Prashant Joshi, MD PGY-6, Hematology-Oncology Porphyrias Prashant Joshi, MD PGY-6, Hematology-Oncology

Background First cases described in 1800s with neurologic manifestations described in 1890 by Ranking and Pardington. Prior to intensive biochemical analysis, reports published on characteristic reddish-purple discoloration in the urine after prolonged exposure to light and air.

What is porphyria? Inborn error of heme biosynthesis. Heme biosynthesis involves 8 enzymatic steps in conversion of glycine and succinyl-coenzyme A to heme. 8 specific types of Porphyria associated with defects along the heme synthetic pathway. These disorders produce disturbances of multiple organ systems including the skin, the liver, and central and peripheral nervous systems.

Role of Heme Heme is an oxygen carrier, essential for aerobic respiration and ATP production via the electron transport chain. Necessary for production of hemoglobin, myoglobin and cytochromes Cytochrome production necessary for metabolism of multiple drugs in the body, most notably by our friend Cytochrome P450 system in the liver. Heme formation takes place in the liver and bone marrow.

Heme Synthesis

Regulating Heme production Hemoglobin synthesis in the erythroid precursor cells accounts for ~85% of daily heme synthesis in humans. Hepatocytes account for most of the rest, primarily for synthesis of Cytochrome P450 enzymes, abundant in liver endoplasmic reticulum. Heme synthesis is tightly regulated in the liver by negative feedback control of the first and rate-limiting enzyme in the pathway, ALAS1 Erythroid Heme biosynthesis is regulated by availability of iron, which regulates translation of the erythroid-specific ALAS2 mRNA which serves as a substrate for introduction of iron into protoporphyrin by ferrochelatase (FECH) Unlike ALAS1 in the liver, regulatory mechanisms allow a 30-fold greater expression of ALAS2 in the erythroid precursor cells, to meet the demand for large amounts of heme needed for hemoglobin synthesis.

Classification of Porphyrias Traditionally, classified as hepatic or erythropoeitic by primary site of overproduction and accumulation of precursors or porphyrins. Erythropoeitic porphyrias manifest with skin findings without neurologic involvement Hepatic porphyrias involve the nervous system, except porphyria cutanea tarda. Both groups can have overlapping features.

Hepatic Porphyrias Acute Intermittent Porphyria (AIP) Hereditary Coproprophyria (HCP) Variegate Porphyria (VP) Porphyria Cutanea Tarda (PCT)

Hepatic Porphyrias Hepatic porphyrias are characterized by overproduction and initial accumulation of the porphyrin precursors ALA and PBG and/or porphyrins, primarily in the liver.

No neurologic involvement!

Hepatic Porphyrias Acute Intermittent Porphyria (AIP), Hereditary Coproporphyria (HCP) and Variegate Porphyria (VP) are autosomal dominant Symptoms: Abdominal pain Constipation Increased abdominal distention, decreased bowel sounds No inflammation so fever, leukocytosis and diarrhea uncommon. Neurologic symptoms such as peripheral neuropathy (motor, asymmetric). Rarely SAH due to HTN, respiratory failure (muscle weakness), seizures. Psychiatric symptoms common Other symptoms: Nausea, vomiting, headaches, tachycardia, hypertension, extremity, neck or chest pain, muscle weakness, sensory loss, tremors, sweating, bladder distention. Most common symptom!

Diagnosis During acute attacks: urine PBG is almost always markedly elevated. Not seen in any other acute medical condition. Trace PBG (rapid) kit available, but not widely utilized. Subsequent Urinary and Fecal porphyrin testing can determine which specific type of acute hepatic porphyria is present. Genetic testing can be pursued once a type is identified, mutations now known that are associated with AIP, HCP and VP. This is important for counseling for asymptomatic heterozygote at-risk relatives to avoid drugs, fasting, hormones and other precipitant of acute attacks. Testing available at Mt Sinai Hospital’s Porphyria Diagnostic Library

Pathogenesis Pathogenesis had been hotly debated but now the consensus seems to be that the accumulation of ALA and PBG may interact with gamma- aminobutyric acid (GABA) or glutamate receptors plays a major role Direct Heme toxicity to tissue Decreased heme synthesis in “high use” areas Porphyrin damage to tissue

Treatment Strategies: Prevention! Most important strategy in patients with porphyria is to prevent acute attacks. Avoid prolonged fasting Avoid alcohol and smoking, especially in AIP. Avoid medications that can induce the Cytochrome P450 system Activation of Cytochrome P450 system uses up heme and in case of porphyria, increases heme production and its toxic intermediates. List of drugs that are contraindicated for patients with porphyria can be found at http://www.porphyriafoundation.com/drug-database Liver transplant can be curative for patients with severe, recurrent episodes.

