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Disorders of Heme synthesis
HEME-CONTAINING PROTEINS
Hemoglobin
Myoglobin
Cytochromes
Catalase
Some peroxidases
STRUCTURE OF HEME
Ferrous iron (Fe2+)
Protoporphyrin IX: contains 4 pyrrole rings linked together by methenyl bridges
The two major cell types that are active in heme synthesis
are hepatocytes and bone marrow erythroblasts
85% of total synthesis occurs in erythroid cells
80% of liver production is used for cytochromes
Heme Synthesis
Disorders of Heme metabolism
Heme biosynthesis
Porphyrias
Heme degradation Jaundice
BLOOD CELLS
LIVER
Bilirubin diglucuronide(water-soluble)
2 UDP-glucuronic acid
via bile duct to intestines
Stercobilin excreted in
feces
Urobilinogen formed by bacteria
KIDNEY
Urobilin excreted in urine
COBiliverdin IX
Heme oxygenase
O2
Bilirubin (water-insoluble)
NADP+
NADPHBiliverdin
reductase
HemeGlobin
Hemoglobin
reabsorbed into blood
Bilirubin (water-insoluble)via blood
to the liver
INTESTINE
Figure 2. Catabolism of hemoglobin
The Porphyrias
Group of inherited or acquired disorders of heme production
8 enzymes in heme biosynthetic pathway
First and the last 2 are mitochondrial, while the other five are in the cytosol.
Classification of the Porphyrias Multiple ways to categorize porphyrias:
Hepatic vs. Erythropoietic: Organ in which accumulation of porphyrins and their precursors appears
Cutaneous vs. Non- cutaneous Acute and non-acute forms
Acute: Aminolevulinate dehydratase deficiency porphyria
(ALA-D) Acute intermittent porphyria (AIP) Hereditary coproporphyria (HCP) Variegate porphyria (VP)
Chronic: Porphyria cutanea tarda (PCT) Erythropoietic protoporphyria (EPP) Congenital erythropoietic porphyria (CEP) Hepatoerythropoietic porphyria (HEP)
Enzymatic Deficiencies
All of the heme pathway intermediates are potentially toxic.
Their overproduction causes the characteristic neurovisceral and/or photosensitizing symptoms.
PORPHYRIA CUTANEA TARDA
Most common porphyria
Hepatic, autosomal dominant
Disease is caused by a deficiency in uroporphyrinogen decarboxylase, which is involved in the conversion of uroporphyrinogen III to coproporphyrinogen III
Uroporphyrinogen accumulates in urine Patients are photosensitive (cutaneous photosensitivity)
Accumulation of porphyrinogens results in their
conversion to porphyrins by lightPorphyrins react with molecular oxygen
to form oxygen radicalsOxygen radicals can cause severe
damage to the skin
PORPHYRIA CUTANEA TARDA
Acute intermittent porphyria
Mary Queen of Scots
Van Gogh
King George III
Acute intermittent porphyria The prevalence of AIP in the United States is thought to be 5–10
per 100 000. It is more common in northern European countries, such as
Sweden (60–100 per 100 000), Britain and Ireland.
Acute intermittent porphyria PBGD gene mutation is inherited in an autosomal dominant fashion.
Affects women more than men, with a ratio of 2:1. Most patients become symptomatic at age 18-40 years.
Attacks occurring before puberty or after age 40 years are unusual unless a major provocation
Most patients are completely free of symptoms between attacks. Course of the neurological manifestations is highly variable.
Acute attacks of porphyria may resolve quite rapidly. Sudden death may occur, presumably due to cardiac
arrhythmia.
Attacks involve neuro-visceral symptoms but no skin manifestations: The sequence of events in attacks usually is (1) abdominal pain, (2)
psychiatric symptoms, such as hysteria, and (3) peripheral neuropathies, mainly motor neuropathies.
Gastroenterological Symptoms most common: Constipation (48–84%), colicky abdominal pain (occurring in 85–
95% cases), vomiting (43–88%), diarrhea (5–12%) Patients may have CNS signs consisting of seizures (10–20%), mental
status changes, cortical blindness, and coma.
Patients often experience peripheral neuropathies (42–60%) that are predominantly motor and can mimic Guillain-Barré syndrome.
Patients may develop fever(9–37%), hypertension (36–54%) and tachycardia (28–80%).
Symptoms
Mechanism The exact mechanism underlying these complaints is
not yet well understood, various hypotheses have been put forward:
Excess amounts of PBG or ALA may cause neurotoxicity (Meyer et al, 1998)
Increased ALA concentrations in the brain may inhibit gamma-aminobutyric acid release (Mueller & Snyder,
1977; Brennan & Cantrill, 1979)
Heme deficiency may result in degenerative changes in the central nervous system (Whetsell et al, 1984)
Decreased heme synthesis in the liver results in decreased activity of hepatic tryptophan pyrrolase
(TP), a heme-dependent enzyme, possibly resulting in increased levels of serotonin
Precipitants
Drugs: most common precipitate of acute attacks : Barbiturates and sulphonamides being most common
Reduced energy intake: even brief periods of starvation during dieting, postoperative periods, or concurrent illness.
