Porphyria

Question 1

Porphyrias result from a mutation in WHAT

Answer 1

one of the enzymes in the heme biosynthetic pathway

Question 2

Clinical manifestations of porphyrias results from WHAT

Answer 2

Accumulation of toxic metabolites (porphyrins) that cannot be cleared, due to deficient enzyme action.

The porphyrins have no useful function and act as highly reactive oxidants and damage tissues

Question 3

Inheritance pattern of porphyrias:

Answer 3

These enzyme deficiencies are inherited as autosomal dominant, autosomal recessive, or X-linked traits, with the exception of porphyria cutanea tarda (PCT), which usually is sporadic.

Question 4

Heme is part of hemoglobin, ____, _____, ____, and ____

Answer 4

Heme is part of hemoglobin, myoglobin, catalases, peroxidases, and cytochromes

Question 5

Heme is made in what cells?

Answer 5

Heme is made in every human cell (85% in erythroid cells & much of the rest in the liver, where it is used to make the P450 cytochromes)

Question 6

What is the rate-limiting step of heme synthesis?

Answer 6

First (and rate-limiting) enzyme in heme synthesis pathway is Aminolevulinic acid (ALA) synthetase (ALAS)

Question 7

Increased demand for ____ induces ALAS

Answer 7

heme

Question 8

The heme molecule downregulates ___ by feedback inhibition

Answer 8

ALAS

Question 9

ALAS:

Answer 9

ALAS is a mitochondrial enzyme that catalyzes the conversion of glycine and succinyl CoA to form delta-aminolevulinic acid. This requires pyridoxal-5’-phosphate as a cofactor.

Question 10

How is ALAS1 induced? Why are these important clinically?

Answer 10

• Depletion of the hepatic pool of heme
• Drugs, hormones which induce CYPs (and ALAS1)
• Caloric and carbohydrate restriction
• Metabolic stress, which may induce hepatic heme oxygenase and accelerate heme destruction

These are the same things that can induce a flare of the porphyria AIP

Question 11

If there’s a downstream block of heme synthesis, then inducing ____ feeds raw materials into the ____ cycle, leading to backup accumulation of the toxic porphyrins—giving symptoms of the respective porphyria

Answer 11

If there’s a downstream block, then inducing ALAS feeds raw materials into the porphyria cycle, leading to backup accumulation of the toxic porphyrins—giving symptoms of the respective porphyria

Question 12

Acute Intermittent Porphyria is caused by a deficiency of _____

Answer 12

hepatic PBG deaminase (aka hydroxymethylbilane synthase)

Question 13

What is the inheritance pattern of AIP?

Answer 13

Autosomal dominant with incomplete penetrance

Question 14

Affected individuals with AIP have a 50% reduction in _____ activity

Answer 14

erythrocyte PBG deaminase activity

Question 15

When does AIP appear clinically?

Answer 15

Generally around/after puberty

Question 16

What populations are affected by AIP?

Answer 16

Symptoms more common in females than males

Question 17

How is AIP diagnosed?

Answer 17

Test urine ALA and PBG during crisis - increased levels suggest AIP.

Question 18

In addition to low levels of PGBD activity, disease expression requires _____

Answer 18

induction of ALAS1

Question 19

Describe the clinical symptoms of an acute AIP attack:

Answer 19

GI symptoms - esp. abdominal pain (distinct from e.g. appendicitis because no inflammatory signs)

Peripheral neuropathy - sensory and motor neuropathy may precede abdominal pain. Prolonged attacks can result in bulbar paralysis, respiratory impairment, and death.

Increased catecholamines

Elevated heart rate and BP

Seizures

SIADH - hyponatremia

Dark or reddish-brown urine

Question 20

What are factors that can exacerbate an acute attack of AIP?

Answer 20

•Drugs that increase demand for hepatic heme (especially cytochrome P450 enzymes)

•Crash diets (decreased carbohydrate intake)

•Endogenous hormones (progesterone)

•Cigarette smoking (induces cytochrome P450)

•Metabolic stresses (infections, surgery, psychological stress)

Question 21

How is AIP diagnosed?

Answer 21

•Send urine for PBG and ALA during an acute exacerbation

•If these are not elevated, then stop.

•If these are markedly elevated, then send PBG deaminase enzyme activity (decreased in 90% of patients, even in asymptomatic periods)

•Genetic testing is available.

Question 22

A slight elevation of urine or stool prophyrins with a normal urine ALA and PBG IS/IS NOT porphyria:

Answer 22

IS NOT!

• These are relatively non-specific, especially if only minimally elevated.
• Unlike AIP (or other acute porphyrias), other causes of abdominal pain do not cause elevations of urinary PBG. However, other causes of abdominal pain may be associated with elevations in urinary porphyrins (eg, hepatobiliary disease) or ALA (lead poisoning).

