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PowerPoint Presentation:

The porphyrias are metabolic disorders, each resulting from the deficiency of a specific enzyme in the heme biosynthetic pathway and subsequent accumulation of porphyrins and their precursors resulting in a variety of neurologic,hematologic & dermatologic manifestations. These enzyme deficiencies are inherited as autosomal dominant, autosomal recessive, or X-linked traits, with the exception of porphyria cutanea tarda (PCT), which usually is sporadic.

Heme central to understanding Porphria:

Heme central to understanding Porphria Heme is part of hemoglobin, myoglobin , catalases , peroxidases , and cytochromes Heme is made in every human cell (85% in erythroid cells & much of the rest in the liver) First enzyme in heme synthesis pathway is Aminolevulinic acid (ALA) synthetase (ALAS) Increase demand induces ALAS Heme downregulates ALAS by feedback inhibition Partial block in this pathway induces ALAS and causes accumulation of heme precursors upstream from block

Porphyria is a disruption in the heme pathway:

Porphyria is a disruption in the heme pathway Group of metabolic diseases resulting from a partial deficiency of an enzyme in the heme biosynthetic pathway Seven enzymes in the pathway Four of the porphyrias cause acute attacks Increased demand for heme can precipitate attacks secondary to overproduction of toxic heme precursors (porphyrins, ALA) The porphyrins have no useful function and act as highly reactive oxidants damaging tissues


CLASSIFICATION The porphyrias are classified as either hepatic or erythropoietic , depending on the primary site of overproduction and accumulation of their respective porphyrin precursors or porphyrins . acute or cutaneous , based on their clinical manifestations

Overview of the Four Acute Porphyrias:

Overview of the Four Acute Porphyrias Four acute porphyrias cause acute, self-limiting attacks that lead to chronic and progressive deficits Symptoms of acute attacks mimic other diseases and increase the potential for misdiagnosis. Acute porphyrias are clinically indistinguishable during acute attacks, except the neurocutaneous porphyrias (variegate porphyria and hereditary coproporphyria ) can cause dermatologic changes Acute attacks arise after puberty and occur more frequently in women Acute attacks lead to an increase in porphobilinogen (PBG) and 5-aminolevulinic acid (ALA) which can be detected in the urine Things that make diagnosis difficult: variable clinic course, lack of understanding about diagnostic process, and lack of a universal standard for test result interpretation

Patient Focus: Acute Intermittent Porphyria:

Patient Focus: Acute Intermittent Porphyria Most common porphyria Deficiency of hepatic PBG deaminase Autosomal dominant pattern with incomplete penetrance Affected individuals have a 50% reduction in erythrocyte PBG deaminase activity Latent prior to puberty Symptoms more common in females than males Increased urinary ALA & PBG

Prevalence in the General Population:

Prevalence in the General Population 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 NOTE: Incidence of acute intermittent porphyria is higher in the psychiatric population compared with the general population

Key Clinical Features:

Key Clinical Features AIP is exculsively neuropsychiatric without any cutaneous findings Gastrointestinal symptoms - Abdominal pain (most common presenting complaint), nausea/vomiting, constipation, and diarrhea. Dehydration Hyponatremia Cardiovascular symptoms - tachycardia, hypertension, arrhythmias Neurologic manifestations - motor neuropathy, sensory neuropathy, mental symptoms(behavioral changes, agitation, confusion,stupor , hallucinations, and depression (can resolve when acute attack over), seizures.

Pathophysiology of the Acute Attack:

Pathophysiology of the Acute Attack Autonomic Nervous System Peripheral Nervous System Hypothalamus Limbic area Porphyrins excreted from liver ALA crosses BBB  Causes oxidative damage Accumulates in brain with neuronal and glial cell damage Symptoms due to porphyrin Precursor accumulation Rather than deficiency of Heme Porphyrins don’t Cross BBB ALA induces liver Damage via oxidative effects

PowerPoint Presentation:

Symptoms during an acute attack are thought to be secondary to accumulation of porphyrin precursors rather than from deficiency of heme Massive amounts of porphyrins are excreted from the liver Porphyrins are neurotoxic and affect areas of the nervous system not protected by blood-brain barrier -Autonomic Nervous System -Peripheral Nervous System -hypothalamus -limbic area It has also been proposed that accumulation of ALA may lead to neurological symptoms by crossing the blood-brain barrier and accumulating in the brain  ALA has a pro- oxidative effect with generation ROS which cause neuronal and glial cell damage In addition, ALA accumulates in the liver and can cause liver damage through these oxidative effects

Exacerbating Factors of Acute Attack:

Exacerbating Factors of Acute Attack Drugs that increase demand for hepatic heme (especially cytochrome P450 enzymes) Crash diets (decrease carbohydrate intake) Endogenous hormones (progesterone) Cigarette smoking (induces cytochrome P450) Metabolic stresses (infections, surgery, psychological stress)

Diagnosis of Acute Porphyria:

Diagnosis of Acute Porphyria 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 ) normal: PBG 118 mg/24 hrs (0-4 mg/d) ALA 18.8 mg/24hrs (1-7 mg/d) If only ALA is elevated (and not PBG), then ALA dehydratase deficiency porphyria should be considered Note : Urinary PBG may not be substantially elevated if pt already receiving treatment with hemin

Steps to Confirm Acute Intermittent Porphyria Diagnosis:

