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neurological manifestations in porphyria and approach to diagnosis of porphyria
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Neurological
Manifestations in
Porphyria
Outline
Introduction
Heme biosynthesis
Types of porphyria
Acute porphyria – types and clinical features
Diagnosis of acute porphyria
Treatment
Introduction
o The porphyrias are metabolic disorders caused by
altered activities of enzymes within the heme
biosynthetic pathway.
o It is usually due to an inherited mutation in the gene for
that specific enzyme except in porphyria cutanea tarda
(PCT), the most common of the porphyrias which is
aquired
Introduction
o The term porphyria is derived from the Greek
word porphyra, meaning "purple pigment".
o The name is derived in reference to the purple
discolouration of feces and urine when exposed to light
in patients during an attack
o The disease was first explained biochemically by Felix
Hoppe-Seyler in 1871
o Acute porphyrias were described by the Dutch
physician Barend Stokvis in 1889
Heme Biosynthetic Pathway
Heme is produced in all tissues, but the bone marrow and
liver are the most active organs involved
Bone marrow accounts for >80 percent of daily heme
synthesis and utilized as the prosthetic group for hemoglobin.
In the liver, heme is utilized primarily for the production of the
various cytochrome P450 enzymes (CYPs).
Other important heme-containing proteins (eg, myoglobin,
respiratory cytochromes, catalase, nitric oxide synthase) are
present in various tissues
Heme Biosynthetic Pathway
o The eight enzymes and intermediates comprise the heme
synthetic pathway
o First enzyme in this pathway, delta-aminolevulinate synthase
(ALAS) is a mitochondrial enzyme
o Catalyzes the conversion of glycine and succinyl-coenzyme
A to form delta-aminolevulinic acid (ALA)
o ALAS occurs in two forms
1. ALAS1- found in all tissues
2. ALAS2 – erythrocyte specific form
Heme Biosynthetic Pathway
o ALAS1 acts as the rate limiting enzyme for heme synthesis
o heme pool acts as a feedback mechanism for hepatic ALAS1 and
its transport into mitochondria
o ALAS1 is up-regulated when the need for heme in the liver is
increased, and down-regulated when the heme supply is
sufficient
o Most of the heme synthesized in liver is used for the production of
CYPs and hence induction of CYPs by drugs and other factors
would also lead to induction of ALAS1 through this feedback
mechanism
Heme Biosynthetic Pathway
Accordingly, the acute porphyrias may be treated with
exogenous heme , which is taken up primarily in
hepatocytes,
o Repletes the regulatory heme pool
o Down-regulates ALAS1
Classification of porphyrias
Porphyrias are classified in two ways
o Symptoms
o Pathophysiology
Symptomatically,
Acute porphyrias - primarily present with nervous system
involvement, often with gastrointestinal manifestations
Cutaneous porphyrias present with skin manifestations
Physiologically- accumulation of heme precursors
Hepatic
Erythropoietic
Acute Porphyria
Acute porphyria
Four Types
Acute intermittent porphyria
Variegate Porphyria
Hereditary coproporphyria
ALA dehydratase deficiency
Acute porphyria
o Four acute porphyrias cause acute, self-limiting attacks that may
rarely lead to chronic and progressive deficits
o Symptoms of acute attacks mimic other diseases and have the
potential for misdiagnosis
o Acute porphyrias are clinically indistinguishable during acute
attacks, except the neurocutaneous porphyrias (variegate
porphyria and hereditary coproporphyria) can cause
dermatologic changes
o Acute attacks arise after puberty and occur more frequently in
women
Acute porphyrias
