CASE DISCUSSION

A 16 year old boy, admitted in surgical ward with c/o acute abdomen. On investigation with CBC, RBS, RFT, ELECTROLYTE, SGPT, CxR, USG all normal. Diagnostic laparoscopy done which was normal. The next day he developes convulsion. Medical refer done. Phenytoin loaded. Pt developes altered sensorium. Again all reports with brain imaging normal. During routine round a houseman noticed blackish-red urine in urobag. On Ix U. PBG turns out positive.

Porphyria

King George III (1738 to 1820)

History and nomenclature

The word porphyria derives from the Greek word porphyrus, 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 madness suffered by King George III (1738 to 1820) resulted from an acute hereditary porphyria, variegate porphyria. Investigation suggested that Queen Victoria may also have suffered from the disease as well as her daughter and granddaughter.

Basis of the Porphyrias

Porphyrias
pathway

are disorders of the Heme synthesis

Primary requirements for Heme are in: Bone Marrow (erythropoiesis) Liver (cytochromes)

Basis of the Porphyrias

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

Enzymes 1 2 3 4 ALA synthase ALA dehyratase PBG deaminase Urogen III cosynthase 5 Uro-gen decarboxylase 6 Coprogen oxidase 7 Protogen oxidase 8 Ferrochelatase

Basis of the Porphyrias

Regulation of ALAS is critical to the expression of most of the porphyrias

2 Forms of ALA synthase (ALAS) exist Coded 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 pathway Erythropoietic form (chXp11.2) is not regulated by Heme Deficiency of ALA synthase does not cause porphyria, but does cause sideroblastic anemia

Basis of the Porphyrias

Excretion Patterns of the Heme intermediates Intermediates up through Coproporphyrinogens are water soluble and thus show up in the urine Protoporphyrinogen and Protoporphyrin are insoluble and are excreted via bile into the stool Thus excretion of heme intermediates in the urine or stool helps diagnose porphyria and the site of the deficiency

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

Basis of the Porphyrias

Inheritance of the Acute porphyrias is Autosomal Dominant Thus most porphyriacs have 50% activity of the enzyme which is missing When some environmental stimulus decreases the level of Heme in the liver, ALA synthase activity increases, augmenting the levels of the Heme precursors Precursors then back up at the point in the pathway where the enzyme deficiency exists

Basis of the Porphyrias

The elevated levels of Heme precursors give rise to the symptoms of porphyria. When the heme level comes back to normal, then the level of the precursors returns to normal and symptoms abate.

Basis of the Porphyrias

Triggers of Acute Porphyria:

Drugs:
Dieting:

Any drugs which require hepatic P450s for metabolism can trigger porphyria
Reduction in caloric intake triggers activity of Heme Oxygenase lowering Heme levels

Stress:
Menses:

Including Illnesses, Infections, Surgery Alcohol Excess

Some women have monthly attacks

Pathophysiology of the Acute Attack

ALA induces liver Damage via oxidative effects

Autonomic Nervous System

Peripheral Nervous System
Porphyrins dont Cross BBB Porphyrins excreted from liver

Hypothalamus Limbic area

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

Basis of the Porphyrias

Toxicity of the Heme intermediates Neurovisceral caused by ALA or PBG Abdominal Pain/Vomiting/Constipation Muscle weakness Mental symptoms Limb/Head/Neck/Chest Pain Hypertension/Tachycardia Convulsions Sensory Loss Fever

Basis of the Porphyrias

Toxicity of the Heme intermediates

Photosensitivity caused by porphyrin accumulation in the skin accumulation of water soluble uro- and coproporphyrins leads to blistering. accumulation of the lipophilic protoporphyrins leads to burning sensations in the exposed skin Porphyrins absorb light energy which is released as fluorescence or formation of singlet oxygen
Worst on sun exposed areas

Basis of the Porphyrias

Toxicity of the Heme intermediates
Hemolytic anemia rare and only seen in the erythropoietic porphyrias

Classification of porphyrias

Clinical classification
Acute episodes and no skin changes
Acute episodes and skin changes Skin changes only

Acute intermittent porphyria ALA-dehydratase deficiency

Hereditary coproporphyria Vareigate porphyria Congenital erythropoietic porphyria Erythropoietic protoporphyria Porphyria cutanea tarda Hepatoerythropoietic porphyria

