Heme Structure & Clinical Significance😊😍

Heme Structure & Clinical Significance

• Heme is a metal-containing Protoporphyrin ring
• A metal is at the center.
• It is surrounded by four Pyrrol rings.

• Porphyrinogen:



• Pyrrol rings are connected by single bond methylene bridges.
• Example: Protoporphyrinogen IX.

• Porphyrin:



• Pyrrol rings are connected by double bond bridges.
• Example: Protoporphyrin IX.

• Clinical significance of double bond bridges:
• They absorb light at 400 nm.
• They emit light at 600 nm.
• Corresponds to red color.
• Free energy liberated → excites oxygen → superoxide radicals → photooxidative damage → photosensitivity.

• Heme structure → churidar pattern → buy at 400 Rs sell at 600 Rs

• Soret band:
• Caused by light absorption at 400 nm.
• Simple bedside test for porphyrin in fluid.
• White light passes through a urine sample with porphyrin.
• Light viewed through a spectroscope shows a dark band at 400 nm.

Heme Synthesis Pathway

• Primarily located in mitochondria and cytoplasm.
• So NO Heme synthesis RBCs

• Essential for haemoglobin and cytochromes production.

• Intermittently dehydrate → turn mental

• photo sensitive → blood (Erthro) in skin (Cutanea tarda)

• Very Hereditary → Both

• AD → Very Hereditary Intermittently, others → AR

Heme Synthesis Disorders

• UCP → U have congenital Porphyria

• Imagine Amazed by touching Rich (Ehrlich) Purple (PURPle) vampire (Porphyria) hand → Ask
• How, What (Hoe, Watson)
• like a Sore Wood (Soret, Woodlamb)

Ehrlich test:

• Pink indicates Urobilinogen (UBG)

• Red indicates Porphobilinogen (PBG)

• (PURPLE)

• Other tests:
• Hoesch Test
• Watson Schwartz test
• Diff b/w UBG and PBG
• Soret band at 400 nm
• Wood lamb → Red fluorescence

Introduction

• Most defects in heme synthesis pathways are partial.
• Anemia is not in with partial defects

• The only complete defect is in the first enzyme → ALA synthase 2.
• ALA synthase 2 is in RBC precursors.
• It is related to hemoglobin synthesis.

In a complete defect:

• Heme & Protoporphyrin is not synthesized → anemia

• Iron enters mitochondria of RBC precursors → accumulates
• forms Ring sideroblasts.

• This condition is X-linked Sideroblastic anemia.

In partial defects:

• ↓ heme synthesis leads to feedback stimulation of ALA synthase → ↑ heme synthesis

• Precursor accumulation

• Accumulation of
1. ALA, PBG (toxic to neurons)
• Neuropsychiatric manifestation.
• Sensory neuropathy.
• Recurrent abdominal pain.
• Cyclical bizarre behaviour.
2. Porphyrins
• Photosensitivity.

By Clinical Manifestations

Classification of Porphyrias

By Enzyme Deficiency

Sideroblastic anemia

• Causes
• B6 deficiency
• Alcohol
• ALA synthase (XLR)
• Lead poisoning

Sideroblasts

• Normal immature erythroid precursors in bone marrow

• Present in <30% of marrow cells

• Ringed Sideroblasts
• Bone marrow smear
• Formed when Protoporphyrin is absent
• Iron cannot bind → accumulates as granules around mitochondria

• Iron deposits appear scattered around the nucleus
• ≥5 granules
• ≥1/3rd nucleus

• Detected by:
• Pearl stain/ Prussian Blue Stain

Lead Poisoning

Mnemonic: ABCDEFG

• Saturn → Leading planet → 2 rings (cabots, cirum oral pallor)

