Author: Payal Bhandari, M.D.

Contributors: Amer Džanković, Hailey Chin,  Nigella Umali Ruguian, Vivi Chador

Key Insights 

The body’s blood proteins are mainly albumin and globulin, with globulin making up 40%. Globulin, made by the liver and immune cells, includes proteins, enzymes, and antibodies. High globulin levels may point to dehydration or gut issues causing inflammation. Low levels can signal malnutrition or liver and kidney damage. Problems with protein absorption can also lower globulin, leading to risks like heart disease, cancer, and infections. Regular tests can catch early signs of these problems. Globulin levels are affected by diet, medications, stress, and health conditions, which also guide treatment.

What is Globulin? 

Blood contains three main proteins: albumin, fibrinogen, and globulins. These proteins are mostly made in the liver, except for gamma globulins, which come from immune cells.

• Albumin (55-60% of blood protein): Keeps fluid in blood vessels and carries hormones, vitamins, and drugs.

• Fibrinogen (4%): Turns into fibrin to form blood clots and heal wounds.

• Globulins (30-40%):

• Carry hormones like androgens and estradiol.

• Transport fatty acids and prevent harmful cholesterol buildup.

• Fight infections by attacking bacteria, viruses, and parasites.

• Assist in blood clotting.

• Support liver and kidney function.

Figure 1: Blood proteins include albumin, fibrinogen, and globulins. Most are made in the liver, except gamma globulins, which are made by B lymphocytes. Albumin makes up 55-60% of plasma proteins and helps keep fluid in blood vessels and transport substances. Fibrinogen makes up 4% and helps form blood clots. Globulins are divided into three types, each with a specific role: alpha (α), beta (β), and gamma (γ). 

Globulins are divided into three groups by electrophoresis: alpha (α), beta (β), and gamma (γ) that are organized into various subtypes, including carrier proteins, enzymes, complements, clotting factors, and immunoglobulins (antibodies) . 

Hemoglobin Synthesis

In the bone marrow, stem cells called erythroblasts make messenger RNA (mRNA) from specific globin genes. This mRNA helps produce hemoglobin, a protein in red blood cells (RBCs) that carries oxygen. Hemoglobin is made by combining two alpha chains with either two beta or gamma chains. This allows hemoglobin to bind to four oxygen molecules and deliver them to the body for energy.

Figure 2: Globin chains (alpha and beta subunits) are made in the red blood cell’s cytoplasm to form hemoglobin. At the same time, heme is produced in the mitochondria and then moves to the cytoplasm to join with the globin chains, forming hemoglobin.

Acute-Phase Reactants and Transporter Proteins for Toxic Cellular Byproducts In the Circulation

The α globulin group includes proteins like antitrypsin, macroglobulin, and haptoglobin. These proteins increase during inflammation, especially when the kidneys lose proteins in the urine (nephrotic syndrome). Haptoglobin clears damaged red blood cells and rises when oxygen levels drop, which can harm organs and cells.

The β globulin group includes transferrin and complement proteins (C3, C4, C5). Transferrin moves iron after red blood cells break down. High β globulin levels may signal severe iron deficiency.

The γ globulin group contains antibodies like IgG, IgA, IgM, IgE, and IgD. IgG is the most common and fights bacteria and viruses. High IgG levels can cause inflammation, tissue damage, and overstimulation of the immune system, leading to higher levels of pathogens, cancer cells, and toxins.

Figure 3: Immunoglobulins (Ig) are proteins secreted by or present on the surface of B lymphocytes. They are assembled from identical pairs of heavy and light chains connected by a disulfide bond. The variable N-terminal regions are the fragment antigen-binding (Fab) portion. The constant domains interact with the fragment crystallizable (Fc) receptors on the effector cells.

Globulin Formation and Regulation 

The liver makes most globulins, except gamma globulins, which are made by B lymphocytes in white blood cells and become immunoglobulins (Ig). The bone marrow, spleen, and other tissues also produce globulins. Bone marrow creates immune cells to fight infections.

