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Path - chempath > Porphyrias > Flashcards

Porphyrias Flashcards

1
Q

what is porphyria?

A

Porphyria is a group of liver disorders in which substances called porphyrins build up in the body, negatively affecting the skin or nervous system

Defects in various enzymes in the pathway of haem synthesis can lead to group of disorder called porphyrias

causes an overproduction of toxic haem precursors

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2
Q

briefly which porphyrias are acute and which are chronic?

A

acute:
neuro-visceral attacks
cutaneous symptoms

chronic:
cutaneous symptoms

can classify by clinical presentation; acuteness
or by site of deficiency; erythroid or hepatic

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3
Q

how does one get porphyria?

A

Most types of porphyria are inherited from one or both of a person’s parents and are due to a mutation in one of the genes that make heme.

They may be inherited in an autosomal dominant, autosomal recessive, or X-linked dominant manner

the underlying mechanism results in a decrease in the amount of heme produced and a build-up of substances involved in making heme - toxic haem precursors

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4
Q

what is the structure of Haem?

A

Is made from 4 pyrroles, which are small pentagon-shaped molecules made from 4 carbons and 1 nitrogen.

Four pyrroles together form a Tetrapyrrole.

Porphyrin is a tetrapyrrole that has substitutions on the side chains which allow it to hold a metal ion.

Thus, a heme is an iron-holding porphyrin

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5
Q

what are the properties of Haem?

A

Oxygen binds reversibly to haem

The heme iron serves as a source or sink of electrons during redox reactions.

Used to make cytochromes and erythroid cells

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6
Q

where is haem made?

A

In the CYTOPLASM & MITOCHONDRIA of All cells

Most pronounced in;

Liver
(in which the rate of synthesis is highly variable, depending on the systemic heme pool)

 Bone marrow 
(in which rate of synthesis of Heme is relatively constant and depends on the production of globin chain),
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7
Q

which enzyme catalyses the first step in the production of haem?

A

ALA Synthase

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8
Q

which is the rate-limiting enzyme responsible for the reaction that initates haem synthesis?

A

ALA Synthase

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9
Q

what is the reaction that initates haem synthesis?

where are the component parts from?

A

Succinyl CoA + Glycine –> 5-Aminolaevulinic Acid (ALA)

components from the citric acid/Krebs cycle

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10
Q

ALA synthase is negatively regulated by ?

A

negatively regulated by glucose and heme concentration

it is inhibited also by a porphyrin called HEMIN

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11
Q

in the synthesis of haem, which reactions involve the eixiting or entry from the mitochondria?

name the enzyme

A

Leaving;
ALA leaves the mitochondrion and be converted to
por-pho-bilinogen (PBG) by PBG synthase

Entering:
• Co-pro-por-phyrinogen III goes into the mitochondria and is converted to protoporphyrinogen IX (via coproporphyrinogen oxidase)

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12
Q

these enzyme deficiencies broadly lead to?

A

build of;

ALA,PBG, porphyrinogens

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13
Q

porphyria disorders correspond to what?

A

deficiencies of each enzyme in the haem synthesis pathway

so deficiency of each enzyme leads to a unique porphyria

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14
Q

clinical presentation of porphyrias can affect which systems?

A

Cutaneous - skin
Nervous system
Gastrointestinal

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15
Q

acute intermittent porphyria is caused by which enzyme deficiency?

A

HMB - Synthase:

hydroxymethylbilane synthase

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16
Q

Aminolevulinic acid dehydratase deficiency porphyria (ALA-deficiency porphyria) aka Plumboporphyria

is caused by which enzyme deficiency?

A

PBG Synthase aka

ALA-Dehydratase

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17
Q

congenital erythropoietic porphyria is caused by which enzyme deficiency?

A

Uroporphyrinogen III Synthase (uro III synthase)

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18
Q

porhyria cutanea tarda is caused by which enzyme deficiency?

A

Uroporphyrinogen decarboxylase

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19
Q

Hereditary Coproporphyria

is caused by which enzyme deficiency?

A

Coproporphyrinogen oxidase

remember: both names have copro in them

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20
Q

Erythropoietic protoporphyria
is caused by which enzyme deficiency?

which reaction does this enzyme catalyse

A

ferrochetolase

The last reaction in the pathway;
Protoporphyrin IX -> Haem

21
Q

Variegate Porphyria

is caused by which enzyme deficiency?

A

Protoporphyrinogen oxidase

22
Q

which are the acute porphyria’s?

A

HAAV

Hereditary Coproporphyria
ALA Dehydratase / Plumboporphyria
Acute Intermittent Porphyria
Variegate Porphyria

23
Q

which are the non-acute porphyrias?

A

CEPEP

Congenital Eryrthopoietic porphyria
Porphyria cutanea tarda
Erythorpoietic protoporphyria

24
Q

How are activated porphyrins made?

what 2 things are required and what 2 things are made?

A

Porphyrinogens are Oxidised to

Porhyrin. In the presence of light these become activated & O2 is made

required: oxidsation, light
made; activated porph, O2

25
Q

what are the properties of porphyrinogens?

A

Colourless compounds

Unstable and readily oxidised to the corresponding porphyrin by the time urine /faeces reaches lab

26
Q

what are the properties of porphyrins?

A

highly coloured

Porphyrins near start of the pathway are water soluble – urine (urorphyrinogens-)
Porphyrins near end less soluble – faeces (coproporphyrinogens- made just 1 step after uro’s)

27
Q

which enzymee in the hame synthesis pathway presents the 1st porphyria?

