Blood formation and bilirubin: the pathway in the body

This page shows the biochemical pathway behind the laboratory value Blood count: which stations follow one another, which enzymes carry out each step and which cofactors they use. Every statement has a source. The page describes general textbook knowledge and says nothing about any individual person.

In brief

The blood count counts the cells that the bone marrow forms from stem cells: red blood cells, white blood cells and platelets. Old red blood cells are broken down mainly in the spleen; their haem gives rise to bilirubin, which the liver excretes via the bile.

The pathway step by step

Each station states what the compound does there. Three signs: ↑ supplies — builds up or makes available · ↓ depletes — inhibits, consumes or withholds · ↕ both, depending on amount. Behind it stands what the statement rests on: established physiology, observed in studies, or contested. The signs do not grade; they name the direction.

1. Blood stem cell → White cells, platelets The same stem cells give rise to the white blood cells of the immune system and, via large bone marrow cells, to platelets. The full blood count separates the white cells by type. Source 1, 10↑ supplies White blood cells recognise and remove pathogens and cell debris. Platelets attach to injured vessel walls and start clotting. established physiology Source 1, 10
   ⚖ When the balance tips

   too much — During immune responses the bone marrow releases more white cells, above all neutrophils; their number in the blood then rises quickly.

   too little — If the bone marrow forms few white cells or platelets, their number in the blood falls; platelets live only a few days, so their number follows production quickly.

   established physiology · Source 1, 10

2. Blood stem cell → Erythroblast Erythropoietin · Folate, Vitamin B12 Under the kidney hormone erythropoietin, precursors mature into erythroblasts. They divide several times and need folate and vitamin B12 to make genetic material. Source 2, 3, 4↑ supplies Within a few days, erythroblasts build up large amounts of haemoglobin; they acquire the iron for it via the transferrin receptor. Finally they expel their nucleus. established physiology Source 2, 4
   ⚖ When the balance tips

   too much — If the kidney senses little oxygen, it makes more erythropoietin, and more erythroblasts survive and mature.

   too little — If little folate or vitamin B12 is available, erythroblasts divide more slowly and grow larger; if little iron is available, they stay smaller and contain less haemoglobin.

   established physiology · Source 3, 4

3. Erythroblast → Reticulocyte Haemoglobin build-up · Iron After expelling its nucleus, the cell becomes a reticulocyte. It passes from the bone marrow into the blood and matures there within one to two days. Source 2↑ supplies Reticulocytes supply the stream of new red blood cells. Their number in the blood shows how many new cells the bone marrow is currently releasing. established physiology Source 2
   ⚖ When the balance tips

   too much — If the bone marrow steps up production, for example after blood loss, more reticulocytes appear in the blood.

   too little — If it produces little, few reticulocytes appear, and ageing red blood cells are replaced more slowly.

   established physiology · Source 2, 3

4. Reticulocyte → Erythrocyte Maturation in blood Red blood cells have neither a nucleus nor mitochondria and are filled with haemoglobin. They live about 120 days. The blood count counts them and measures their size and haemoglobin content. Source 2, 6↑ supplies With their haemoglobin, red blood cells carry oxygen from the lungs to the tissues and bring carbon dioxide back. They gain their energy from glycolysis alone. established physiology Source 2, 6
   ⚖ When the balance tips

   too much — If there are many red blood cells, their share of the blood volume rises and more oxygen can be carried; the blood also becomes more viscous.

   too little — If there are few red blood cells or they contain little haemoglobin, the blood carries less oxygen; the kidney then makes more erythropoietin.

   established physiology · Source 3, 6

5. Haem → Biliverdin Haem oxygenase · Oxygen, NADPH Haem oxygenase opens the haem ring. This produces biliverdin, iron and carbon monoxide. Source 7↑ supplies Biliverdin is the intermediate on the way to bilirubin. As it forms, the iron is released from haem and can be reused. established physiology Source 7
   ⚖ When the balance tips

   too much — If much biliverdin forms, biliverdin reductase converts correspondingly more of it into bilirubin.

   too little — If little biliverdin forms, bilirubin formation also stays low.

   established physiology · Source 7

6. Biliverdin → Bilirubin Biliverdin reductase · NADPH Biliverdin is reduced to yellow bilirubin. It is fat-soluble and travels in the blood bound to albumin to the liver. It is measured together with the conjugated form as total bilirubin. Source 8↕ both, depending on amount In cell experiments, bilirubin scavenges reactive oxygen species. Unbound and in large amounts it can pass into tissues; bound to albumin it stays in the blood. observed in studies Source 8, 7
   ⚖ When the balance tips

   too much — If more bilirubin forms than the liver absorbs and conjugates, or the liver conjugates more slowly, unconjugated bilirubin in the blood rises; skin and eyes can look yellowish.

   too little — If there is little bilirubin in the blood, little is being formed or the liver is absorbing it quickly.

   established physiology · Source 8

   Field of research — The amount of bilirubin in the blood is studied in conditions of the liver, bile ducts and blood. Source 11

7. Bilirubin → Bilirubin glucuronide UGT1A1 · UDP-glucuronic acid In the liver cell, the enzyme UGT1A1 attaches glucuronic acid to bilirubin. This makes it water-soluble, and it passes with the bile into the gut. Source 8↓ depletes Binding to glucuronic acid removes fat-soluble bilirubin from the blood and makes it excretable. Only in this form can the liver cell pump it into the bile. established physiology Source 8
   ⚖ When the balance tips

   too much — If bile backs up, conjugated bilirubin returns to the blood and then also appears in the urine.