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REMEMBER :
MOST COMMON PORPHYRIA : PCT
MOST COMMON ACUTE PORPHYRIA : AIP

MOST COMMON CHILDHOOD PORPHYRIA : EPP

Acute Intermittent Porphyria

The most common acute 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

United States: ~ 1 in 10,000-20,000

Prevalence in the General Population

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

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

ALA induces liver Damage via oxidative effects

Autonomic Nervous System

Peripheral Nervous System
Porphyrins dont Cross BBB Porphyrins excreted from liver

Hypothalamus Limbic area

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

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)

http://www.drugs-porphyria.org

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) 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 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

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

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

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% glucose at 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

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)

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

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)

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

Theory of injury Vasospasm from:
1. 2.

Porphyrin metabolites & an upregulated SNS urinary excretion of catecholamines during an acute attack

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

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 implicated in HCC caused by HBV or aflatoxin)

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 HEP G2 cells Reduced free heme pool cytochrome P450 & antioxidant enzymes reactive oxygen species DNA damage ALA that accumulates can oxidize proteins & cause DNA damage

Proposed Mechanism of cirrhosis / carcinogenesis:

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

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

PORPHYRIA CUTANEA TARDA :

Epidimiology

It is the most common porphyria.

It may be acquired (type I) genetically inherited (typeII). or

60% of PCT patients are male, most of whom ingest excess alcohol. Women who develop PCT are often on estrogencontaining 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

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.

Investigation

Pathology

Subepidermal blister with minimal cell-poor dermal inflammatory infiltrate.

Treatment

Erythropoietic Protoporphyria:

Epidemiology

It is the most common childhood porphyria.

It is usually evident by 2 years of age.

Pathogenesis

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

Clinical features, complications and base line investigation

Treatment

Congenital Erythropoietic porphyria ( Gunther's disease ):

Epidemiology

It is a very rare autosomal recessive disorder. Patients usually present during infancy and rarely present in adult life with milder forms.

Pathogenesis

It is caused by elevation of both watersoluble and lipid-soluble porphyrin levels due to deficiency of uroporphyrinogen III synthase enzyme.

Clinical features

Very severe photosensitivity with phototoxic burning and blistering leading to mutilation of light exposed parts. Erythrodontia. Madorosis. Scleromalacia perforans. Hypersplenism. Hemolytic anemia. Thrombocytopenia

Treatment

Variegate Porphyria

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, or both.

Variegate Porphyria

Enzyme activity is approximately half-normal in cultured skin fibroblasts, peripheral blood leukocytes/lymphocytes, and hepatocytes
However, most individuals who inherit PPO deficiency remain asymptomatic Why the disease becomes manifest in some individuals and not others is not fully understood

Clinical Manifestations in Variegate Porphyria

Neurovisceral

Cutaneous

Abdominal pain Tachycardia Vomiting Constipation Hypertension Neuropathy Back pain Confusion Bulbar paralysis Psychiatric symptoms Fever Urinary frequency Dysuria Hyponatremia

Increased fragility Vesicles Bullae Erosions Milia Hyperpigmentation Hypertrichosis of sun-exposed areas

Histology: PAS-positive thickening and IgG deposition in the vessel walls, and reduplication of the basal lamina

Variegate Porphyria

Attacks are generally milder than those in AIP, and recurrent attacks are much less common Drug exposure is a frequent precipitant of the acute attack in VP, whereas hormonal factors were significantly more important in AIP Skin manifestations generally occur separately from the neurovisceral symptoms, and are usually of longer duration

Variegate Porphyria

Symptoms rarely occur before puberty, however, the disease may present late in life
The same drugs, steroid hormones, and nutritional factors that are detrimental in AIP can also provoke exacerbations of VP Chronic liver abnormalities, which are generally mild, may be seen in VP Some patients with VP have developed hepatocellular carcinoma, which suggests that the risk of this tumor may be increased in patients with VA, as in AIP and PCT

