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