o A Acute attacks lead to an increase in porphobilinogen
(PBG) and/or aminolevulinic acid (ALA) which can be
detected in the urine
o Things that make diagnosis difficult
variable clinic course
lack of understanding about diagnostic process
lack of a universal standard for test result
interpretation
Acute Intermittent Porphyria
(AIP)
AIP- Incidence
Most common acute porphyria worldwide 1-5 in 1,00,000
United States: ~ 1 in 10,000-20,000
However, clinical disease manifests itself in approximately 10% of these
carriers
Finland & Western Australia: ~ 3 in 100,000
Sweden: ~ 1 in 10,000
Highest prevalence
High incidence in African countries
Exact incidence in india not known
Acute Intermittent Porphyria
o Also called as
o Swedish porphyria
o Pyrroloporphyria
o Resulting from a deficiency of
Porphobilinogen deaminase
During an attack of AIP heme pool in
the liver is depleted causing
induction ALAS1 accumulation of
delta-aminolevulinic acid (ALA) and
porphobilinogen (PBG)
Pathophysiology of the Acute Attack
Autonomic Nervous System
Peripheral Nervous System
Porphyrins excreted from liver
ALA crosses BBB
Causes oxidative
damage
Accumulates in brain with neuronal and glial cell damage
Porphyrins don’tCross BBB
ALA induces liverDamage via oxidativeeffects
PBG mimics the action of serotonin and
acts as a false neurotransmitter
Interaction of ALA with GABA receptors
deficiency of production of heme-
containing proteins for oxygen transport,
electron transport
AIP-Exacerbating Drugs
A
AIP-Exacerbating Factors
o Smoking increases the risk of attack
o Endocrine factors —
rarity of symptoms before puberty
more common clinical expression in women, and occurrence
of attacks in luteal phase of the menstrual cycle.
Certain metabolites of progesterone and testosterone can act
as an inducer
o Nutritional factors- With starvation or other conditions where
glucose levels are low precipitate attacks
o Stress – increased risk may occur during illness, surgery.
AIP – Clinical Manifestations
o Most often in the third or fourth decades of life, and are more
common in women than in men
o Attacks in AIP develop over hours or days and persist for days
or weeks, depending upon precipitating factors and
treatment
o The common clinical pattern of symptom progression
involves acute abdominal pain, followed by psychiatric
disturbances, and then acute neuropathy.
AIP – Clinical Manifestations
o Abdominal and urinary symptoms —
Abdominal pain is the most common symptom in AIP (80-90%)
usually severe, steady, and poorly localized
often accompanied by constipation and signs of ileus such
as nausea, vomiting, abdominal distension, reduced bowel
sounds.
Bladder dysfunction may cause urinary retention,
incontinence, and dysuria.
Dark or reddish-brown urine is often an early symptom
AIP – Clinical Manifestations
Neuropsychiatric manifestations- include anxiety,
restlessness, agitation, hallucinations, hysteria,
disorientation, delirium, apathy, depression, phobias and
altered consciousness, ranging from somnolence to
coma.
Seizures may be due to hyponatremia or represent a
neurological manifestation of porphyria.
AIP – Clinical Manifestations
Peripheral Neuropathy- The neuropathy in a full attack
usually develops within 2 to 3 days of the onset of
abdominal and psychiatric symptoms.
Features similar to AIDP
• Motor predominant
• Predominantly proximal
• Symmetric
• Associated with limb and back pain
AIP – Clinical Manifestations
Contrast to AIDP-o Discending pattern of weakness may be seen, beginning
with cranial nerves
o The distribution of weakness may be patchy, with prominent
proximal weakness and distal sparing or weakness of
selected muscle groups, particularly in the upper limbs.