B lymphocytes come from stem cells in the bone marrow, which also produce red blood cells, platelets, and white blood cells. These stem cells become myeloid or lymphoid cells. Myeloid cells form certain white blood cells, while lymphoid cells produce T and B lymphocytes and natural killer cells. Most white blood cells (60-70%) are made in the bone marrow, with the rest made in other tissues.

Figure 4: All blood cells come from hematopoietic stem cells, also called hemocytoblasts, which develop into myeloid progenitor cells. Bone marrow, the soft tissue inside bones like the skull, ribs, pelvis, and sternum, turns these cells into immature red blood cells, platelets, and white blood cells (WBCs). WBCs then develop into monocytes, lymphocytes, eosinophils, neutrophils, and basophils.

After leaving the bone marrow, B lymphocytes move to the spleen, where they receive signals like B-cell activating factor(BAFF). These signals help B cells create B-cell receptors (BCRs) displayed as IgM, marking them as immature. When a BCR detects a pathogen, the B cell activates and becomes a plasma cell that produces antibodies.

Globulin production and function depend on several factors:

• Fluid balance in blood and cells.

• The liver’s ability to make proteins.

• The kidneys’ ability to filter blood and keep proteins.

• The number of globulin-binding receptors on cells.

• The presence of harmful microbes, immune cells, or cancerous cells affecting white blood cell death and immune function.

• Lifestyle factors like stress and poor sleep, which disrupt globulin production.

The kidneys filter most globulins except immunoglobulins (Ig) by processing 180 liters of blood daily. Lymphatic tissues, like the spleen, lymph nodes, and tonsils, remove damaged B cells and Ig:

• Tonsils trap pathogens from the mouth or nose.

• Peyer’s Patches in the small intestine monitor gut bacteria and fight infections.

• Appendix supports immune health and gut balance.

Balancing globulin production and removal reduces inflammation, prevents immune attacks, and lowers the risk of autoimmune diseases, infections, cancer, and organ damage.

Clinical Significance of High Globulin Blood Levels

Hyperglobulinemia happens when there are too many globulins (proteins like alpha, beta, and gamma globulins) in the blood. This can occur if the liver makes too many proteins, the spleen produces too many antibodies, or the kidneys lose proteins in urine. It is linked to inflammation and changes in metabolism and the immune system caused by tissue or cell damage.

Dehydration

Dehydration increases globulin levels because the liver makes more of this protein when the body lacks water. Without enough water, cells shrink, lose function, and are more prone to damage. This allows harmful substances from damaged cells to enter the blood.

Common causes of dehydration include:

• Severe burns

• Diarrhea or vomiting

• Overuse of diuretics or laxatives

• Heavy sweating from exercise, fever, or heatstroke

• Not drinking enough water

• Heavy periods or blood loss (from surgery, trauma, or blood donation)

• Chronic inflammation or rapid red blood cell breakdown (worsened by dehydration)

Figure 5: Osmosis is the movement of water in and out of cells based on solute concentration. In hypotonic cells, there’s more solute inside, so water moves in. In isotonic cells, the solute concentration is the same inside and outside, so water moves in and out equally. In hypertonic cells, there’s less solute inside, causing water to move out.

Dehydration Leads to Dysbiosis 

Dehydration increases osmotic pressure, lowers blood flow to organs, and disrupts gut bacteria. The gut bacteria aid digestion, nutrient absorption, and waste removal. With less blood flow, digestion slows, waste builds up, and gut bacteria become unbalanced, leading to nutrient shortages and undigested food in the gut and blood.

Figure 6: A healthy gut microbiome is key to good digestion and metabolism. When healthy gut bacteria decrease (dysbiosis), it can disrupt metabolism, lower energy production, and increase inflammation and harmful substances in the body.

Dysbiosis Leads to Metabolic Disorders and Atherosclerosis-Induced Vascular and Peripheral Tissue Inflammation

Undigested food in the blood harms red blood cells (RBCs), reducing oxygen delivery and causing cell damage. The liver responds by making more globulins to remove toxins, but this triggers inflammation and creates harmful substances. These changes lower fat metabolism, forcing the liver to break down muscle for glucose, which raises blood sugar.