Question 23

How should an acute AIP attack be treated?

Answer 23

•Hospitalization to control/treat acute symptoms:

•Withdraw all unsafe medications

•Monitor respiratory function, muscle strength, neurological status

•Intravenous 10% glucose at least 300 g per day

•Intravenous hematin ASAP (can give IV glucose while waiting for IV hematin)—hematin is heme, which can feedback inhibit ALA-synthase.

• Cimetidine for treatment of crisis and prevention of attacks
• In rare instances where pts have severe, unremitting symptomatic disease, liver transplantation has been done
• There is a clinical trial using siRNA to shut off synthesis of ALAS1 for patients with frequent relapses

Question 24

Hematin mechanism of action:

Answer 24

Reduces production of ALA /porphyrins by negative feedback inhibition on ALA synthetase

Derived from outdated PRBCs from community blood banks

Question 25

What are the adverse reactions of hematin?

Answer 25

(Due to degradation products binding to endothelial cells, platelets, & coagulation factors) * Thrombophlebitis * Anticoagulation (transient ↑ PT, bleeding may occur) * Thrombocytopenia * Iron overload with repeated use

Question 26

Porphyria Cutanea Tarda is caused by a deficiency of \_\_\_

Answer 26

Uroporphyrinogen decarboxylase (UROD)

Question 27

Is porphyria cutanea tarda inherited or acquired?

Answer 27

Can be either - Acquired - type I Inherited - type II

Question 28

Describe the patient population with Cutanea Tarda:

Answer 28

* 60% of PCT patients are **male**, most of whom ingest excess **alcohol**. * Women who develop PCT are often on **estrogen-containing medications.** * Most patients are ≥ 40 years, and 66% have evidence of iron overload.

Question 29

Uroporphyrinogen decarboxylase (UROD):

Answer 29

This enzyme catalyzes the sequential decarboxylation of the four acetyl side chains of uroporphyrinogen to yield coproporphyrinogen.

Question 30

Pathogenesis of cutanea tarda:

Answer 30

•Iron overload leads to reduced activity of the **UROD** enzyme which leads to elevated porphyrin levels, in particular uroporphyrins. **•Hepatic iron levels are correlated with clinical expression of disease.** * Dysregulation of hepcidin, leading to increased iron absorption. * PCT does not appear to be associated with marked upregulation of delta-aminolevulinic acid (ALA) synthase (ALAS1) * Associated disorders : * **Alcoholism.** * **Hemochromatosis.** * **Hepatitis C**

Question 31

Describe the skin findings associated with cutanea tarda:

Answer 31

**•Uroporphyrinogen is made in the liver, but deposits in the skin.** Upon exposure to sunlight, reactive oxygen species are generated which further damage the skin, leading to the skin findings * Blisters, bullae, increased fragility, scarring and hyper- and hypopigmentation **affecting sun-exposed areas** of the body, such as the backs of the hands, forearms, face, ears, neck, and feet. * Bullae contain porphyrin-rich serous or serosanguinous fluid, and may be painful and become infected * **Hirsutism** is also common, especially on the cheeks and forearms

Question 32

How is the liver affected by PCT?

Answer 32

* Liver enzymes (AST and ALT) are almost always elevated * Liver damage is multifactorial: * Porphyrins damage the liver * Associated disorders are also associated with liver damage * Hepatitis C * hemochromatosis **•Increased risk for cirrhosis and hepatocellular carcinoma**

Question 33

How is PCT diagnosed?

Answer 33

* Screening test - Total plasma porphyrin levels * ALA and PBG will be normal, since ALAS1 is not induced * Confirmatory testing - More specific levels of urinary porphyrins to speciate the porphyria

Question 34

How is PCT treated?

Answer 34

•First, **remove all offending agents** * **No alcohol** * **Withhold estrogen** * **Stop smoking** **•Cover sun-exposed areas** and fanatic application of sunscreen •Next, start **phlebotomy** every week or 2: * This removes iron sequentially—do this until the ferritin falls to \<20 * Hold for anemia * Almost everyone achieves remission

Question 35

What levels are considered lead toxicity?

Answer 35

Blood levels \>10mcg/dL for adults Blood levels \>5mcg/dL for children

Question 36

What are common sources of lead in adult patients?

Answer 36

Workplace exposure - manufacturing batteries, solder, radiators, some cosmetics, ammunition, etc. **Leaded gasoline** Mining Lead paint - esp. construction workers X-ray film stored in lead boxes **Moonshine** and marijuana Firing ranges

Question 37

What are common sources of lead exposure in children?

