Heme Metabolism and Disorders

bilirubin

human adults form 250-350mg of ____ per day, a toxic waste product from the breakdown of heme that must be eliminated by hepatocytes

hemoglobin

human adults turn over approximately 6g of ______ daily
iron (Fe) → recycled
heme → bilirubin (toxic waste product)
globin chains → amino acids (recycled)

biliverdin

1.RBCs removed from circulation by spleen, heme librated from hemoglobin
2.heme oxygenase converts heme into _____ (green tetrapyrrolic bile pigment)

gives the greenish color to healing bruises (ecchymosis/hematoma)

Bilirubin normal metabolism

unconjugated

Biliverdin reductase converts biliverdin → ________ bilirubin (indirect bilirubin) which is transported to the liver and bound to albumin
*not water soluble!

bile

1.in the liver, bilirubin-UDP-glucuronosyl transferase converts unconjugated bilirubin → conjugated bilirubin (direct bilirubin) with addition of glucuronic acid
2.Conjugated bilirubin is incorporated into _____, secreted into GI tract to ingest fatty foods → excreted in the stool
*water soluble

urobilinogen

In the terminal ilium and colon bacteria reduce some bilirubin to ______ (colorless), which is oxidized to urobilin and excreted in stool

porphyria (general)

Etiology
-caused by alterations in the eight enzymes of heme biosynthesis
-requires a genetic mutation + environmental insult

Pathophysiology
-porphyrinogens spontaneously oxidize to the inactive form (porphyrin) which increases levels in plasma, urine, stool, skin

Clinical Presentation: cutaneous (photosensitivity) or acute (neurovisceral)

porphyria cutanea tarda (PCT)

Epidemiology/Risk Factors
-most common porphyria overall, most common cutaneous porphyria
-usually adults, seen with liver disease due to changes iron metabolism

Etiology
-Deficient activity of fifth enzyme (UROD) of heme biosynthesis, an acquired inhibition

porphyria cutanea tarda (PCT)

Pathophysiology
-Porphyrins that accumulate are transported to skin, cause phytotoxic damage with exposure to light

Clinical Presentation
-chronic, blistering cutaneous photosensitivity and scarring of skin

Evaluation
-Total porphyrins (plasma or urine)

porphyria cutanea tarda (PCT)

Which disorder of heme metabolism presents in adults with chronic, blistering cutaneous photosensitivity and scarring of skin?

acute intermittent porphyria (AIP)

Epidemiology/Risk Factors
-second most common porphyria
-most common acute porphyria worldwide
-usually adults, N. European (Sweden)

Etiology
-Deficient activity of third enzyme (PBGD/HMBS) of heme biosynthesis due to genetic mutation + insult (increasing demand for heme production)

acute intermittent porphyria (AIP)

Pathophysiology
-Porphobilinogen (PBG) accumulates → neurotoxic effects

Clinical Presentation
1.abdominal pain (85-90%)
2. peripheral neuropathy
3. neuropsychiatric changes

Evaluation
-urine porphobilinogen (PBG)
-total porphyrins (plasma or urine)

acute intermittent porphyria (AIP)

Which disorder of heme metabolism presents with a triad of:
1.abdominal pain (85-90%)
2. peripheral neuropathy
3. neuropsychiatric changes

erythropoietic porphyria (EEP)

Epidemiology/Risk Factors
-third most common porphyria overall
-typically kids, an inherited condition (family history)

Etiology
-deficiency of the eighth enzyme (FECH) last enzyme of heme biosynthesis

erythropoietic porphyria (EEP)

Pathophysiology
-Protoporphyrin IX accumulates in bone marrow, erythrocytes, plasma
→bound to hemoglobin, light irradiation may promote release from erythrocytes

Clinical Presentation
-acute, painful non-blistering photosensitivity (typically kids/young adults)

Evaluation
-total erythrocyte porphyrins

erythropoietic porphyria (EEP)

Which disorder of heme metabolism presents with acute, painful non-blistering photosensitivity (typically kids/young adults)?

lead poisoning

Epidemiology/Risk Factors
-exposure is worse for kids (more vulnerable)
-occupational exposure (adults)
-low-income countries gasoline/industrialized uses of lead

Etiology
-ingestion of chips/dust from lead paint
-contaminated soil from gasoline emissions
→Inhalation: 30-50% retained in lungs
→Ingestion: 70% absorbed (kids), 20% (adults)

lead poisoning

In the US, highest among urban children who live in deteriorating housing built before 1970s
→ black children have statically higher risk, as well as refugee children and foster care

25 years

What is the half life for lead in mineralizing tissues (bone) and 70% of the total body burden for children?

two years

Children younger than ____ of age retain approximately 50% of absorbed lead

Half-Life:
Blood: 28-26 days
Soft tissue: 40 days
Mineralizing tissues >25 years

lead poisoning

Pathophysiology
-affects nervous system (neurocognitive deficits, hearing loss, peripheral neuropathy)
-heme biosynthesis, renal system, cardiovascular system

Clinical Presentation
-lead line deposits in gums
-skeletal lines in bones
-lead flecks in abdomen

Evaluation
-test blood lead level (BLL) via capillary (finger-stick) or venous

lead poisoning

Which condition affects heme biosynthesis interfering with the maturation of the cytoplasm, and in severe cases can observe coarse basophilic stippling of RBCs under the microscope?

lead poisoning

Which disorder of heme metabolism presents with neurocognitive deficits, hearing loss, peripheral neuropathies and the findings pictured (typically kids/adults with occupational exposure)?

lead poisoning

Primary Prevention
No safe or nontoxic blood level exists, screening recommendations are targeted for young children (between 12-24 months) at increased risk of exposure