The primary porphyrin can be divided into 3 main categories

-acute neurovisceral

-chronic blistering cutaneous photosensitivity

-acute non blistering

CEP is referred to as

gunther's disease

Porphyrins are considered secondary if they are ______

acquired

The term porphyria were recognized in the late 19th century the term is attributed to ________

Dr.Gunther in 1911 in his naming of the congenital erythropoietic porphyria (CEP)

Porphyrins are considered primary if they are ______

inherited

Disordered can be caused by heme could either be ___________ or_____________.

inherited; acquired

What is Porphyria

Group of diseases caused by the accumulation of heme substrates caused by primary genetic defects altering any of 8 critical enzymes in the synthesis pathway in combination with environmental or metabolic issues which further reduce affected enzyme activity

The basic porphyrin structure is ___________

composed of four pyrrole rings linked by methene bridges.

Porphyrins have biological activity only when chelated to a _________

metal

porphyrins are the oxidized form of ___________

porphrinogens

The word porphyrin is derived from the root word ______

purple

porphyrin have a strong absorbance at ____________

400 nm

porphyrin have excitation at 400 nm, and emission at _________

550 and 650 nm

heme does not ______

fluorescence

(True or False) Heme is a protein.

False

Heme structure

a metalloporphyrin with iron as the central iron

The majority of heme is produced in the ____________

bone marrow (70%)

liver (15%)

The heme biosynthetic pathway __________

consists of 8 enzymes

Where are the 8 enzymes in the heme pathway?

four are found in the mitochondria and the other four are found in the cytosol

Only series III are _______

Metabolized to heme

Acute porphyria's are associated with __________

-abdominal pain, neuropathy, mental disturbances

-AIP,ADP, RCP, VP

Cutaneous porphyria's are associated with _________

-skin manifestation

-CEP,HCP,VP,EPP,HEP,PCT

What is the major enzyme that controls heme production pathway?

Do porphoryia's affect that enzyme?

- 5-Aminolevulinate synthase (ALAS)
- NO - that is why you get plenty of heme, but you get a buildup of other enzymes (since defect is later down the line) and thus, porphoryia

Porphyria is Greek for _____________

purple, the color urine containing excessive heme substrates changes when exposed to sunlight (UV light)

When should you suspect porphyria?

-unexplained neurovisceral symptoms such as sever abdominal pain or physiatry symptoms

-cutaneous photosensitive on sun-exposed areas, with or without blistering

What is Acute Intermittent Porphyria (AIP)?

Neurovisceral disease; most common of acute porphyrias

What is the main symptoms of Acute Intermittent Porphyria (AIP)?

abdominal pain, visceral; neuro-psychiatric disturbances; peripheral neuropathy including bulbar (difficulty swallowing etc.)

What is the most common porphyria?

Porphyria cutanea tarda (PCT)

What is the defect in Porphyria cutanea tarda (PCT)?

typically results from an ACQUIRED loss of enzymatic function.

Acute Porphyrias - Symptoms are secondary to what?

to the accumulation of high levels of delta-aminolevulinic acid (ALA) and porphobilinogen (PBG).

Laboratory investigation of porphyria?

-Measurements of urine porphobilinogen (PBG) in acute attacks

-Must be in a light protected tube if not some anilities could be degraded giving false positive

More soluble porphyria are excreted in _________

urine

Less soluble porphyria are excreted in _________

bile or stool

Urine appearance on in porphyria

appears "port wine" due to the conversion of porphobilinogen (PBG) to uroporphyrinogen

To diagnose acute porphyria testing

-begin with a urine screening that includes precursors to PBG and ALA

-if possible wait to collect urine sample during an acute episode when the patient is experiencing symptoms

What is the sample type for porphyrin analysis?

24-hour urine collection preserved with sodium carbonate and freeze immediately

protected from light

HPLC/UPLC separates ___

the water-soluble porphyrins as well as other porphyrins by HPLC using fluorescence detector

What is the most rare porphyria?

X-linked erythropoietic protoporphyria (XLP)

X-linked results from ___________?

an inherited GAIN of function mutation.

X-Linked Sideroblastic Anemia

Rare, inherited deficiency of ALA synthase
Most common hereditary sideroblastic anemia

X-Linked Sideroblastic Anemia Treatment

Responds to Vitamin B6 which activates the remaining delta-ALA synthase.

phlebotomy and or chelation therapy to reduce accumulation off iron levels

X-Linked Sideroblastic Anemia Lab Findings

Microcytic, hypochromic anemia

X-Linked Sideroblastic is caused by _________

reduced heme synthesis, which in ineffective increasing erythron iron turnover. causing excess iron in the bone marrow

Acid dehydratase-deficiency porphyria (ADP) caused by

deficiency in the second heme synthesis pathway.

defective activity of 5-aminovulinic acid dehydratase

deficiency porphyria (ADP) caused by

autosomal recessive inherited. both parents would has to have the defect

deficiency porphyria (ADP) caused by

deficiency in the ALA dehydrate activity

Symptoms of ADP?

