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CASE DISCUSSIONA 16 year old boy, admitted in surgical ward

with c/o acute abdomen. On investigation with

CBC, RBS, RFT, ELECTROLYTE, SGPT, CxR, USG allnormal. Diagnostic laparoscopy done which wasnormal. The next day he developes convulsion.Medical refer done. Phenytoin loaded. Pt developes

altered sensorium. Again all reports with brainimaging normal. During routine round a housemannoticed blackish-red urine in urobag. On Ix U. PBGturns out positive.


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Porphyria

King George III (1738 to 1820)


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History and nomenclature

The word porphyria derives from the Greek wordporphyrus, which means red or purple.

Stokvis reported the first case of porphyria in 1889

Campbell described its pathology in 1898.

In 1969, it was proposed that the episodic madnesssuffered by King George III (1738 to 1820) resultedfrom an acute hereditary porphyria, variegateporphyria.Investigation suggested that Queen Victoria may

also have suffered from the disease as well as herdau hter and randdau hter.


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Basis of the Porphyrias

Porphyrias are disorders of the Heme synthesispathway

Primary requirements for Heme are in:

Bone Marrow (erythropoiesis)Liver (cytochromes)


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Key to understanding the porphyrias is a grasp of theregulation of Heme synthesis


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Enzymes

1 ALA synthase2 ALA dehyratase3 PBG deaminase4 Urogen III

cosynthase5 Uro-gen

decarboxylase6 Coprogen

oxidase7 Protogen

oxidase8 Ferrochelatase


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Regulation of ALAS is

critical to the expression of most of the porphyrias

2 Forms of ALA synthase (ALAS) existCoded for by different genes

Housekeeping form (ch3p21.1) is found in all tissues,but especially in the liver

Housekeeping form is negatively regulated by Heme

which is the end product of the pathwayErythropoietic form (chXp11.2) is not regulated by HemDeficiency of ALA synthase does not cause porphyria,

but does cause sideroblastic anemia


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Excretion Patterns of the Heme intermediates

Intermediates up through Coproporphyrinogens arewater soluble and thus show up in the urine

Protoporphyrinogen and Protoporphyrin are insolubleand are excreted via bile into the stool

Thus excretion of heme intermediates in the urine or stoolhelps diagnose porphyria and the site of the deficiency

Several other conditions can mimic porphyria due toaccumulation of porphyrin precursors:Lead poisoning Fe Deficiency


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Inheritance of theAcute porphyrias isAutosomal Dominant

Thus most porphyriacs have 50% activity of the

enzyme which is missing

When some environmental stimulus decreases thelevel of Heme in the liver, ALA synthase activity

increases, augmenting the levels of the Hemeprecursors

Precursors then back up at the point in the pathway

where the enzyme deficiency exists


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The elevated levels of Heme precursors give riseto the symptoms of porphyria.

When the heme level comes back to normal, thenthe level of the precursors returns to normaland symptoms abate.


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Triggers of Acute Porphyria:

Drugs: Any drugs which require hepatic P450sfor metabolism can trigger porphyria

Dieting: Reduction in caloric intake triggersactivity ofHeme Oxygenase loweringHeme levels

Stress: Including Illnesses, Infections, SurgeryAlcohol Excess

Menses: Some women have monthly attacks


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Pathophysiology of the AcuteAttack

Autonomic Nervous System

Peripheral Nervous System

Hypothalamus

Limbic area

Porphyrins excreted from liver

ALA crosses BBBCauses oxidativedamage

Accumulates in brain withneuronal and glial cell damage

Symptoms due to porphyrinPrecursor accumulationRather than deficiency ofHeme

Porphyrins dontCross BBB

ALA induces liver

Damage via oxidativeeffects


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Toxicity of the Heme intermediates

Neurovisceral caused by ALA or PBG

Abdominal Pain/Vomiting/Constipation

Muscle weaknessMental symptomsLimb/Head/Neck/Chest PainHypertension/TachycardiaConvulsionsSensory LossFever


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Photosensitivity caused by porphyrin accumulationin the skin

accumulation of water soluble uro- and

coproporphyrins leads to blistering.accumulation of the lipophilic protoporphyrinsleads to burning sensations in the exposed skin

Porphyrins absorb light energy which is released asfluorescence or formation of singlet oxygen

Worst on sun exposed areas


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Hemolytic anemia rare and only seen in theerythropoietic porphyrias


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Classification of porphyrias