Answer 37

Primarily ingestion - * Lead-containing dust * **Paint** * Soil * **Water** * **Food** * Breastfeeding * Leaded objects (e.g. fishing weights) Some problems with inhalation in children near home renovations or factories.

Question 38

How does lead enter the body?

Answer 38

* **Inhalation** - Major route in **adults** (40% absorption rate) * **Ingestion** - Major route in **children** (50% absorption)

Question 39

What does lead do once it enters the body?

Answer 39

**•99% bound to red cells** * 1% in plasma, transported and exchanged in soft tissues (kidney, brain, liver, bone marrow) * Can be **excreted via the kidneys**—gone in 30 days if normal kidney function * Can be **stored in the bone**: * Can last for decades—95% of body lead stored here * Released from bone during times of high bone turnover (Pregnancy, hyperthyroidism, menopause, breast feeding)

Question 40

Lead inhibits sulfhydral groups in RBC enzymes ___ and ___ in the heme synthetic pathway.

Answer 40

ALAS and ferrochelatase

Question 41

Lead inhibits \_\_\_\_\_, leading to degradation of ribosomal RNA in red blood cells that causes ____ (visible on smear)

Answer 41

Lead inhibits **Pyrimidine 5' nucleotidase**, leading to degradation of ribosomal RNA in red blood cells that causes **basophilic stippling** (visible on smear).

Question 42

Lead competes with _____ in biologic symptoms, which especially impacts the nervous system and mitochondrial respiration

Answer 42

calcium

Question 43

\_\_\_\_ alters the permeability of the blood brain barrier and accumulates in astroglia

Answer 43

Lead

Question 44

Lead promotes the generation of ____ in endothelial and vascular smooth muscle cells. Lead also affects ____ and \_\_\_\_.

Answer 44

Lead promotes the generation of **reactive oxygen species** in endothelial and vascular smooth muscle cells. Lead also affects **cell membranes** and **DNA/RNA**.

Question 45

What is shown in this image?

Answer 45

**Basophilic Stippling** - characteristic of **lead poisoning** * Coarse dark blue inclusions in red cells, representing precipitated ribosomes * Seen in young red cells in conditions associated with RNA instability

Question 46

Describe the acute symptoms of lead toxicity:

Answer 46

•GI effects - crampy abdominal pain (**lead colic**), constipation **•Anemia—typically microcytic** •Neurologic effects – confusion, seizures, fatigue, headache, difficulty concentrating, sleep disturbance * Peripheral neuropathy (predominantly affecting motor nerves) * classic finding – **wrist and foot drop** * Muscle and joint pain * Decreased libido **•“Lead line”** around teeth/gums

Question 47

Describe the chronic effects/symptoms of lead exposure:

Answer 47

•Hypertension (an association between lead levels in bone and blood and hypertension) **•Neuropsychiatric effects** * Declines in neurocognitive function * Psychiatric symptoms – phobia, anxiety, depression, hostility * Distal sensory and motor neuropathy * EKG conduction delay * Decreased hearing acuity * Mortality – increased mortality with chronic exposure, even to low levels of lead * Reproductive effects: * Increased miscarriages and stillbirths with high maternal lead levels * Reduced birth weight and cognitive impairment in children born of mothers exposed to lead * Abnormal sperm morphology and decreased sperm concentration, total sperm count, and total motile sperm count. •Lead nephropathy – pathology shows a chronic interstitial nephritis associated with high lead levels. * Associated with increased hypertension and gout * **“Saturnine gout”** (gout and depression/sadness) * May accelerate renal damage in patients with underlying renal injury

Question 48

How is lead toxicity diagnosed?

Answer 48

**•Blood lead levels:** * **key clinical monitoring test for diagnosing lead toxicity** * **Make sure to use adult ranges for adults and childhood ranges for kids** * **Venous stick,** rather than earlobe capillary stick (which can be contaminated by skin surface lead) •Free erythrocyte protoprophyrin (FEP) and Zn protoporphyrin (ZPP) levels measure lead’s effect on heme production: * can be used as an indicator of lead exposure (and effect) over the preceding three-month period * If the FEP or ZPP are elevated, then need to do CBC, renal function testing.

Question 49

How should lead toxicity be managed?

Answer 49

Reduce lead exposure Chelation therapy: * Used when there are symptoms of acute toxicity, or when levels need to be reduced quickly. * no randomized clinical trials that have proven the efficacy of chelation on clinical outcomes, particularly long-term outcomes, in lead poisoned adults * **Chelation with any agent should not be undertaken unless exposure has been definitively curtailed, since its use in the presence of continuing exposure may result in enhanced absorption of lead and worsening, rather than amelioration of toxicity.** * Two agents most commonly used are DMSA and Calcium EDTA (NOT disodium EDTA)