Tobacco smoke: polycyclic aromatic hydrocarbons, are known inducers of hepatic cytochrome P450 enzymes and heme synthesis. An association between cigarette smoking and repeated
attacks of porphyria was found in a survey of 144 patients with AIP in Britain (Lip et al, 1991).
Infections, surgery and stress.
Diagnosis Demonstration of porphyrin precursors, such
as ALA and/or PBG, is essential for the diagnosis of acute porphyrias.
Porphyrin analysis is necessary for the diagnosis of porphyrias with cutaneous photosensitivity. PBG usually is not included in a urine
porphyrin screen and must be ordered specially
Molecular diagnostic testing: Detection of PBGD mutations in AIP provides
95% sensitivity and around 100% specificity Possible to screen asymptomatic gene
carriers. Less Useful in acute attacks
PBG in urine is oxidized to
porphobilin upon standing, which
gives a dark-brown color to
urine, and often referred to as
‘port-wine reddish urine’.
Erythropoietic Protoporphyria It is the most common childhood porphyria. It is usually evident by 2 years of age.
Pathogenesisdeficient activity of
ferrochelatase enzyme
Lab. finding:Plasma porphyrin level and fluorescence spectrumIncreased free protoporphyrin in RBCs, stoolCBC, LFTsLiver/gallbladder imaging
Congenital Erythropoietic porphyria ( Gunther's disease ): It is a very rare autosomal recessive disorder.
Patients usually present during infancy and rarely present in adult life with milder forms.
PathogenesisIt is caused by elevation of both water-soluble and lipid-soluble porphyrin levels due to deficiency of uroporphyrinogen III synthase enzyme.
Clinical features1. Very severe photosensitivity with phototoxic burning and blistering leading to mutilation of light exposed parts.
2. Erythrodontia.3. Scleromalacia perforans.4. Hypersplenism.5. Hemolytic anemia.6. Thrombocytopenia
Uroporphyrin and Coproporphyrin in urineCorproporphyrin in stool
Lab. finding
Hepatoerythropoietic PorphyriaInheritance/Pathogenesis:
ADUroporphyrinogen (UROGEN) decarboxylase deficient
Incidence: Very rare -Presents at age 1
Prognosis: Normal life span
SkinSimilar to CEP—Severe photosensitivity with burning, edema,
vesicles/bullae, erosions, infectionLate changes—Mutilating scars with deformation of nose,
ears, fingers; scarring alopecia, pigmentary changes, sclerodermoid changes
HypertrichosisTeeth
Red/brown color Eyes
Photophobia, ectropion, conjunctivitis
Clinical picture:
HemeHemolytic anemia
GISplenomegaly
GUDark urine at birth
Plasma porphyrin level and fluorescence spectrumprotoporphyrin in RBCsurinary uroporphyrinfecal coproporphyrinCBC
Lab. finding:
Varigeate PorphyriaInheritance:
ADProtoporphyrinogen oxidase gene (PROTOGEN)Severe forms associated with hemochromatosis gene
Prenatal Diagnosis:DNA analysis
Incidence:Most common in South African whites 1:330Elsewhere is 1:50,000 to 100,000M=F
Age at Presentation:Begins after puberty in second and third decade of life
Pathogenesis:Mutation in PROTOGEN oxidase gene causes a 50% decrease in PROTOGEN oxidase activityAcute attacks precipitated by:
Drugs: barbiturates, estrogen, griseofulvin, sulfonamidesInfectionFeverAlcoholPregnancyDecreased caloric intake
Increase Δ-aminolevulinic acid (ALA) synthetase with attacks
Clinical picture:
Skin: Identical to PCT with bullae, erosions, skin fragility, scarring,
hypertrichosis, hyperpigmentation on photodistributed face, neck and dorsum of hands
Acute Attacks (i.e., Acute Intermittent Porphyria and Hereditary Coproporphyria):
Gastrointestinal:• Colickly abdominal pain, nausea, vomiting, constipation
CNS:• Peripheral neuropathy with pain, weakness, paralysis• Confusional state, anxiety, depression, delerium• Seizures, coma
CV:• Tachycardia, hypertension
Laboratory Data:
Plasma porphyrin level Plasma porphyrin fluorescence spectrum—626 nm is
diagnostic 24 hour urine porphyrin levels: coproprophyrin = or >
uroporphyrin Urine ALA and porphobillinogen (PBG) levels increased
during attacks Fecal prophyrin levels: markedly elevated,
protoporphyrin>coproporphyrin
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