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Clinical classification

Acute episodes and no skinchanges

Acute intermittent porphyriaALA-dehydratase deficiency

Acute episodes and skin changes Hereditary coproporphyriaVareigate porphyria

Skin changes only Congenital erythropoietic porphyriaErythropoietic protoporphyriaPorphyria cutanea tardaHepatoerythropoietic porphyria


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REMEMBER :

MOST COMMON PORPHYRIA : PCT

MOST COMMON ACUTE PORPHYRIA : AIP

MOST COMMON CHILDHOOD PORPHYRIA : EPP


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Acute Intermittent Porphyria

The most common acute porphyria

Deficiency of hepatic PBGdeaminase

Autosomal dominant pattern withincomplete penetrance

Affected individuals have a 50%reduction in erythrocyte PBGdeaminase activity

Latent prior to puberty

Symptoms more common infemales than males

Increased urinary ALA & PBG


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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 inthe psychiatric population compared with the general population


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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.


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Pathophysiology of the AcuteAttack

Autonomic Nervous System

Peripheral Nervous System

Hypothalamus

Limbic area

Porphyrins excreted from liver

ALA crosses BBBCauses oxidativedamage

Accumulates in brain withneuronal and glial cell damage

Symptoms due to porphyrinPrecursor accumulationRather than deficiency ofHeme

Porphyrins dontCross BBB

ALA induces liver

Damage via oxidativeeffects


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Exacerbating Factors of AcuteAttack

Drugs that increase demandfor hepatic heme (especiallycytochrome P450 enzymes)

Crash diets (decrease

carbohydrate intake) Endogenous hormones

(progesterone)

Cigarette smoking (inducescytochrome P450)

Metabolic stresses (infections,surgery, psychological stress)


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http://www.drugs-porphyria.org


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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 PBG20-200 mg/d)

PBG 118 mg/24 hrs (0-4 mg/d)

ALA 18.8 mg/24hrs (0-7 mg/d)

If only ALA is elevated (and not PBG), then ALA dehydratasedeficiency porphyria should be considered

Note: Urinary PBG may not be substantially elevated if pt alreadyreceiving treatment with hemin


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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 (mutationsusually family-specific)


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Algorithm for Acute Porphyria Diagnosis


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Treatment of the Acute Attack Hospitalization to control/treat acute symptoms:

Seizures Seizure precautions, medications?

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% glucoseat least 300 g per day

Severe attacks Intravenous hemin (3-4 mg/kg qdaily for 4 days)

Cimetidine for treatment of crisis and prevention of attacks


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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% albuminrecommended

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


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Hematin (continued)

thrombophlebitis if giventhrough large vein orcentral line

Dosing: Acute attacks: 3-4

mg/kg/day x 4 or more days

Max daily dose 6 mg/kg or313 mg (1 vial) even in

obese patients Prevention of attacks: not

well established; once or twiceweekly infusions


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Long-Term Complications from Symptomatic Disease

Neurological Sequelae

Hypertension

Renal failure Cirrhosis

Hepatocellular carcinoma


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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) Renal biopsies (n=16) ischemic lesions, ? related to

protracted vasospasm

Theory of injury Vasospasm from:1. Porphyrin metabolites &

2. an upregulated SNS urinary excretion of catecholamines during anacute attack

By this theory, hypertension is not the sole cause of renalinsufficiency


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Hepatocellular Carcinoma (HCC)

Estimated 60 to 70-fold risk of HCC in AIP patients

Andersson Retrospective population-based mortality study

HCC 27% with AIP vs 0.2% deceased without AIP

HCC more common in women (2:1) HCC more common in those with symptomatic disease

Cirrhosis more common in AIP pts (12%) vs non-AIP (0.5%)

Cirrhosis in AIP pts higher in W>M 3:1

Retrospective analysis for genetic mutations in 17 pts with

AIP & HCC (L Bjersing) Is PBGD a tumor suppressor gene? (No, 1 allele present in tumor)

No mutations seen in p53 or ras (these mutations have been implicatedin HCC caused by HBV or aflatoxin)


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Hepatocellular Carcinoma

(continued) De Siervi et al ALA is toxic to two hepatocellular cancer cell

lines (HEP G2 & HEP 3B)

Degree of cytotoxicity was directly related to concentration of ALA

Adding hemin or D-glucose to ALA + cells decreased toxicity with HEPG2 cells

Proposed Mechanism of cirrhosis / carcinogenesis: Reduced free heme pool cytochrome P450 & antioxidant enzymes reactive oxygen species DNA damage

ALA that accumulates can oxidize proteins & cause DNA damage


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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

risk from GNRH analogues, immobility, malnutrition, & vitamin D

deficiency


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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-foldhigher than the general population

Delayed diagnosis and treatment contribute to highermortality


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Future Treatment Directions

Liver transplantation

Animal models used to mimic porphyrias withexperiments to correct enzyme deficiency in tissues

Non-viral mediated gene transfers


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PORPHYRIACUTANEA TARDA :


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Epidimiology

It is the most common porphyria.