Diagnosis

During an acute attack urinary aminolevulinate (ALA) and porphobilinogen (PBG) are increased
VP can be distinguished from AIP by the finding of increased plasma porphyrins and marked increases in urinary and fecal coproporphyrin. if properly performed fecal porphyrin analysis is most useful for diagnosis of VP In patients with cutaneous symptoms it is important to differentiate VP from PCT, because PCT is considerably more common than VP, and treatments that are effective for PCT (phlebotomy & chloroquine) are not effective in VP Plasma porphyrin analysis provides a simple and reliable means of rapidly distinguishing VP from the other cutaneous porphyrias

Treatment

Neurovisceral complaints

Treatment measures that are effective in AIP, such as glucose and heme 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 cutaneous symptoms

A patient who underwent liver transplantation showed recovery from VP post-transplantation

Vampire Folklore

The term Vampire was popularised in the early 18th century and arose from the folklore of southeastern Europe depicted as revenents who visited loved ones and caused mischief or deaths in the neighbourhoods they inhabited when they were living They wore cloaks, did not bear fangs and were often described as bloated and of ruddy or darkened countenance

Porphyria and Vampirism?

Pallor Anemia (pica? craving of red meat?) Teeth that appear larger than normal due to gingival recession However, suggestions that porphyria patients crave the heme in human blood, or that the consumption of blood might ease the symptoms of porphyria, are largely based on a misunderstanding of the disease

Pseudoporphyria:

Pseudoporphyria

In certain settings patient develop blistering and skin fragility identical to PCT with the histologic features but with normal urine and serum porphyrins.
Hypertrichosis, dyspigmentation and cutaneous sclerosis do not occur. This condition called pseudoporphyria.

Pseudoporphyria

Most commonly due to medications especially NSAIDs , usually naproxen . other NSAIDs and tetracycline can cause similar picture . Some patient on hemodyalisis develop a similar PCT-like picture.

References
1. 2.

3.
4.

5. 6.

7.

8.

9.

10.

11.

12.

Anderson, K. E. Recommendations for the Diagnosis and Treatment of the Acute Porphyrias. Annals of Internal Medicine. 2005; 142: 439-450. Kauppinen, R. Porphyrias. Lancet. 2005; 365: 241-52. James M.F. & Hift, R.J. Porphyrias. British Journal of Anaesthesia. 2000; 85: 143-53. Sies, C. Clinical Indications for the Investigation of Porphyrias: Case Examples and Evolving Laboratory Approaches to its Diagnosis in New Zealand. The New Zealand Medical Journal. 2005; 118: 1-10. Soonawalla, Z.F. Liver Transplantation as a Cure for Acute Intermittent Porphyria. The Lancet. 2004; 363: 705-6. Onuki, J. Is 5-Aminolevulinic Acid Involved in the Hepatocellular Carcinotgenesis of Acute Intermittent Porphyria? Cellular and Molecular Biology. 2002: 48: 17-26. Cimetidine and Acute Intermittent Porphyria Floderus, Y. Variation in PBG and ALA Concentrations in Plasma and Urine from Asymptomatic Carriers of the Acute Intermittent Porphyria Gene with Increased Porphyrin Precursor Excretion. Clinical Chemistry. 2006; 52: 701-701. Johansson, A. Correction of the Biochemical Defect in Porphobilinogen Deaminase Deficient Cells by Non-Viral Gene Delivery. Molecular and Cellular Biochemistry. 2003; 250: 65-71. Andersson, C. Renal Symptomatology in Patients with Acute Intermittent Porphyria. Journal of Internal Medicine. 2000; 248: 319-325. 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. Anderson, C. The epidemiology of Hepatocellular Carcinoma in Patients with Acute Intermittent Porpyria. Journal of Internal Medicine. 1996; 240: 195-201.

References
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De Siervi et al. Aminolevulinic acid cytotoxic effects on human hepatocarcinoma cell lines. BMC Cancer. 2002, 2: 1-6. Seth, A. et al. Liver Transplantation for Porphyria: Who, When, and How? Liver Transplantation. 2007, 13: 1219-1227. Bonkovsky, H. et al. Reconstitution of Hematin for Intravenous Infusion. Annals of Internal Medicine. 2006, 144: 537-538. Siegert, S & Holt, R. Physicochemical Properties, Pharmacokinetics, and Pharmacodynamics of Intravenous Hematin: a Literature Review. Adv Ther. 2008; 25: 842-857.

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