Steps to Confirm Acute Intermittent Porphyria Diagnosis Determine type of porphyria by measuring individual porphyrin levels in the urine, feces, and plasma (by chromatography & fluorometry) Confirmation of diagnosis = erythrocyte PBG deaminase activity (only 50% of the normal activity) DNA testing for patients & at-risk family members (mutations usually family-specific)

Algorithm for Acute Porphyria Diagnosis:

Algorithm for Acute Porphyria Diagnosis

Treatment of the Acute Attack:

Treatment of the Acute Attack Hospitalization to control/treat acute symptoms: Seizures – Seizure precautions, medications- benzodiazepines,gabapentine . Electrolyte abnormalities Dehydration / hyponatremia Abdominal Pain – narcotic analgesics Nausea/vomiting – phenothiazines Tachycardia/hypertension – Beta blockers Urinary retention / ileus Withdraw all unsafe medications Monitor respiratory function, muscle strength, neurological status Mild attacks (no paresis or hyponatremia ) – Intravenous 10% glucose at least 300 g per day Severe attacks – Intravenous hemin (3-4 mg/kg qdaily for 4 days) ASAP (can give IV glucose while waiting for IV hemin ) Cimetidine for treatment of crisis and prevention of attacks In rare instances where pts have severe, unremitting symptomatic disease, orthotopic liver transplantation has been done

Hematin (Panhematin):

Hematin (Panhematin) Used in the treatment of the acute porphyrias since the 1970s Mechanism of Action : Reduces production of ALA / porphyrins by negative feedback inhibition on ALA synthetase Derived from outdated PRBCs from community blood banks Reconstitution of lyophilized hematin with 25% albumin recommended Reconstituted in sterile water originally –> less stable / degraded easily Degradation products cause an ↑ in adverse reactions Adverse reactions : Due to degradation products binding to endothelial cells, platelets, & coagulation factors Thrombophlebitis Anticoagulation (transient ↑ PT, bleeding may occur) Thrombocytopenia

Hematin (continued):

Hematin (continued) ↓ thrombophlebitis if given through large vein or central line Dosing : Acute attacks : 3-4 mg/kg/day x 4 or more days Max daily dose 6 mg/kg or 313 mg (1 vial) – even in obese patients Prevention of attacks : not well established; once or twice weekly infusions




Epidimiology It is the most common porphyria. It may be acquired (type I) or genetically inherited (typeII). 60% of PCT patients are male, most of whom ingest excess alcohol. Women who develop PCT are often on estrogen-containing medications. Most patients are ≥ 40years, and 66% have evidence of iron overload.


Pathogenesis Iron overload leads to reduce activity of the uroporphyrinogen decarboxylase enzyme which leads to elevated porphyrin levels, in particular uroporphyrins. Associated disorders : Alcoholism. Hematochromatosis. HCV. HIV. HBV. CMV.

Pathogenesis :

Pathogenesis PCT presenting in a young adult should lead to consideration of HIV infection , alternatively familial PCT could be the explanation. familial PCT (typeII) accounts for 10-20 % of cases. It is inherited as an autosomal dominant trait. Most PCT is acquired (typeI) and multifactorial in origin.

Erythropoietic Protoporphyria::

Erythropoietic Protoporphyria:


Epidemiology It is the most common childhood porphyria. It is usually evident by 2 years of age.

Pathogenesis :

Pathogenesis Protoporphyrin levels are elevated because of deficient activity of ferrochelatase enzyme.

Clinical features, complications and base line investigation:

Clinical features, complications and base line investigation

PowerPoint Presentation:

Porphyria variegata - protoporphyrinogen oxidase 50% deficient. –hepatic and skin porphyria Gene locus 1q2320. 20,000 S. Africans descended from a Dutch lady in 1688 who went to S. African for marriage to another Dutch settler . Now 3/1000 S.Africans have this! Symptoms: skin and acute porphyria if exposed to sunlight,neurovisceral symptoms (abdominal pain),liver cancer Diagnosis :- plasma fluoresces when exposed to UV. Precipitated by sunlight Treatment: increase ALA synthetase by heme arginate , glucose

PowerPoint Presentation:

35 Congenital erythropoietic porphyria ( Erythroid , Photosensitive) -Fe overload of b.m ., uroporphyrin overload of skin and erythrocytes  hemolysis 1. Symptoms: skin lesions (light) , risk of infection in early infancy Anemia ( hemolysis ) Teeth reddish brown (fluorescence) 2. Uroporphyrinogen III synthase deficiency Uroporphyrinogen I and coproporphyrin I accumulation in the skin, bone marrow, erythrocytes, urine, plasma 3. Treatment: activated charcoal (oral); b.m . transplant; gene therapy for bone marrow; blood transfusion to stop erythropoiesis in b.m .

Long-Term Complications from Symptomatic Disease:

Long-Term Complications from Symptomatic Disease Neurological Sequelae Hypertension Renal failure Cirrhosis Hepatocellular carcinoma

If You Were Asleep….Key Points to Remember:

If You Were Asleep…. Key Points to Remember Porphyrias are metabolic diseases resulting from a partial deficiency of an enzyme in the heme biosynthetic pathway Cause acute attacks secondary accumulation of heme precursors Clinical features: abdominal pain, tachycardia, hypertension, hyponatremia, seizures, motor neuropathy etc. Screen for porphyria with qualitative urinary PBG and if elevated measure quantitative urinary PBG and ALA Confirm diagnosis with urinary and fecal fractionated porphyrins and DNA testing Treat acute attacks with IV hemin Prevent acute attacks with smoking cessation, avoidance of inciting agents

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