It may be acquired (type I) orgenetically inherited (typeII).

60% of PCT patients are male, most of whomingest excess alcohol.

Women who develop PCT are often on estrogen-containing medications.

Most patients are 40years, and 66% haveevidence of iron overload.


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Pathogenesis

Iron overload leads to reduce activity of theuroporphyrinogen decarboxylase enzyme whichleads to elevated porphyrin levels, in particular

uroporphyrins.

Associated disorders : Alcoholism.

Hematochromatosis. HCV. HIV. HBV. CMV.


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Pathogenesis

PCT presenting in a young adult should lead toconsideration of HIV infection , alternativelyfamilial PCT could be the explanation.

familial PCT (typeII) accounts for 10-20 % ofcases. It is inherited as an autosomal dominanttrait.

Most PCT is acquired (typeI) and multifactorial inorigin.


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I ti ti


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Investigation


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Pathology

Subepidermal blister with minimalcell-poor dermal inflammatory infiltrate.


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Treatment


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ErythropoieticProtoporphyria:


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Epidemiology

It is the most common childhoodporphyria.

It is usually evident by 2 years of age.


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Pathogenesis

Protoporphyrin levels are elevatedbecause of deficient activity offerrochelatase enzyme.

Clinical features complications


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Clinical features, complicationsand base line investigation


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Treatment


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Treatment


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Congenital Erythropoietic

porphyria( Gunther's disease ):


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Epidemiology

It is a very rare autosomal recessive

disorder.

Patients usually present during infancy

and rarely present in adult life with milderforms.


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Pathogenesis

It is caused by elevation of both water-soluble and lipid-soluble porphyrin levelsdue to deficiency of uroporphyrinogen IIIsynthase enzyme.


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Clinical features

Very severe photosensitivity withphototoxic burning and blistering leading

to mutilation of light exposed parts. Erythrodontia.

Madorosis.

Scleromalacia perforans. Hypersplenism.

Hemolytic anemia.

Thrombocytopenia


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Treatment


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Variegate Porphyria


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Variegate Porphyria

autosomal dominant hepatic porphyria

results from deficient activity of protoporphyrinogen oxidase

(ppo)

first described in 1937

The disease was termed "variegate" because it can present

with neurologic manifestations, cutaneous photosensitivity, orboth.


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Variegate Porphyria

Enzyme activity is approximately half-normal in cultured skinfibroblasts, peripheral blood leukocytes/lymphocytes, andhepatocytes

However, most individuals who inherit PPO deficiency remainasymptomatic

Why the disease becomes manifest in some individuals and not

others is not fully understood


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Clinical Manifestations in VariegatePorphyria

Neurovisceral

Abdominal pain Tachycardia

Vomiting Constipation Hypertension Neuropathy Back pain Confusion

Bulbar paralysis Psychiatric symptoms Fever Urinary frequency Dysuria Hyponatremia

Cutaneous

Increased fragility Vesicles

Bullae Erosions Milia Hyperpigmentation Hypertrichosis of sun-exposed

areas

Histology: PAS-positivethickening and IgG depositionin the vessel walls, andreduplication of the basallamina

Variegate Porphyria


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Variegate Porphyria

Attacks are generally milder than those inAIP, and recurrent attacks are much lesscommon

Drug exposure is a frequent precipitant ofthe acute attack in VP, whereas hormonalfactors were significantly more importantin AIP

Skin manifestations generally occurseparately from the neurovisceralsymptoms, and are usually of longer

duration


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Variegate Porphyria

Symptoms rarely occur before puberty, however, the disease maypresent late in life

The same drugs, steroid hormones, and nutritional factors that aredetrimental in AIP can also provoke exacerbations of VP

Chronic liver abnormalities, which are generally mild, may be seenin VP

Some patients with VP have developed hepatocellular carcinoma,

which suggests that the risk of this tumor may be increased inpatients with VA, as in AIP and PCT


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Diagnosis

During an acute attack urinary aminolevulinate (ALA) and porphobilinogen(PBG) are increased

VP can be distinguished from AIP by the finding of increased plasmaporphyrins and marked increases in urinary and fecal coproporphyrin. if

properly performed fecal porphyrin analysis is most useful for diagnosis ofVP

In patients with cutaneous symptoms it is important to differentiate VP fromPCT, because PCT is considerably more common than VP, and treatmentsthat are effective for PCT (phlebotomy & chloroquine) are not effective inVP