abdominal pain and neuropathy symptoms such as disorientation, agitation, hallucination and muscle weakness

Treatment of ADP includes __________

IV panhematin (hemin) (feedback inhibition)

acute symptoms (antibodies, seizure medication)

In the lab for testing for ADP we see a marked elevation in the ____________

5-aminolvulinic acid (ALA) and slightly marked elevation in (PBG)

Acute intermittent porphyria (AIP )

enzyme deficiency of enzyme hydroxymethybilane synthase, higher prevalence in scandanavian countries, drugs most commonly precipitate the cause of disease (barbituates, sulfonamides)

AIP is a ________

Autosomal dominant inheritance and only 1 defective parent is needed

AIP is caused by ___________

deficiency of the non-erythroid form

Clinical symptoms of AIP

abdominal pain that can be very sever

hypertension, restlessness, tremors and excess sweating, overactive sympathetic nervous systems

treatment of AIP

Panhematin (IV hemin)

GIVLAARI injection

In the lab for testing for AIP we see a marked elevation in the ____________

Total serum porphyria

PBG

Pathophysiology of acute attack caused by ___

excess ALA from the liver leads to neuronal toxicity

CEP

deficiency of uroporphyrinogen III cosynthase, one of the rarest porphyrias, Gunther's disease, teeth will fluoresce red under ultra violet light, red-brownish discoloration under normal light

CEP caused by a _______

mutation in the UROS gene

Symptoms of CEP

sever anemia, cutaneous photosensitive, blistering symptoms on sun exposed skin, reoccurring skin damage

In the lab for testing for CEP we see a marked elevation in the ____________

uroporphyrin and coproporphyrin

normal PBG

porphyria cutanea tarda (PCT)

the most common porphyria

Where is the defect in Porphyria cutanea tarda (PCT)?

typically results from an acquired loss of enzymatic function.

decreased activity of uroporphyrinogen III decarboxylase (UROD, Step 5) in the liver.

Porphyria cutanea tarda (PCT) type I is ________

(acquired) (80% of the cases)

Porphyria cutanea tarda (PCT) type II is ________

(inherited) (autosomal dominate) (20% of the cases)

Porphyria cutanea tarda (PCT) type III is ________

Homogenize inherited family (HEP) (both parent would have to have the defect (very rare)

What is the main symptoms of Porphyria cutanea tarda (PCT)?

chronic blistering cutaneous porphyria

What triggers PCT symptoms?

-Iron overload (commonly due to hemochromatosis resulting from mutation of the HFE gene)

- Hepatitis C infection

- Alcohol abuse

- Medicinal estrogen use

PCT - should be considered when?

These porphyrias should be considered whenever a patient presents with the characteristic blistering response to sunlight.

What is the most appropriate initial test for PCT?

The measurement of total porphyrins in plasma, but total porphyrins are also elevated in the urine.

What are some final confirmatory tests?

DNA-based mutation detection, but remember that in PCT only 20% to 30% will have an identifiable mutation.

What are the effective treatments for PCT?

phlebotomy and chloroquine.

Chloroquine takes longer to work, and may exacerbate hepatotoxicity, but is LESS invasive than regular phlebotomy.

Hepatoerythropoietic Porphyria (HEP) results from __________

a homozygous mutation of both alleles of the UROD gene and is so called because porphyrins accumulate in both the red cells and liver.

symptoms of Hepatoerythropoietic porphyria (HEP)

Cutaneous symptoms, photosensitivity, abnormal hair growth, liver disease; appears in childhood, skin damage

In the lab for testing for HEP we see a marked elevation in the ____________

Uroporphyriay, heptacarboxyporphyrin, pentacarboxylin

Treatment of HEP includes __________

phlebotomy

avoid sun and iron

low dose of chloroquine

hereditary coproporhyria HCP

neurocutaneous symptoms

hereditary coproporhyria HCP inheritance

it is autosomal dominant and symptoms are similar to AIP. symptoms in female can coincide with the menstural cycle

coproporphyrinogen oxidation

This enzyme is involved in the production of a molecule called heme. catalyzes the oxygen-dependent oxidation of protoporphyrinogen IX to protoporphyrin IX.

In the lab for testing for HCP we see a marked elevation in the ____________

coproporphyrin III in the urine

Which of the five hepatic poryphrias presents with blistering skin lesions?

PCT - porphyria cutanea tarda

HCP - hereditary coproporphyria & VP - variegate porphyria

How do you diagnose Hereditary Corproporphyria (HCP)?

COPRO III is markedly increased in the urine and feces in symptomatic patients and often persists (especially in feces) when there are no symptoms.

Urinary ALA and PBG levels are increased, though not to the extent that is present in AIP.

How do you treat Hereditary Corproporphyria (HCP)?

You treat the neuro sxs (as you do in AIP) but phlebotomy and chloroquine are not effective treatments for cutaneous lesions

Variegate Porphyria (VP) is a dominant hepatic porphyria that results from deficient activity of...

PROTO-oxidase, the seventh enzyme in the heme biosynthetic pathway

Who gets Variegate Porphyria (VP)?

