neurological manifestations in porphyria and approach to diagnosis of porphyria

1. Neurological
Manifestations in
Porphyria

2. Outline
 Introduction
 Heme biosynthesis
 Types of porphyria
 Acute porphyria – types and clinical features
 Diagnosis of acute porphyria
 Treatment

3. 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

4. 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

5. 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

8. 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

9. 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

10. 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

11. 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

14. Acute Porphyria

15. Acute porphyria
Four Types
 Acute intermittent porphyria
 Variegate Porphyria
 Hereditary coproporphyria
 ALA dehydratase deficiency

16. 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

17. 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

18. Acute Intermittent Porphyria
(AIP)

19. 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

20. 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)

21. Pathophysiology of the Acute Attack
Autonomic Nervous System
Peripheral Nervous System
ALA induces liver
Damage via oxidative
effects
Porphyrins excreted from liver
ALA crosses BBB 
Causes oxidative
damage
Porphyrins don’t
Cross BBB
Accumulates in brain with
neuronal and glial cell damage
 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

22. AIP-Exacerbating Drugs
A

23. 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.

24. 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.

25. 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

26. 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.

27. 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

28. 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

29. 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

30. AIP – Clinical Manifestations

31. 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)

32. 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

33. 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

34. 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

35. 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.

36. 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

37. 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

38. Diagnosis of acute porphyria

40. 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

41. 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

42. 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

43. 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

44. Thanks

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