Plasma porphyrin analysis provides a simple and reliable means of rapidlydistinguishing VP from the other cutaneous porphyrias


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Treatment

Neurovisceral complaints

Treatment measures that are effective in AIP, such as glucose andheme therapy, are also effective for acute neurovisceral attacks in VP

Cutaneous symptoms

Protection from sunlight is highly important

Heme therapy has not been found to be beneficial for cutaneoussymptoms

A patient who underwent liver transplantation showed recoveryfrom VP post-transplantation


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Vampire Folklore The term Vampire was popularised in the early

18th century and arose from the folklore ofsoutheastern Europe

depicted as revenents who visited loved ones and

caused mischief or deaths in the neighbourhoodsthey inhabited when they were living

They wore cloaks, did notbear fangs and wereoften described as bloated and of ruddy ordarkened countenance


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Porphyria and Vampirism?

Pallor

Anemia (pica? craving of red meat?)

Teeth that appear larger than normal due togingival recession

However, suggestions that porphyria patientscrave the heme in human blood, or that the

consumption of blood might ease the symptomsof porphyria, are largely based on amisunderstanding of the disease


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Pseudoporphyria:


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Pseudoporphyria

In certain settings patient developblistering and skin fragility identical to PCTwith the histologic features but withnormal urine and serum porphyrins.

Hypertrichosis, dyspigmentation and

cutaneous sclerosis do not occur.

This condition called pseudoporphyria.


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Pseudoporphyria

Most commonly due to medicationsespecially NSAIDs , usually naproxen .

other NSAIDs and tetracycline can causesimilar picture .

Some patient on hemodyalisis develop

a similar PCT-like picture.


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References1. Anderson, K. E. Recommendations for the Diagnosis and Treatment of the Acute Porphyrias. Annals of Internal

Medicine. 2005; 142: 439-450.2. Kauppinen, R. Porphyrias. Lancet. 2005; 365: 241-52.

3. James M.F. & Hift, R.J. Porphyrias. British Journal of Anaesthesia. 2000; 85: 143-53.

4. Sies, C. Clinical Indications for the Investigation of Porphyrias: Case Examples and Evolving LaboratoryApproaches to its Diagnosis in New Zealand. The New Zealand Medical Journal. 2005; 118: 1-10.

5. Soonawalla, Z.F. Liver Transplantation as a Cure for Acute Intermittent Porphyria. The Lancet. 2004; 363: 705-6.

6. Onuki, J. Is 5-Aminolevulinic Acid Involved in the Hepatocellular Carcinotgenesis of Acute Intermittent Porphyria?Cellular and Molecular Biology. 2002: 48: 17-26.

7. Cimetidine and Acute Intermittent Porphyria

8. Floderus, Y. Variation in PBG and ALA Concentrations in Plasma and Urine from Asymptomatic Carriers of theAcute Intermittent Porphyria Gene with Increased Porphyrin Precursor Excretion. Clinical Chemistry. 2006; 52:701-701.

9. Johansson, A. Correction of the Biochemical Defect in Porphobilinogen Deaminase Deficient Cells by Non-ViralGene Delivery. Molecular and Cellular Biochemistry. 2003; 250: 65-71.

10. Andersson, C. Renal Symptomatology in Patients with Acute Intermittent Porphyria. Journal of Internal Medicine.2000; 248: 319-325.

11. Bjersing, L. Hepatocellular Carcinoma in Patients from Northern Sweden with Acute Intermittent Porphyria:Morphology and Mutations. Cancer Epidemiology, Biomarkers, and Prevention. 1996; 5: 393-397.

12. Anderson, C. The epidemiology of Hepatocellular Carcinoma in Patients with Acute Intermittent Porpyria. Journalof Internal Medicine. 1996; 240: 195-201.


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References

13. De Siervi et al. Aminolevulinic acid cytotoxic effects on human hepatocarcinoma cell lines. BMC Cancer. 2002,2: 1-6.

14. Seth, A. et al. Liver Transplantation for Porphyria: Who, When, and How? Liver Transplantation. 2007, 13:1219-1227.

15. Bonkovsky, H. et al. Reconstitution of Hematin for Intravenous Infusion.Annals of Internal Medicine. 2006, 144:537-538.

16. Siegert, S & Holt, R. Physicochemical Properties, Pharmacokinetics, and Pharmacodynamics of IntravenousHematin: a Literature Review. Adv Ther. 2008; 25: 842-857.

www.porphyriafoundation .com/


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Thank you