High blood sugar makes hemoglobin bind to glucose, reducing oxygen to tissues. Harmful molecules (ROS) damage cholesterol, forming oxysterols that cause clots and repair vessel damage. Over time, this leads to blocked arteries (atherosclerosis).

High globulin levels (hyperglobulinemia) cause chronic inflammation, worsen atherosclerosis, and harm organs, leading to poor blood flow and organ damage.

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Figure 7: Rising globulin levels in the blood are closely associated with reduced arterial blood flow, excess fat, and scar tissue deposition, and clot formation that mount an inflammatory process that reduces blood flow to various organs.  

Stress

When the body faces stress—like trauma, surgery, or serious health issues—it releases stress hormones such as cortisol and catecholamines (epinephrine and norepinephrine). These hormones cause several changes:

• Muscle Breakdown: The body breaks down muscle protein into glucose for energy.

• Metabolism Issues: Fat and protein metabolism slow, causing buildup that triggers inflammation.

• Increased Fat Storage: Extra fat accumulates in organs and tissues, making it harder to produce energy.

• Hormone Changes: More thyroid and growth hormones are produced.

• Health Problems: Conditions like atherosclerosis and anemia from inflammation occur, raising albumin levels in the blood.

Chronic sleep deprivation increases stress and raises globulin levels. High cortisol levels at night reduce insulin, leading to higher blood sugar. This signals the liver to produce more thyroid hormones (T4 and T3), helping the body use energy better.

Chronic Stress Leads to Hormonal Imbalances 

Chronic stress can cause hyperthyroidism and raise globulin levels, leading to more energy use and harmful byproducts in the liver. Stress also causes inflammation and triggers proteins that remove waste from damaged cells, preventing white blood cells from dying. This can lead to autoimmune diseases like Graves’ disease and organ failure. A study found 15-76% of people with untreated thyroid problems had abnormal globulin levels. Treatment that lowers thyroid antibodies improved liver function by 70%. Monitoring thyroid and liver health is important for understanding globulin changes and identifying issues like heart disease and organ damage.

Diet

Diet plays a crucial role in managing protein metabolism and globulin synthesis. Usually, the liver increases globulin synthesis in response to the increased availability of amino acids in the circulation following a protein-rich meal. 

Animal Protein Versus Plant-Forward Diet

Animal proteins like meat, eggs, and milk provide essential amino acids, including methionine (Met), which is needed daily at 13 milligrams per kilogram of body weight. Too much methionine from foods like meat, nuts, and oils can increase glutathione (GSH), boosting liver function and raising globulin levels. This also increases an enzyme called gamma-glutamyltransferase (GGT), which breaks down GSH and releases hydrogen sulfide (H2S), potentially damaging cells and causing inflammation. A lack of B vitamins, zinc, and iron can make this worse. Eating B-vitamin-rich foods, reducing methionine intake, staying hydrated, and supporting gut health can help balance GSH and globulins.

Figure 8: Eating too much methionine from animal products and nuts can lower antioxidant levels (glutathione) and increase harmful hydrogen sulfide. A lack of B vitamins, zinc, and iron from plants also lowers glutathione, raises hydrogen sulfide, and causes inflammation, which can raise blood globulin levels . 

Heme-Iron Versus Non-Heme-Iron Rich Diet 

There are two types of iron in food: heme and non-heme. Non-heme iron is found in plant foods like grains, beans, and vegetables, while heme iron is in animal products like meat and fish. Heme iron is absorbed better by the body, and red meat has more of it than white meat. Eating meat helps the body absorb both types of iron.

Heme iron makes up most of the iron used by the body, helping the liver produce transferrin to move iron. In Western diets, most iron comes from heme, even though it’s eaten less. A diet high in heme iron can affect liver function and help infections and cancer cells grow.

Figure 9 : The protein heme in meat fuels cancer cell progression and albumin synthesis. Compared to normal cells, cancer cells increase the expression of heme transporters, such as albumin, enabling free heme uptake from the bloodstream and regulating inflammatory processes. 