- netherland descent living in south africa
- 3 in 1000 whites

Variegate Porphyria (VP) clinical features

- skin photosensitivity
- acute neurovesical crises

blistering skin manifestations are worse than those in PCT and they are more difficult to treat and usually of longer duration

How do you diagnose Variegate Porphyria (VP)?

- urine ALA and PBG levels are increased during acute attacks but may return to normal more quickly than in AIP

In the lab for testing for Variegate Porphyria (VP) we see a marked elevation in the ____________

- increases in fecal protoporphyrin and COPRO III and in urinary COPRO III

- plasma porphryn levels are also increased, particularly when there are cutaneous lesions

Treatment of Variegate Porphyria (VP)

- acute attacks are treated as in AIP
- hemin should be started early in most cases
- avoiding sun exposure (few other effective measures for treating skin lesions)

X-linked Sideroblastic Anemia (XLSA) results from the deficient activity of the...

erythroid form of the ALA-synthase (ALA-synthase 2)

X-linked Sideroblastic Anemia (XLSA) is associated with...

ineffective erythropoiesis, weakness , and pallor

What are the clinical features of X-linked Sideroblastic Anemia (XLSA)?

refractory hemolytic anemia, pallor, and weakness during infancy

They have secondary hypersplenism, become iron overloaded, and can develop hemosiderosis.

How do you diagnose X-linked Sideroblastic Anemia (XLSA)?

- bone marrow examination reveals hypercellularity with a left shift and megaloblastic erythropoiesis with an abnormal maturation
- sideroblasts

In the lab for testing for X-linked Sideroblastic Anemia (XLSA) we see a marked elevation in the ____________

- levels of urinary porphyrin precursors and of both urinary and fecal porphyrins are normal

-activity of erythroid ALA-synthase 2 is decreased in bone marrow, but this enzyme is difficult to measure in the presence of the normal ALA-synthase housekeeping 1 enzyme

X-linked Sideroblastic Anemia (XLSA) Treatment

- pyridoxine supplementation
- transfusions and chelation therapy if refractory to pyroxidine supplementation

EPP - erythropoietic protoporphyria

Erythropoietic protoporphyria (EPP) is the most common porphyria to cause....

Erythropoietic Protoporphyria (EPP) primary source of excess protoporphyrin?

bone marrow reticulocytes

Erythropoietic Protoporphyria (EPP) results of excess protoporphyrin?

liver function abnormalities and liver failure requiring transplantation

Erythropoietic Protoporphyria (EPP) Diagnosis

- substantial increase in protoporphyrin, which is predominantly free and not complexed with zinc, is the hallmark of EPP

Erythropoietic Protoporphyria (EPP) Treatment

- avoid sunlight and wear protective clothing
- cholestyramine and other porphyrin absorbents may be helpful to promote fecal excretion to prevent enterohepatic circulation

The only acquired porphyria is:

a. Erythropoietic protoporphyria (EPP)
b. Acute intermittent porphyria (AIP)
c. Porphyria cutanea tarda (PCT)
d. Variegate prophyria (VP)

c. Porphyria cutanea tarda (PCT)

Which of the following is NOT a part of the therapy for an attack of acute porphyria, such as AIP?

a. IV heme (hemin)
b. Progesterone
c. IV glucose
d. IV saline

b. Progesterone

Hemochromatosis has been identified as the cause of which of the following porphyrias?

a. Acute intermittent porphyria (AIP)
b. Erythropoietic protoporphyria (EPP)
c. Porphyria cutanea tarda (PCT)

c. Porphyria cutanea tarda (PCT)

When evaluating a patient with acute neurovisceral symptoms and an elevated spot PBG level, the practitioner should wait for final confirmation by quantitative prophyrin measurements before beginning therapy.

TRUE or FALSE

FALSE

Patients with erythropoietic protoporphyria present with macrocytosis.

TRUE or FALSE

FALSE

Which of the following is NOT an effective therapy for porphyria cutanea tarda (PCT)?

a. IV heme (hemin)
b. Phlebotomy
c. Chloroquine

a. IV heme (hemin)

Patients with erythropoietic protoporphyria typically present with:

a. Chronic blistering, scarring, and photomutilation
b. Acute neurovisceral attacks
c. Burning pain, erythema, and edema of the skin after sun exposure
d. Macrocytic anemia

c. Burning pain, erythema, and edema of the skin after sun exposure

Describe the first step in the heme synthesis pathway? and what two precursors are used in the synthesis of porphyrins?

Succinyl-CoA + Glycine

Describe the second step in the heme synthesis pathway?

Describe the third step in the heme synthesis pathway and which disorder is associated with it ?

Describe the fourth step in the heme synthesis pathway and which disorder is associated with it ?

Describe the fifth step in the heme synthesis pathway and which disorder is associated with it ?

Describe the sixth step in the heme synthesis pathway and which disorder is associated with it ?

Describe the seventh step in the heme synthesis pathway and which disorder is associated with it ?

Describe the eight step in the heme synthesis pathway and which disorder is associated with it ?