Treatment of Acute Attacks Nutritional supplementation with IV glucose administration (300-500g per 24 hours) to decrease ALA synthase activity Narcotic analgesia for abdominal pain Phenothiazines (Compazine) are effective for nausea, vomiting, anxiety restlessness IV Hemin (lypophilized hematin, heme arginate or heme albumin) should be used early for moderate-severe porphyria attacks. Dose of Hemin: 3-4mg/kg daily for 4 days. Synthetic heme provides negative feedback to stop production of additional heme in liver.

Neurologic complications in Hepatic Porphyrias Actual mechanism to damage to nervous system is poorly understood Affects both the central and the peripheral nervous system. ALA and GABA are structurally similar so it is postulated that its accumulation impairs normal GABA function in the nervous system, leading to its CNS effects. Other mechanisms include direct heme damage to nervous system tissue, inadequate heme synthesis in the brain or toxic damage to CNS by porphyrin precursors. A vascular etiology (vasospasms) has been described with brain lesions similar to multiple sclerosis described on MRI of the brain during an acute attack. After resolution of acute attack

Neurologic Complications of Acute Hepatic Porphyrias Motor Neuropathy Patients can have a motor predominant neuropathy with proximal and distal components as seen in AIDP or CIDP but the damage is axonal, not demyelinating. Autonomic dysfunction (tachycardia, orthostatic hypotension, hypertension) Seizures are rare and difficult to treat due to interactions Phenytoin, Phenobarbital, Clonazepam and Valproic Acid all can worsen attacks. Gabapentin, IV Magnesium, Keppra (Levitiracetam) all have some safety data in porphyria patients. Subarachanoid hemorrhage due to hypertension is rare but described. PRES can also occur in these patients.

Porphyria Cutanea Tarda: The hepatic cutaneous porphyria PCT is the most common porphyria! Type 1 is sporadic and Type 2 is familial (autosomal dominant but incomplete penetrance) Uro-decarboxylase activity is <20% of normal or less in symptomatic disease. Patients with Type 2 PCT have mutations in the UROD gene and have approximately half-normal enzyme activity systemically when they are asymptomatic. Type 1 PCT patients have no mutations detected in the UROD gene and have normal enzyme activity when they are asymptomatic.

PCT: Symptoms Blistering skin lesions [1], commonly on backs of hands These rupture and crust over, leaving areas of atrophy and scarring. Lesions can also occur on forearms, face, legs and feet. Skin friability and small white papules called milia [2] are common on backs of hands/fingers. Occasionally sun exposed skin becomes severely thickened with scarring and calcification resembling systemic sclerosis. No neurologic symptoms! 2 1

Pathogenesis Uroporphomethene, an oxidized form of uroporphyrinogen, which is a substrate for UROD was shown to be the enzyme inhibitor. This oxidation in the liver is iron-dependent Other factors leading to uroporphomethene formation are Chronic Hep C, HIV, alcohol abuse and estrogen use. Alcohol and Hep C decrease hepcidin production leading to increased iron absorption leading to increased oxidative stress and uroporphomethene production.

Diagnosis Elevated ALA level in urine PBG level is normal! Urinary porphyrins are highly elevated – mostly uroporphyrin and heptacarboxylate porphyrin Plasma porphyrins are also elevated, helpful for screening. Increased isocorproporphyrin, primarily in feces, is diagnostic for UROD enzyme deficiency.

Treatment Discontinue risk factors such as alcohol, estrogens and iron supplements. Repeated phlebotomy to reduce hepatic iron. Phlebotomy of 1u PRBCs every 2 weeks until Ferritin at goal (<25-50ng/ml) Follow Hemoglobin and Hematocrit to prevent anemia Can document normalization of serum porphyrins after normalization of serum ferritin. Continue phlebotomy PRN after reaching goal ferritin level. Low dose chloroquine or hydroxychloroquine can be utilized as it mobilizes and promotes excretion of excess porphyrins in the liver. Monitor for development of HCC.