Liver Toxins

Chronic or excess use of recreational drugs, such as nicotine and alcohol, can reduce blood flow to various organs, alter metabolic pathways, and increase globulin synthesis. 

Smoking reduces blood flow to organs and raises harmful molecules that damage the liver. Cadmium in nicotine disrupts liver functions, lowers protein production, and causes inflammation, raising globulin levels. Long-term smoking can also weaken the immune system and lower globulin levels.

Alcohol can change liver enzymes and increase harmful chemicals, which lower antioxidants and raise globulin levels. Studies show avoiding alcohol helps the liver heal and balance globulin levels.

Pharmaceutical Medications

Long-term use of certain drugs can harm the liver and increase globulin levels. These drugs use up iron and oxygen, affecting other organs. Drugs that can damage the liver and cause heat-related damage include:

• Corticosteroids, synthetic hormones, NSAIDs

• Statins and cholesterol-lowering meds

• Acetaminophen (paracetamol)

• Antibiotics, antimalarials, antifungals, and antivirals

• Opioids

• Chemotherapy drugs (e.g., busulfan)

• Vitamin A (retinoids)

• Cocaine and methamphetamines

Drug-induced liver injury (DILI) is a major cause of liver failure and is linked to abnormal globulin levels. It is a common reason for drug recalls. There are two types of DILI: intrinsic and idiosyncratic.

• Intrinsic DILI is predictable. For example, taking over 7.5 grams of acetaminophen at once can harm the liver, and the standard dose may raise liver enzymes in some people.

• Idiosyncratic DILI is unpredictable, with symptoms appearing weeks to months after drug use. It makes up 10-15% of liver failure cases in the U.S. Changes in gut bacteria can increase reactions to drugs, causing allergies. Using the drug repeatedly raises the risk of liver damage.

DILI often looks like a viral liver infection and is hard to diagnose without skin symptoms, like jaundice or hives. A liver biopsy may not always help.

Figure 10: Drug-Induced Liver Injury. The accumulation and metabolism of drugs in the liver can cause various pathophysiological complications that dysregulate the synthesis of various globulins. 

Clinical Significance of Low Globulin Blood Levels

Hypoglobulinemia is when blood globulin levels are too low. This can happen because of:

• Reduced production in the liver and immune cells

• Increased loss of globulins in the urine through the kidneys

• Increased destruction of B lymphocytes in the lymphatic system, spleen, lymph nodes, or other lymphoid tissues like the tonsils, small intestine, or appendix.

Hormonal Imbalances 

Low globulin levels can affect hormone transport in the body. Globulins like sex hormone-binding globulin (SHBG), thyroxine-binding globulin (TBG), and corticosteroid-binding globulin (CBG) carry hormones such as sex hormones, thyroid hormones, and stress hormones.

Low SHBG can cause:

• Fluid retention

• Weight gain

• More muscle

• Mood swings

• Acne

• Sexual issues

• Enlarged breasts

In women, it can lead to ovary problems, irregular periods, infertility, early menopause, and PCOS.

Low TBG can raise free T4 levels, which lowers thyroid hormone production and increases energy.

Low CBG raises free cortisol, which affects stress response and increases the risk of mood disorders, inflammation, infections, autoimmune diseases, cancer, heart disease, and organ failure.

Dysregulated Metabolism 

Low globulin levels, especially beta-globulins and lipoproteins, can make it harder for the body to move fat and lipids, raising triglycerides and bad cholesterol. The liver produces more energy but also increases glucose, breaks down muscle, stores fat, and lowers HDL cholesterol, which helps clear cholesterol. Fewer LDL receptors in the liver mean less cholesterol is removed from the blood. Over time, low globulin levels can lead to excess fat in the blood, causing gallstones, low red blood cell function, and damage to cells, blood vessels, and the immune system, raising the risk of infections, cancer, and autoimmune diseases.

