivity.
++
The peripheral neuropathy is the result of axonal degeneration
(rather than demyelination) and affects primarily motor neurons.
Significant neuropathy does not occur with all acute attacks; abdominal
symptoms are usually more prominent. Motor neuropathy initially
affects the proximal muscles, more often in the shoulders and arms.
The course and degree of involvement are variable. Deep-tendon reflexes
may be normal or hyperactive but are usually decreased or absent with
advanced neuropathy. Motor weakness can be asymmetric and focal
and may involve cranial nerves. Sensory changes such as paresthesias
and loss of sensation are less prominent. Progressive muscle weakness
can lead to respiratory and bulbar paralysis and death when diagnosis
and treatment are delayed. Sudden death may result from sympathetic
overactivity and cardiac arrhythmia.
++
Mental symptoms, such as anxiety, insomnia, depression, disorientation,
hallucinations, and paranoia, can occur in acute attacks. Seizures
can be caused by neurological effects or by hyponatremia. Treatment
of seizures is difficult, because virtually all antiseizure drugs
(except bromides) may exacerbate AIP (clonazepam may be safer than
phenytoin or barbiturates). Hyponatremia results from hypothalamic
involvement and inappropriate secretion of antidiuretic hormone,
or from electrolyte depletion due to vomiting, diarrhea, poor intake,
or excess renal sodium loss. Persistent hypertension and impaired
renal function may occur. When an attack resolves, abdominal pain
may disappear within hours, and paresis begins to improve within
days and may continue to improve over several years.
++
ALA and PBG levels are increased in plasma and urine during acute attacks.9 Although the
diagnosis of an acute attack is based on clinical findings and not
the absolute level of these porphyrin precursors, the increase is
expected to be substantial. PBG excretion is usually 50 to 200 mg/24
hr (220–880 mmol/24 hr; normal, 0–4 mg/24
hr [0–18 mmol/24 hr]), and urinary ALA
excretion is 20 to 100 mg/24 hr (150–760 mmol/24
hr; normal, 1–7 mg/24 hr [8–53 mmol/24
hr]). The excretion of these compounds generally decreases
with clinical improvement, particularly after hematin infusions. A
normal urinary PBG level effectively excludes AIP as a cause for
current symptoms. Fecal porphyrins are usually normal or minimally
increased in AIP, in contrast to HCP and VP. Most asymptomatic (“latent”)
heterozygotes with HMB synthase deficiency have normal urinary excretion
of ALA and PBG. Therefore, measuring HMB synthase in erythrocytes
may be useful to confirm the diagnosis and to screen asymptomatic
family members.
++
The enzyme deficiency is detectable in erythrocytes from most
AIP heterozygotes (classic AIP). Note that the activity is higher
in young erythrocytes and may increase into the normal range in
AIP when erythropoiesis is increased due to a concurrent condition.
However, patients with the rare erythroid form of AIP (erythroid
or variant AIP) have normal enzyme levels in erythrocytes and deficient activity
in nonerythroid tissues. The erythroid and housekeeping forms of
HMB synthase are encoded by a single gene that has two promoters.
One promotes transcription of a messenger RNA for the housekeeping
form found in all tissues, and the other promotes formation of the
erythroid-specific transcript found only in erythroid cells. Over
250 mutations causing AIP have been identified (see the Human Gene Mutation
Database, www.hgmd.org). Mutations that cause erythroid
AIP variants with half-normal enzyme in nonerythroid tissues but
normal activity in erythrocytes include point mutations in the initiation
methionine codon (which prevent translation) or in the 5'-donor
splice site of intron 1 (which causes abnormal splicing of the HMB
synthase transcript).
++
Identifying the gene in an index case enables detection of latent
family members and prenatal diagnosis of an at-risk fetus using
cultured amniotic cells or chorionic villi. However, this is seldom
done, because the prognosis of individuals with HMB synthase mutations
is generally favorable.
++
During acute attacks, narcotic analgesics are usually required
for abdominal pain, and phenothiazines are useful for nausea, vomiting,
anxiety, and restlessness.9 Chloral hydrate can
be given for insomnia, and benzodiazepines in low doses are probably
safe if a minor tranquilizer is required. Carbohydrate loading,
usually with intravenous glucose (at least 300 g/dL), may
be effective in milder acute attacks of porphyria (without paresis,
hyponatremia, etc). Because intravenous hemin is more effective
and the response slower if treatment is delayed, it is no longer
recommended that hemin therapy for a severe attack be started only
after an unsuccessful trial of intravenous glucose for several days.
Hemin should be used initially for severe attacks and for mild attacks
that do not respond to carbohydrate loading within 1 to 2 days.
The standard regimen is 3 to 4 mg of heme in the form of lyophilized
hematin (Ovation Pharmaceuticals), heme albumin (hematin reconstituted
with human albumin) or heme arginate (Orphan Europe), infused daily
for 4 days.9,11 Heme arginate and heme albumin
are chemically stable and are less likely than hematin to produce
phlebitis or an anticoagulant effect. The rate of recovery from
an acute attack depends on the degree of neuronal damage and may be
rapid (1 to 2 days) with prompt therapy. Recovery from severe motor
neuropathy may continue for months or years. Identifying and avoiding
inciting factors can hasten recovery from an attack and prevent
future attacks. Multiple inciting factors may contribute to a symptomatic
episode. Frequent, clear-cut cyclical attacks occur in some women
and can be prevented with a gonadotropin-releasing hormone analogue
(which prevents ovulation and progesterone production).
++
An allogeneic liver transplant was performed on a 19-year-old
female AIP heterozygote who had 37 acute attacks in the 29 months
prior to transplantation.3 Post-transplantation,
her elevated urinary ALA and PBG levels returned to normal in 24
hours, and she did not experience acute neurological attacks for
more than 18 months. Liver transplantation is a high-risk procedure and
should not be considered as an established treatment for acute porphyrias.
+++
Homozygous Dominant
Aip
++
Homozygous dominant AIP is a rare form of porphyria presenting
in infancy. Patients inherit HMB synthase mutations from each of
their heterozygous parents; therefore, they have very low (<
2%) enzyme activity.10 In these homozygous-affected
patients, disease manifestations included failure to thrive, developmental
delay, bilateral cataracts, or hepatosplenomegaly. Acute attacks
did not occur. Urinary ALA and PBG were markedly elevated. Studies
of brain MRIs of children with homozygous AIP have suggested damage
primarily in white matter that was myelinated postnatally, while
tracks that myelinated prenatally were normal.10 These findings
suggest that a neurotoxic endogenous product, such as ALA or PBG,
present in large amounts postnatally (rather than heme deficiency)
caused nervous tissue damage. Prenatally, excess amounts of ALA
and PBG cross the placenta and are excreted in the mother’s
urine. Most children with homozygous AIP die at an early age.