o Reflexes are usually lost in proportion to the degree of muscle
weakness
o Atrophy is seen early in the clinical course and may be
severe
o Patchy sensory loss can be seen
AIP – Clinical Manifestations
Autonomic features-
Prominent sympathetic hyperactivity
pupillary dilatation, tachycardia, systemic arterial hypertension
Electrolyte disturbances- hypnatremia due to SIADH,
hypomagnesemia and hypercalcemia
o Long term effects —
o chronic pain and other long-term symptoms including
depression and anxiety
o Persistent hypertension and the development of chronic
renal disease
o Persistent elevations is serum transaminases are common
substantially increased risk of hepatocellular carcinoma
AIP – Clinical Manifestations
Variegate Porphyria (VP)
o 2nd most common acute
porphyria
o Autosomal dominant genetic
disorder
o Due to deficient activity of the
mitochondrial enzyme
protoporphyrinogen oxidase
(PPO)
Variegate Porphyria (VP)
o Termed “variegate” because it can cause acute
neurological manifestations, as well as chronic blistering
lesions on sun-exposed areas of the skin
o Prevalence of VP is high in South Africans of Dutch
descent
o They have similar exacerbating factor as that of AIP
o Though neurovisceral symptoms are milder than AIP
Hereditary Caproporphyria (HCP)
3rd common porphyria
deficient activity of the mitochondrial
enzyme coproporphyrinogen oxidase
(CPOX)
mostly reported from Europe and
North America
Milder neurovisceral symtoms than
AIP
Skin manifestations also less common
than VP
ALA dehydratase porphyria (ADP)
ADP is the rarest form of the
inherited porphyrias
An autosomal recessive disorder
resulting from a
deficiency of ALAD
only five reported symptomatic
cases
Presentation is clinically
indistinguishable from AIP
Diagnosis of Acute Porphyria
Screening test- Initial testing with rapid urinary PBG testing
(Ex: Watson-Schwartz, Trace PBG Kit)
PBG Qualitative – **POSITIVE**
Confirm with quantitative PBG and ALA testing (Acute
attacks: urinary PBG 20-200 mg/d and ALA 10-100mg/d
normal: PBG (0-4 mg/d)
ALA (1-7 mg/d)
Both PBG and ALA are increased in acute attacks of AIP,
VP, HPC.
Diagnosis of Acute Porphyria
If screening test for PBG is negative on a spot urine
specimen but the index of suspicion is high
24-hour urine -ALA, PBG, and total porphyrins
Substantial increases in urinary porphyrins, although
nonspecific, may suggest the diagnosis of HCP
or VP, since urinary PBG and ALA are less increased and
fall more rapidly in these disorders
If only ALA is elevated (and not PBG), then ALA
dehydratase deficiency porphyria should be considered
Diagnosis of Acute porphyria
Additional testing utilizes the original spot urine
sample and samples of blood and feces collected before
starting treatment.
Measurement of porphyrins in
o Plasma
o urine
o feces
Erythrocyte PBG deaminase (PBGD) activity.
DNA testing- confirms the diagnosis, but most importantly
enables accurate identification of other gene carriers in
a family
Diagnosis of acute porphyria
Treatment of Acute Porphyria
Hospitalization to control/treat acute symptoms:
o Seizures – treatment of porphyria, Seizure precautions,
medications-benzodiazepines like clonazepam
,gabapentine, Bromides and paraldehyde.
o Correction of electrolyte abnormalities
o Correct dehydration
o Abdominal Pain – narcotic analgesics
o Short-acting benzodiazepines in low doses are probably
safe for anxiety and insomnia
o Nausea/vomiting – phenothiazines
o Tachycardia/hypertension – Beta blockers
Treatment of Acute Porphyria
o Withdraw all unsafe medications
o Monitor respiratory function, muscle strength,
neurological status
o Mild attacks (no paresis or hyponatremia) – Intravenous
10% glucose at least 300-500 g per day
o Severe attacks –
Intravenous hemin (3-4 mg/kg qdaily for 4 days)
Max daily dose 6 mg/kg
Prevention of attacks: not well established; once or
twice weekly infusions
Treatment of Acute Porphyria
o Liver transplantation —effective in patients disabled by
recurrent attacks of AIP without advanced motor
weakness
o Cimetidine also found effective in some studies by
inhibiting CYPs
Preventive therapy
o Stop smoking
o Avoid precipitating factors
o High carbohydrate diet (60-70%)
o GnRH analogue- recurring attacks confined to the luteal
phase of the menstrual cycle
o Hemin prophylactically administered once or twice weekly
can prevent frequent
o Long-term monitoring in patients for developing chronic
renal failure and hepatocellular carcinoma
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