Multiorgan Failure 

Low globulin levels can cause fat buildup in organs, making them work less efficiently. For example, the pancreas produces fewer hormones, leading to diabetes, fatty liver, obesity, and other problems. Fat in the liver affects protein production and metabolism, forcing the body to focus on healing. Chronic liver inflammation can cause scarring and lead to non-alcoholic fatty liver disease (NAFLD), which disrupts normal functions. Low globulin and NAFLD can also make the body more sensitive to drug side effects.

Figure 11: Chronic liver dysfunction dysregulates metabolic pathways and energy harvesting, resulting in vital nutrients shifting towards clearing out tissue debris and repairing wounds, but away from the body maintaining normal physiologic functions. Chronic liver inflammation damages the structure and function of the organ, resulting in excess scar tissue, clot formation, and, eventually, failure. 

NAFLD lowers globulin production and increases fat in the kidneys, affecting fluid balance, vitamin D, and red blood cell production. Kidney problems can cause the loss of water, minerals, and proteins in urine, leading to dehydration and low globulin. Nephrotic syndrome can occur at any age and worsen with drugs or toxins that weaken the immune system. In lupus, the body attacks its own kidneys, damaging them and harming kidney function. Low globulin levels can lead to organ failure.

Prevalence & Significance of Abnormal Globulin Blood Levels 

Abnormal globulin levels are linked to liver and kidney problems, which are becoming more common. In 2016, liver disease was the 8th and 12th leading cause of death in the U.S. and globally. Non-alcoholic fatty liver disease (NAFLD) is now the most common type of liver disease. Chronic kidney disease (CKD) in the U.S. increased from 8.5% in 2000 to 11.2% in 2020. CKD worsens with age and conditions like high blood pressure, diabetes, and obesity.

Programs like the Kidney Early Evaluation Program (KEEP) have helped detect CKD early, but advanced cases are still increasing. CKD affects certain groups more, with non-Hispanic Black people having the highest rates (18.9%) and Hispanics at 12%. People with lower incomes, less education, and those on government health insurance have higher CKD rates due to limited healthcare access and more health problems.

Conclusion 

Globulin is an important protein that helps show how well a person is hydrated, nourished, and how their immune system is functioning. It also plays a role in transporting fats and hormones and protecting the body from infections and inflammation. Abnormal globulin levels can increase the risk of conditions like diabetes, obesity, heart disease, autoimmune disorders, infections, and cancer. Lifestyle changes like staying hydrated, eating a plant-based diet, exercising, managing stress, and adjusting medications can help balance globulin levels. Regular testing can provide valuable information for diagnosing and treating health problems.

Source References and Supplemental Research

1. Busher JT. Serum Albumin and Globulin. In: Walker HK, Hall WD, Hurst JW, editors. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Boston: Butterworths; 1990. Chapter 101. Available from: https://www.ncbi.nlm.nih.gov/books/NBK204/

2. Mathew J, Sankar P, Varacallo M. Physiology, Blood Plasma. [Updated 2023 Apr 24]. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2024 Jan. https://www.ncbi.nlm.nih.gov/books/NBK531504/

3. Fortunati, N. (1999-03-01). “Sex Hormone-Binding Globulin: Not only a transport protein. What news is around the corner?”. Journal of Endocrinological Investigation. 22 (3): 223–234. doi:10.1007/BF03343547. ISSN 1720-8386. PMID 10219893. S2CID 39594500.

4. https://www.sciencedirect.com/science/article/abs/pii/S0168365915006136#:~:text=Regulation%20of%20the%20serum%20half,the%20%20level%20of%20FcRn%20expression.

5. MedlinePlus. (n.d.). Globulin test. [Medline]

6. National Library of Medicine (US). (n.d.). Globulins [MeSH Terms] [PubMed]

7. Hemoglobin Synthesis. sickle.bwh.harvard.edu. Published April 14, 2002. [Harvard Medical School]

8. Grinenko T, Eugster A, Thielecke L, et al. Hematopoietic stem cells can differentiate into restricted myeloid progenitors before cell division in mice. Nat Commun. 2018;9(1):1898. Published 2018 May 15. doi:10.1038/s41467-018-04188-7 [PMC Full Text] [PubMed] [Crosslink]