A

PBG Synthase aka ALA dehydrates

28
Q

ALA Synthase deficiency presents which porphyria?

A

IS NOT A PORPHYRIA

instead, it causes X-linked sideroblastic anaemia

29
Q

give some details of ‘ALA Dehydratase or Plumboporphyria’ ?

A

Very rare!

Build-up of ALA, but not PBG - porphobilinogen

30
Q

what is the clinical presentation of acute intermiittent porphyria; AIP?

what symptoms do you not get and why?

A

90% have no symptoms at all

- Neurovisceral attacks:
Abdo pain (most common) and vomiting
Tachycardia and hypertension
Constipation, urinary incontinence
Hyponatraemia +/- Seizures
Psychological symptoms
Sensory loss / muscle weakness/paresis
Arrythmias / cardiac arrest

RED URINE

No skin symptoms: No production of porphyrinogens

31
Q

what is the aetiology of AIP?

A

HMB Synthase deficiency

Autosomal dominant

Precipitating factors:

ALA synthase inducers
- Barbiturates, steroids, Alcohol, anticonvulsants, Smoking, antibiotics

Stress
- Infection, surgery

Reduced caloric intake

Endocrine factors
- More common in women and premenstrual: oestrogen and progesterone

32
Q

how is AIP diagnosed?

A

conduct a Urinalysis

Increased ‘urinary’ porphobilinogen PBG (and ALA); approx 5x of normal (to differentaite from dehydratoin)

Then must do fecal porphyrin: levels are normal in AIP but elevated in HCP and VP

PBG gets oxidised to porphobilin ;
Decreased HMBS activity in erythrocytes

Also - DNA test can be useful

33
Q

why is fast diagnosis important in AIP?

A

Delays in diagnosis may result in permanent neurological damage or death

34
Q

How is AIP treated?

A

Avoid attacks
Adequate nutritional intake
Precipitant drugs
Prompt treatment infection/illness

iv carbohydrate - high carb diet
iv haem arginate - acute attacks think this inhibits ALA synthase

35
Q

how is AIP differentiated from Hereditary coproporphyria and Variegate porphyria?

A

they are all acute porphyrias and
Urine PBG – raised in all three BUT:

Hereditary coproporphyria & Variegate porphyria - have skin lesions

fecal porphyrin levels test: AIP will have normal levels. others elevated

DNA test - definitive but large number of mutations
Enzyme activity variable

36
Q

what is the aetiology and presentatoin of Hereditary Coproporphyria (HCP)?

A

Coproporphyrinogen oxidase deficient

Autodomal dominant
Acute neurovisceral attack

Skin lesions:
Blistering
Skin fragility

37
Q

what is the aetiology and presentation of Variegate Porphyria (VP)?

A

Protoporphyrinogen oxidase
Autosomal dominant
Acute attacks
Skin lesions

38
Q

what is the presentation of non acute porphyrias?

A

Only present with skin lesions

No neuro-visceral manifestations

39
Q

what is the presentation of Erythropoietic protoporphyria?

diagnosis/ivx?

A

Photosensitivity only, no blisters

photosensitivity, burning, itching oedema following sun exposure

Ivx: Only erythroid cells affected, therefore need to measure RBC protoporphyrin

40
Q

what is the aetiology and presentation of Porphyria Cutanea Tarda PCT?

A 
Presentation:
Blisters, lesions
Excess hair growth
Tense bullae/vesicles on sun-exposed areas of skin crusting, (so skin crusting then bullae on top)
superficial scarring, pigmentation

Aetiology :
1. Inherited or acquired (Formation of specific inhibitor of uroporphyrinogen decarboxylase)

  1. Uroporphyrinogen decarboxylase (UROD) deficiency
41
Q

How is PCT diagnosed? rx?

A

Urinary (& plasma) uroporphyrins & coproporphyrins increased

Ferritin often increased

Rx: Avoid SUNLIGHT, and precipitants (alcohol, hepatic compromise) phlebotomy if due to iron load. treat underlying conditions eg hepatitis

42
Q

if a patient comes in with photosensitivity, how do you ivx?

A

Red cell protoporphyrins

43
Q

which is the MOST COMMON porphyria?

A

• Porphyria Cutanea Tarda

2nd most common: AIP

44
Q

which porphyrias are associated with myelodysplastic syndromes

A

Erythropoietic porphyria and congenital erythropoietic porphyria

45
Q

PCT-like syndrome can be triggered by?

A

hexachlorobenzene - fungicide used in agriculture

46
Q

Hyponatraemia associated with AIP is due to?

A

SIADH

47
Q

PCT can be triggered by what?

A

Iron overload - haemochromatosis
Infection - hepatitis, hiv
alcohol, smoking
estrogen use

ANYTHING that affects the liver because UROD - Uroporphyrinogen decarboxylase is a liver enzyme

48
Q

Symptoms in PCT are due to waht exactly?

A

build up of PORPHYRINOGENS mainly -> which then get oxidised to photosensitizing porphyrins

rather than anything else later on in the pathway

49
Q

why are ALA synthase inducers important in the aetiology of AIP?

A

Because ALA synthase overactivity is what leads to the build of of the neurotoxic susbstances;

ALA and PBG

henceforth the deficient enzyme struggles to keep up. with the excess ALA and PBG

Path - chempath (25 decks)

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