• Abdominal pain

• Blue gums → Burtonian line

• Drop

Letter	Symptom/Sign
A	• Anemia with coarse basophilic stippling ↳ ⛔ rRNA degradation • Lead a course NOTE: Fine Basophilic stippling: • Megaloblastic anemia, Thalassemia
B	• Burtonian lines: ↳ (Bluish lines over gums.)
C	Constipation, abdominal colic ↳ (AKA painter's colic, Saturnine colic/Dry belly ache) Calcification Bone line (Calcium deposition) ↳ Metaphyseal dense opacity
D	Drop (Motor nerve palsy) ↳ (wrist drop, foot drop – neuropathy)
E	Encephalopathy ↳ (infants: ataxia, vomiting, stupor, seizures, coma)
F	Facial pallor ↳ earliest sign ↳ Most consistent finding ↳ Circumoral
G	Gout ↳ Saturnine gout

Congenital Erythropoietic Porphyria (CEP):

• Defective Enzyme: Uroporphyrinogen III synthase
• Menumonic: Congenital - you rose - UROS (UPG 3 synthase)

• Accumulation
• HMB UPG I
• CPG I

• Porphyrin accumulation.
• Causes Photosensitivity due to double bond bridges.
• It is the most severe photosensitive porphyria.

Also called "Vampire disease" = Gunther’s disease

• Photosensitivity fear.

• The patient was only active at night (nocturnal behavior).

• Sun exposure caused blister formation and atrophic scarring.

• Peripheral hair distribution was seen, leading to descriptions of vampires with beards.

• Erythrodontia (red fluorescence of teeth) from porphyrin deposition
• mistaken for blood drinking.

• Port wine urine (resembling red wine)
• emitting light at 600 nm.

• Non-immune Hydrops fetalis

• hemolytic anemia

Acute Intermittent Porphyria (AIP)

• Mneumonic: Oru kudumbathil arkkum Alcohol kudikkan pattilla, avarkk PPPP uudendi varum

• Autosomal dominant

• Defective Enzyme: Porphobilinogen deaminase (HMB synthase),

• Accumulated Substrates: Porphobilinogen, ALA

• Presenting Symptoms (5 P's):
• Neurovisceral manifestations
• AIP → P
• Porphobilinogen deaminase
• Porphobilinogen, ALA
• Painful abdomen (M/C symptom),
• Port wine–colored Pee,
• Polyneuropathy,
• Psychological disturbances,
• Precipitated by factors that ↑ ALA synthase

• Precipitating Factors: CYP450 inducers, barbiturates, alcohol, starvation

• Treatment: Hemin and glucose

Porphyria Cutanea Tarda (PCT)

• Most common porphyria

• Defective Enzyme: Uroporphyrinogen decarboxylase (UROD)

• Accumulated Substrate: Uroporphyrinogen (tea-colored urine)

• Associated with Hepatitis C, alcohol, estrogens, iron overload.

• PCT
• PC → Common Porphyria
• photosensitivity
• Hepatitis C
• tea-colored urine

• Presenting Symptoms:
• Blistering cutaneous photosensitivity,
• hyperpigmentation
• Hyperpigmentation + hypertrichosis (esp. face).

• Exacerbated by: Alcohol

• Investigations
• Urine:
• Dark red/brown (due to ↑ uroporphyrins),
• fluoresces pink-red under Wood’s lamp (UV light).
• Plasma fluorescence at ~620 nm (diagnostic).
• UROD activity decreased.
• Screen for HCV, HIV, iron overload, hemochromatosis (HFE mutation).

• Causes: Familial, hepatitis C

• Treatment:
• Low-dose hydroxychloroquine or chloroquine
• Phlebotomy, sun avoidance, antimalarials, beta-carotene
• PCT issue → give low dose hydroxychloroquine

Erythropoietic Protoporphyria (EPP)

• Most common in children

• Defective Enzyme: Ferrochelatase

• Presenting Symptom: Non-blistering photosensitivity

🩸 Heme Breakdown (Degradation of Heme)

• Heme Oxygenase
• Rate limiting step
• NADPH, Cyt P450, O2 is needed