9. Grinenko T, Eugster A, Thielecke L, et al. Hematopoietic stem cells can differentiate into restricted myeloid progenitors before cell division in mice. Nat Commun. 2018;9(1):1898. Published 2018 May 15. doi:10.1038/s41467-018-04188-7 [PMC Full Text] [PubMed] [Crosslink]

10. MacNee W. Pathology, pathogenesis, and pathophysiology. BMJ 2006;332:1202. 18 May 2006. doi: https://doi.org/10.1136/bmj.332.7551.1202. [BMJ]

11. Watso, J. C., & Farquhar, W. B. (2019). Hydration Status and Cardiovascular Function. Nutrients, 11(8), 1866. https://doi.org/10.3390/nu11081866 [PubMed]

12. Popkin BM, D’Anci KE, Rosenberg IH. Water, hydration, and health. Nutr Rev. 2010;68(8):439-458. doi:10.1111/j.1753-4887.2010.00304.x [PubMed]

13. Billett HH. Hemoglobin and Hematocrit. In: Walker HK, Hall WD, Hurst JW, editors. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Boston: Butterworths; 1990. Chapter 151. Available from: [PubMed]

14. What Is Gut Dysbiosis? Cleveland Clinic. [Cleveland Clinic]

15. Watso, J. C., & Farquhar, W. B. (2019). Hydration Status and Cardiovascular Function. Nutrients, 11(8), 1866. https://doi.org/10.3390/nu11081866 [PubMed]

16. Adiels M, Olofsson SO, Taskinen MR, Borén J. Overproduction of very low-density lipoproteins is the hallmark of the dyslipidemia in the metabolic syndrome. Arterioscler Thromb Vasc Biol. 2008;28(7):1225-1236. doi:10.1161/ATVBAHA.107.160192 [PubMed] [Full Text] [AHA Journals]

17. Yorke E. Hyperthyroidism and Liver Dysfunction: A Review of a Common Comorbidity. Clin Med Insights Endocrinol Diabetes. 2022;15:11795514221074672. Published 2022 Feb 7. doi:10.1177/11795514221074672 [PubMed]

18. Bruinstroop E, van der Spek AH, Boelen A. Role of hepatic deiodinases in thyroid hormone homeostasis and liver metabolism, inflammation, and fibrosis. Eur Thyroid J. 2023;12(3):e220211. Published 2023 Apr 13. doi:10.1530/ETJ-22-0211 [PubMed]

19. Cedars-Sinai Staff. Are animal proteins better for you than plant proteins? Cedars Sinai. January 16, 2019. Accessed September 2, 2024. [Website]

20. Koenig G, Seneff S. Gamma-glutamyltransferase: A predictive biomarker of cellular antioxidant inadequacy and disease risk. Dis Markers. 2015:2015:818570. PMID: 26543300. doi: 10.1155/2015/818570. [PubMed] [Wiley] [PubMed]

21. De Chiara, F., Checcllo, C. U., & Azcón, J. R. (2019). High protein diet and metabolic plasticity in Non-Alcoholic Fatty liver Disease: Myths and Truths. Nutrients, 11(12), 2985. https://doi.org/10.3390/nu11122985 [PubMed]

22. Guoyao Wu; Yun-Zhong Fang; Sheng Yang; Joanne R. Lupton; Nancy D. Turner (2004). “Glutathione Metabolism and its Implications for Health”. Journal of Nutrition. 134 (3): 489–492. doi:10.1093/jn/134.3.489. PMID 14988435 [PubMed] [Crosslink]

23. Ho, P.I.; Ortiz, D.; Rogers, E.; Shea, T.B. Multiple aspects of homocysteine neurotoxicity: Glutamate excitotoxicity, kinase hyperactivation and DNA damage. J. Neurosci. Res. 2002, 70, 694–702. [Google Scholar] [CrossRef] [PubMed]

24. Moll S, Varga EA. Homocysteine and MTHFR Mutations. Circulation. 2015;132(1). doi:https://doi.org/10.1161/circulationaha.114.013311 [AHA Journals]

