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

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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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