Erythopoietic Cutaneous Porphyrias Erythropoietic Protoporphyria (EPP) X-lined form of EPP Congenital Erythropoietic Porphyria (CEP)

Erythopoietic Protoporphyria (EPP) Autosomal Recessive Most common erythropoietic porphyria and most common porphyria in children. Mutation in the FECH gene which markedly reduces activity of FECH enzyme. B. Scarring and thickening of skin and dorsum of hand because of multiple sun/light exposures. A. EPP patient after sun exposure.

X-linked Erythropoietic Protoporphyria (XLP) Gain of function mutation in the last exon of the ALAS2 gene that prematurely truncate the carboxyl-terminus of the endoded erythroid- specific ALAS2 enzyme and increase its activity. Clinically indistinguishable from EPP!

Clinical Manifestations of EPP/XLP Skin photosensitivity which unlike other porphyrias, starts in childhood. Pain, redness and itching occur within minutes of sun exposure. Burning pain can be excrutiating, vesicles and bullae occur in <10% of cases Chronic skin changes such as thickening along with nail changes can be noted. Severe scarring is rare as are pigment changes, hirsutism and friability of skin. Hemolysis and anemia are mild or absent. Palmar keratosis has been noted in these patients. Can have chronic liver failure and abdominal pain Myelodysplastic syndromes associated with EPP or XLP has been described.

Pathogenesis Protoporphyrin accumulates in bone marrow reticulocytes during hemoglobin synthesis Then appears in plasma, taken up in liver and excreted in bile and feces. Protoporphyrins taken up in skin and its blood vessels are photoactivated by sun/light resulting in cutaneous photosensitivity. Protoporphyrin is insoluble at neutral pH and excess amounts form crystalline structures in liver cells and decrease bile flow, causing liver injury.

Diagnosis Primary source of protoporphyrin in excess in EPP/XLP is the bone marrow reticulocytes Erythroid cells exhibit red fluorescence when examined by fluorescence emission microscopy. Diagnosis made by demonstrating markedly increased erythrocyte protoporphyrins. Urinary levels of porphyrins and porphyrin precursors are normal. Confirmation by mutational analyses of FECH and ALAS2 genes. To date >135 loss of function mutations of the FECH gene have been identified. <5% of cases of clinical EPP are due to XLP.

Treatment Avoiding sunlight is essential. Oral beta-carotene (120-180 mg/dl) which leads to mild discoloration of skin due to carotenemia can improve tolerance to sunlight. Plasmapheresis and IV hemin can be used for acute liver injury. Liver transplantation is useful in the short term but the disease eventually recurs in transplanted liver due to continued bone marrow production of excess protoporphyrin.

Congenital Erythropoietic Porphyria (CEP) Autosomal Recessive Markedly reduced but not absent activity of URO-synthase enzyme Leads to accumulation of Uroporphyrin I and Coproporphyrin I isomers

CEP Clinical Features Severe cutaneous photosensitivity begins in early infancy in most cases. Can be recognized in utero as a cause of non-immune hydrops fetalis. Skin is friable, bullae and vesicles are prone to rupture and infection Skin thickening, focal hypopigmentation and hypertrichosis of the face and extremities are classic Secondary infection and bone resorption can lead to significant deformity of extremities and face. Teeth are reddish brown and fluoresce on exposure to long-wave UV light. Hemolysis due to marked increase in erythrocyte porphyrins and leads to splenomegaly. A. Marked skin photosensitivity, scarring and deformation

CEP Diagnosis Uroporphyrin and Coproporphyrin Type I isomers accumulate in bone marrow, plasma, urine and feces. Diagnosis confirmed by demonstrating markedly decreased URO- Synthase enzyme activity or identifying mutations in the UROS gene. >35 UROS gene mutations have been identified An X-lined variant of CEP caused by mutation in GATA1 has been reported.

Treatment of CEP Severe cases often require chronic transfusions for anemia, which can lead to iron overload and other complications. Protection from sunlight Avoiding skin trauma, even minor skin trauma Treat complicating infections promptly. Bone marrow and cord blood transplantation has been successful in some children.

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