25. Kruman, I.I.; Culmsee, C.; Chan, S.L.; Kruman, Y.; Guo, Z.; Penix, L.; Mattson, M.P. Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity. J. Neurosci. 2000, 20, 6920–6926. [PubMed]

26. Ho, P.I.; Ashline, D.; Dhitavat, S.; Ortiz, D.; Collins, S.C.; Shea, T.B.; Rogers, E. Folate deprivation induces neurodegeneration: Roles of oxidative stress and increased homocysteine. Neurobiol. Dis. 2003, 14, 32–42. [PubMed]

27. Schwartz S, Ellefson M. Quantitative fecal recovery of ingested hemoglobin-heme in blood: comparisons by HemoQuant assay with ingested meat and fish. Gastroenterology. 1985;89(1):19-26. doi:10.1016/0016-5085(85)90740-1[PubMed]

28. Han O. Molecular mechanism of intestinal iron absorption. Metallomics. 2011;3(2):103-109. doi:10.1039/c0mt00043d [PubMed][Crossref]

29. Krishnamurthy P., Xie T., Schuetz J.D. The role of transporters in cellular heme and porphyrin homeostasis. Pharmacol. Ther. 2007;114:345–358. [PubMed] [Google Scholar]

30. Hooda J, Shah A, Zhang L. Heme, an essential nutrient from dietary proteins, critically impacts diverse physiological and pathological processes. Nutrients. 2014 Mar 13; 6(3):1080-102. doi:10.3390/nu6031080 [Pubmed]

31. West A.R., Oates P.S. Mechanisms of heme iron absorption: Current questions and controversies. World J. Gastroenterol. 2008;14:4101–4110. doi: 10.3748/wjg.14.4101. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

32. Hooda J, Shah A, Zhang L. Heme, an essential nutrient from dietary proteins, critically impacts diverse physiological and pathological processes. Nutrients. 2014;6(3):1080-1102. Published 2014 Mar 13. doi:10.3390/nu6031080 [PubMed]

33. Song Y, Liu J, Zhao K, Gao L, Zhao J. Cholesterol-induced toxicity: An integrated view of the role of cholesterol in multiple diseases. Cell Metab. 2021;33(10):1911-1925. doi:10.1016/j.cmet.2021.09.001 [PubMed][Crossref]

34. Sritharan M (July 2006). “Iron and bacterial virulence”. Indian J Med Microbiol. 24 (3): 163–4. doi:10.1016/S0255-0857(21)02343-4. PMID 16912433. [PubMed]

35. Yi J, Thomas LM, Musayev FN, Safo MK, Richter-Addo GB. Crystallographic trapping of heme loss intermediates during the nitrite-induced degradation of human hemoglobin. Biochemistry. 2011;50(39):8323-8332. doi:10.1021/bi2009322 and RCSB PDB [PubMed]

36. Hubbard SR, Hendrickson WA, Lambright DG, Boxer SG. X-ray crystal structure of a recombinant human myoglobin mutant at 2.8 A resolution. J Mol Biol. 1990;213(2):215-218. doi:10.1016/S0022-2836(05)80181-0 and RCSB PDB [PubMed]

37. Seo YS, Park JM, Kim JH, Lee MY. Cigarette Smoke-Induced Reactive Oxygen Species Formation: A Concise Review. Antioxidants (Basel). 2023;12(9):1732. Published 2023 Sep 7. doi:10.3390/antiox12091732. [PubMed]

38. Kamat, P. K., Mallonee, C. J., George, A. K., Tyagi, S. C., & Tyagi, N. (2016). Homocysteine, Alcoholism, and Its Potential Epigenetic Mechanism. Alcoholism, clinical and experimental research, 40(12), 2474–2481. https://doi.org/10.1111/acer.13234 [PubMed] [EuropePMC]

39. McGill MR, Jaeschke H. Metabolism and disposition of acetaminophen: recent advances in relation to hepatotoxicity and diagnosis. Pharm Res. 2013;30(9):2174-2187. doi:10.1007/s11095-013-1007-6 [PubMed]