   too little — If UGT1A1 works more slowly, for example because of a common gene variant, more unconjugated bilirubin stays in the blood, especially during fasting.

   established physiology · Source 8

8. Bilirubin glucuronide → Urobilinogen BilR (gut bacteria) In the gut, bacteria remove the glucuronic acid and reduce bilirubin to urobilinogen with the enzyme BilR. This gives rise to the pigments that colour stool brown and urine yellow. Source 9, 8↓ depletes Gut bacteria break bilirubin down further. Part of the urobilinogen is absorbed and excreted via the kidneys; the rest leaves the body with the stool. established physiology Source 9, 8
   ⚖ When the balance tips

   too much — If much bilirubin reaches the gut, more urobilinogen forms and more of it appears in the urine.

   too little — If the gut bacteria carry no BilR, as is often the case in infants, bilirubin stays unchanged in the gut.

   observed in studies · Source 9, 8

9. Haem → Iron Phagocytes release the iron from haem via ferroportin to transferrin in the blood. Most of the iron for new red blood cells comes from this cycle. Source 5↑ supplies Recycled iron supplies most of the iron the bone marrow needs for new haemoglobin; only a small part comes from food. established physiology Source 5
   ⚖ When the balance tips

   too much — If phagocytes break down much haem, they store the surplus iron as ferritin.

   too little — If phagocytes hold back iron, for instance when hepcidin blocks ferroportin, less iron reaches the bone marrow.

   established physiology · Source 5

Further stations

• Blood stem cell — in the bone marrow Blood-forming stem cells divide in the bone marrow. All blood cells arise from them: red blood cells, white blood cells and platelets. Source 1↑ supplies The stem cells renew themselves and at the same time supply precursors for every blood cell line. In this way the bone marrow continuously replaces the cells that age in the blood. established physiology Source 1
  ⚖ When the balance tips

  too much — When more is needed, for example after blood loss or during immune responses, the stem cells give rise to more precursors of the cell line in demand.

  too little — If they divide less often, fewer new cells follow; because blood cells live only for a limited time, their number in the blood then falls gradually.

  established physiology · Source 1

• Haem — from broken-down haemoglobin Aged red blood cells are absorbed by phagocytes, mainly in the spleen. These break down the haemoglobin, releasing the iron-containing pigment haem. Source 5, 6↕ both, depending on amount In haemoglobin, haem binds oxygen. Free haem is reactive and can trigger oxidation; haem oxygenase therefore breaks it down quickly. established physiology Source 7, 5
  ⚖ When the balance tips

  too much — If many red blood cells break down at once, more haem accumulates; the phagocytes then make more haem oxygenase.

  too little — If little haem accumulates, little bilirubin forms and less iron returns from breakdown.

  established physiology · Source 7, 5

Cofactors in this pathway

• Iron — Centre of haem in haemoglobin; erythroblasts acquire it via the transferrin receptor, phagocytes release it again Source 4, 5In the ORY catalogue as a laboratory value: Eisen
• Vitamin B12 — Needed to make DNA building blocks when erythroblasts divide Source 4In the ORY catalogue as a laboratory value: Vitamin B12
• Folate — Supplies carbon units for the DNA building block thymidine; used in every division of erythroblasts Source 4In the ORY catalogue as a laboratory value: Folsäure
• Oxygen — Consumed by haem oxygenase when it opens the haem ring Source 7
• NADPH — Electron donor for haem oxygenase and biliverdin reductase Source 7, 8
• UDP-glucuronic acid — Supplies the sugar residue that UGT1A1 attaches to bilirubin, making it water-soluble Source 8

Sources

1. Orkin SH, Zon LI. Hematopoiesis: an evolving paradigm for stem cell biology. Cell 2008 · PubMed 18295580
2. Dzierzak E, Philipsen S. Erythropoiesis: development and differentiation. Cold Spring Harb Perspect Med 2013 · PubMed 23545573
3. Jelkmann W. Regulation of erythropoietin production. J Physiol 2011 · PubMed 21078592
4. Koury MJ, Ponka P. New insights into erythropoiesis: the roles of folate, vitamin B12, and iron. Annu Rev Nutr 2004 · PubMed 15189115
5. Korolnek T, Hamza I. Macrophages and iron trafficking at the birth and death of red cells. Blood 2015 · PubMed 25778532
6. Thiagarajan P, Parker CJ, Prchal JT. How Do Red Blood Cells Die? Front Physiol 2021 · PubMed 33790808
7. Ryter SW, Alam J, Choi AM. Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications. Physiol Rev 2006 · PubMed 16601269
8. Sticova E, Jirsa M. New insights in bilirubin metabolism and their clinical implications. World J Gastroenterol 2013 · PubMed 24151358
9. Hall B, Levy S, Dufault-Thompson K et al. BilR is a gut microbial enzyme that reduces bilirubin to urobilinogen. Nat Microbiol 2024 · PubMed 38172624
10. Machlus KR, Thon JN, Italiano JE Jr. Interpreting the developmental dance of the megakaryocyte: a review of the cellular and molecular processes mediating platelet formation. Br J Haematol 2014 · PubMed 24499183
11. Fevery J. Bilirubin in clinical practice: a review. Liver Int 2008 · PubMed 18433389

Related pathways

• Iron and ferritin — haem
• Methylation: methionine and homocysteine — Vitamin B12, Folsäure
• Telomeres — Eisen, Folsäure

As of 2026-10-05. Draft written by Claude to schema v2; sources checked in PubMed; expert approval pending
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