The Porphyrias

Question 1

Which acute hepatic porphyrias are Autosomal Dominantly inherited?

Answer 1

acute intermittent porphyria (HMP-synthase deficiency- 50% activity)
hereditary coproporphyria (COPRO-synthase deficiency- 50% activity)
variegate porphyria (PROTO-synthase deficiency- 50% activity)

Question 2

Which acute hepatic porphyrias are Autosomal Recessively inherited?

Answer 2

ALA-dehydratase deficient porphyria (ALA dehydratase deficiency <5% activity)

Question 3

What do patients with acute hepatic porphyrias typically present with clinically?

Answer 3

severe neuropathic abdominal pain (diffuse)
nausea, emesis, abdominal distension, constipation, sometimes diarrhea
pain sometimes in other parts of body such as extrematies, back, or thoracic area
anxiety, hallucinations, agitations, seizures

Question 4

What are some precipitating factors for acute crisis in patients with acute hepatic porphyrias?

Answer 4

drugs/chemicals (antibiotics, alcohol, estrogen, sulfonamides, hydrantions, barbituarates, progestagens, etc)
surgery/anesthesia
luteal phase of menstrual cycle
pregnancy and post partum period
infection
stress
fasting/starvation

Question 5

What clinical features are associated with a suspicion for acute hepatic porphyrias?

Answer 5

dark or reddish urine (~70% of patients)
hyponatremia (low sodium) during acute attacks
new onset HTN (especially in young people)
women > men
muscle weakness
2nd to 4th decade
h/o precipitating factors

Question 6

How are acute hepatic porphyrias diagnosed?

Answer 6

urine porphobilinogen (PBG) is the single most important test
quant ALA, PBG, and total porphryn
send biochemical confirmation
genetic testing for confirmation

Question 7

In general, how are acute hepatic porphyrias managed?

Answer 7

avoid offending drugs/chemicals
maintain nutrition and fluids (treat hyponatremia and supplement dextrose which non-specifically decreases ALA1)
pain management (opioids)
beta blockers (for HTN)
hemin therapy (first line treatment- suppresses hepatic ALAS1 through negative feedback loop) 
gonadotropin releasing hormone analogues (women during luteal phase)
Givosiran (ALAS1 targetign RNA blocks)
liver transplant (last resort)

Question 8

How do you classify the frequency of attacks in acute hepatic porphyrias?

Answer 8

recurrent (>3 attacks per year)
sporatic attacks (<3 attacks per year)
asymptomatic high excreters (clinically asymptomatic with high levels of ALA and PBG- may have h/o attacks)
latent (clinically asymptomatic with normal ALA and PBG levels)

Question 9

What are the long term complications associated with acute hepatic porphyrias?

Answer 9

increased risk of hepato-cellular carcinomas
chronic renal failure
HTN
chronic neuropathy and pain
anxiety and depression
complications of long term therapy (iron overload due to chronic hemin therapy, osteoporosis with GnRH analogues)

Question 10

Name the types of cutaneous poprhyrias.

Answer 10

hepatic (porphyria cutanea tarda- most common and mostly sporatic rather than familial)
erythropoietic (congenital erythropoietic porphyrias, erythropoietic protoporphyrias, and X-linked protoporphyrias)

Question 11

What is porphyria cutanea tarda (PCT)?

Answer 11

skin symptoms and chronic liver disease
associated with hemochromatosis, Hep C, HIV, alcohol, excess estrogen, cytochrome polymorphisms
managed with avoidance of precipitating factors, treatment of HCV and HIV, chloroquine (complexes with porphyrins), and phlebotomy (q2-4 weeks for a total of 7-8 months usually)

Question 12

What is erythropoietic protoporphyria (EPP)?

Answer 12

AR mutation in one FECH allele adn the hypomorphic low expression predisposing common variant (IVS3-48T>C) or one FECH mutation one each allele
most common cutaneous porphyria in children
results from deficiency of ferrochelatase (FECH) resulting in accumulations of protoporphyrins in bone marrow reticulocytes, plasma, and liver
diagnosed biochemically with significantly increased protoporphyrins in erythrocytes with predominate f-PROTO (rather than z-PROTO)

Question 13

How does erythropoietic protoporphyria present?

Answer 13

photosensitivity commencing in childhood (early spring to late summer without blistering)
in some cases liver complications (20-30%)
onset normally around 4 years old but significant diagnostic delay

Question 14

What is X-Linked Protoporphyria (XLP)?

Answer 14

clinically the same as EPP (but males more affected; significant vairability in females)
ALAS2 gene (Xp11.21) encodes for erythroid-specific isoenzyme (rate limiting step of heme synthesis) so deletions in exon 11 result in gain of function which increases the expression of ALAS2
higher protoporphyrin levels and greater risk of liver disease

Question 15

How are erythropoietic porphyrias treated?

Answer 15

beta-carotene (not effective; no longer used)
protective clothing
sunblock (containing zinc oxide or titanium dioxide)
alpha-MSH (increases pigmentation by increasing melanin)
MT7117 (clinical trials)
liver transplant (not curative- need BMT to prevent further damage)
blood transfusions (for CEP to decrease heme biosynthesis)

Question 16

What is congenital erythropoietic porphyria (CEP)?

Answer 16

deficiency of URO-synthase (<10% activity) resulting in severe photosensitivity
buallae, scarring, disfigurement or light-exposed areas
hemolysis, hyperspelenism
hemolytic anemia, splenomegally, secondary HTN, erythrodontia, hypertrichosis
porphyrinuria
red urine (important diagnostic feature)