Acute Intermittent Porphyria

Acute Intermittent Porphyria
Heme/Onc Grand Rounds
By:Jane Chawla, M.D.

History of Present Illness
Physical Exam & Laboratory Data

* VS: T 36.2 P 142 R 20 BP 178/112
* Gen: Sleepy but arousable, AxO x3
* HEENT: PERRL, EOMI, OP Clear
* Neck: Supple, no LAD
* CV: tachy, regular rhythm, no m/g/r
* Lungs: CTAB
* GI: soft, ND, mild periumbilical discomfort to palpation
* Extr: no c/c/e
* Skin: No rashes or skin lesion
* Neuro: CN II-XII intact, strength 4/5 throughout, paresthesia in bilat lower extremities, 2+ reflexes, upgoing toes



Labs:
Random Problem List?
* Hyponatremia
* Tachycardia
* Hypertension
* Elevated Creatinine
* Abdominal Pain
* Transaminitis
* Weakness
* Cortisol – wnl
Cosyntropin Stim Test – wnl
Urine lytes → SIADH
* EKG – sinus tachycardia
CT Angio (-)
Urine VMA/metanephrine (-)
* Renal Ultrasound – wnl
responded to fluids
* LFTs – Mild transaminitis
CT Abdomen/Pelvis (-)
Hepatitis panel (-)

PORPHYRIA
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 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
* 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

Overview of the Seven 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 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
* 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
Key Clinical Features
* 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, seizures.

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
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
Algorithm for Acute Porphyria Diagnosis
Treatment of the Acute Attack
* Hospitalization to control/treat acute symptoms:
o Seizures – Seizure precautions, medications?
o Electrolyte abnormalities
o Dehydration / hyponatremia
o Abdominal Pain – narcotic analgesics
o Nausea/vomiting – phenothiazines
o Tachycardia/hypertension – Beta blockers
o 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

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
o Reconstituted in sterile water originally –> less stable / degraded easily
o Degradation products cause an ↑ in adverse reactions
* Adverse reactions: Due to degradation products binding to endothelial cells, platelets, & coagulation factors
o Thrombophlebitis
o Anticoagulation (transient ↑ PT, bleeding may occur)
o Thrombocytopenia

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

A Study of Hemin Use in Clinical Practice

* Hemin approved under Orphan Drug Act of 1983
* Hemin removed from market in 2000 by FDA: 8/00-6/01
o Abbott Laboratories required to conduct open-label study of the safety of hemin manufactured at a new facility
o Largest trial / case series to date on hemin therapy
* Study design: “Real world” data about acute porphyria diagnosis, treatment & perceived efficacy of treatment
* Methods:
o Hemin only available through study participation – compassionate basis
o All pts judged to need hemin by their physicians were enrolled
o Confirmation of diagnosis not required
o Pts received hemin as normally prescribed by their physicians
o No specific outcome measures, exclusion criteria, or follow-up

Results of Hemin Used in Clinical Practice

* Study Population: 130 pts; 92% Caucasian; 72% female
* Precipitating factors: (40/130 pts): drugs (22%); hormonal (24%)
* Results:
o 111 pts treated for 305 acute attacks & 40 pts for prophylaxis
o Diagnostic lab findings reported in 53% (half with +results)
o Hemin regarded as effective for 73% of patients
+ Despite doses less than recommended in 20% of pts (< 3-4 mg/kg/day)
o Propylaxis with hemin in 1/3 of patients
+ Wide variability in prophylaxis regimens  lack of published guidelines
+ Among 31 receiving hemin prophylaxis for >1 month, 68% did not require subsequent tx for acute attacks
o 44% of pts experienced adverse events – most attributed to underlying disease and not hemin
+ Phlebitis was most common adverse event attributed to hematin

Long-Term Complications from Symptomatic Disease

* Neurological Sequelae
* Hypertension
* Renal failure
* Cirrhosis
* Hepatocellular carcinoma

Renal failure: Is hypertension the cause or the effect

* Debate about cause: Hypertension or another etiology?
* Increased risk of renal failure in those with more acute attacks
* Andersson et al  Population-based study (Sweden)
o Renal biopsies (n=16)  ischemic lesions, ? related to protracted vasospasm
o Theory of injury  Vasospasm from:
+ Porphyrin metabolites &
+ an upregulated SNS  ↑ urinary excretion of catecholamines during an acute attack
o By this theory, hypertension is not the sole cause of renal insufficiency

Hepatocellular Carcinoma (HCC)

* Estimated 60 to 70-fold ↑ risk of HCC in AIP patients
* Andersson  Retrospective population-based mortality study
o HCC  27% with AIP vs 0.2% deceased without AIP
o HCC more common in women (2:1)
o HCC more common in those with symptomatic disease
o Cirrhosis more common in AIP pts (12%) vs non-AIP (0.5%)
o Cirrhosis in AIP pts higher in W>M 3:1
* Retrospective analysis for genetic mutations in 17 pts with AIP & HCC (L Bjersing)
o Is PBGD a tumor suppressor gene? (No, 1 allele present in tumor)
o No mutations seen in p53 or ras (these mutations have been implicated in HCC caused by HBV or aflatoxin)
* De Siervi et al ALA is toxic to two hepatocellular cancer cell lines (HEP G2 & HEP 3B)
o Degree of cytotoxicity was directly related to concentration of ALA
o Adding hemin or D-glucose to ALA + cells decreased toxicity with HEP G2 cells
* Proposed Mechanism of cirrhosis / carcinogenesis:
o Reduced free heme pool  ↓ cytochrome P450 & antioxidant enzymes reactive oxygen species DNA damage
o ALA that accumulates can oxidize proteins & cause DNA damage

Prevention & Follow-up: Caring for Patients Between Attacks
* Avoidance of alcohol, smoking, and exacerbating drugs
* Adequate carbohydrate intake
* Medical alert bracelets/wallet cards
* Gonadotropin-releasing hormone analogues
* Iron overload from hemin (100 mg of hemin contains 8 mg of iron)
* Hepatocellular carcinoma screening
* End-Stage renal disease prevention
* Screening for Osteoporosis
o risk from GNRH analogues, immobility, malnutrition, & vitamin D deficiency

Prognosis
* Prior to 1970, fatality rates were 10% to 52%, now 10%
* Since introduction of hematin mortality has decreased
* Overall mortality in patients with acute attacks is 3-fold higher than the general population
* Delayed diagnosis and treatment contribute to higher mortality
Future Treatment Directions
* Liver transplantation
* Animal models used to mimic porphyrias with experiments to correct enzyme deficiency in tissues
* Non-viral mediated gene transfers
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

References
Acute Intermittent Porphyria.ppt