40. Ashar U, Desai D, Bhaduri A. Flutamide-induced hepatotoxicity with possible potentiation by simvastatin. J Assoc Physicians India. 2003;51:75-77. [PubMed]

41. Yin LK, Tong KS. Elevated Alt and Ast in an Asymptomatic Person: What the primary care doctor should do?. Malays Fam Physician. 2009;4(2-3):98-99. Published 2009 Aug 31.[PubMed][CrossRef]

42.  Whitcomb DC, Block GD. Association of acetaminophen hepatotoxicity with fasting and ethanol use. JAMA. 1994;272(23):1845-1850. doi:10.1001/jama.1994.03520230055038 [PubMed] [Crossref]

43. Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology. 2010;52(6):2065-2076. doi:10.1002/hep.23937 [PubMed]

44. Hoy SM, Lyseng-Williamson KA. Intravenous busulfan: in the conditioning treatment of pediatric patients prior to hematopoietic stem cell transplantation. Paediatr Drugs. 2007;9(4):271-278. doi:10.2165/00148581-200709040-00008 [PubMed][CrossRef]

45. Geubel AP, De Galocsy C, Alves N, Rahier J, Dive C. Liver damage caused by therapeutic vitamin A administration: estimate of dose-related toxicity in 41 cases. Gastroenterology. 1991;100(6):1701-1709. doi:10.1016/0016-5085(91)90672-8 [PubMed]

46. Guollo F, Narciso-Schiavon JL, Barotto AM, Zannin M, Schiavon LL. Significance of alanine aminotransferase levels in patients admitted for cocaine intoxication. J Clin Gastroenterol. 2015;49(3):250-255. doi:10.1097/MCG.0000000000000056 [PubMed] [Crossref]

47. Kuo CJ, Tsai SY, Liao YT, et al. Elevated aspartate and alanine aminotransferase levels and natural death among patients with methamphetamine dependence [published correction appears in PLoS One. 2012;7(1). doi:10.1371/annotation/3bca7672-2fca-4a7e-942d-cc1b4aaa7b60] [published correction appears in PLoS One. 2012;7(1). doi:10.1371/annotation/85803bd9-3be6-4450-b70f-cd4104b87817]. PLoS One. 2012;7(1):e29325. doi:10.1371/journal.pone.0029325 [PubMed]

48. Larrey D, Pageaux GP. Drug-induced acute liver failure. Eur J Gastroenterol Hepatol. 2005;17(2):141-143. doi:10.1097/00042737-200502000-00002 [PubMed] [Crosslink]

49. Fontana RJ, Hayashi PH, Gu J, et al. Idiosyncratic drug-induced liver injury is associated with substantial morbidity and mortality within 6 months from onset. Gastroenterology. 2014;147(1):96-108.e4. doi:10.1053/j.gastro.2014.03.045 [PMC Full Text] [PubMed] [Crosslink]

50. McGill MR, Jaeschke H. Metabolism and disposition of acetaminophen: recent advances in relation to hepatotoxicity and diagnosis. Pharm Res. 2013;30(9):2174-2187. doi:10.1007/s11095-013-1007-6 [PMC Full Text] [PubMed] [Crosslink]

51. McGill MR, Sharpe MR, Williams CD, Taha M, Curry SC, Jaeschke H. The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation. J Clin Invest. 2012;122(4):1574-1583. doi:10.1172/JCI59755 [PMC Full Text] [PubMed] [Crosslink]

52. Watkins PB, Kaplowitz N, Slattery JT, et al. Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA. 2006;296(1):87-93. doi:10.1001/jama.296.1.87 [PubMed] [Crosslink]

53. Yuan L, Kaplowitz N. Mechanisms of drug-induced liver injury. Clin Liver Dis. 2013;17(4):507-vii. doi:10.1016/j.cld.2013.07.002 [PMC Full Text] [PubMed] [Crosslink]

54. Harshad Devarbhavi, Raj S, Aradya VH, et al. Drug‐induced liver injury associated with stevens‐Johnson syndrome/toxic epidermal necrolysis: Patient characteristics, causes, and outcome in 36 cases. 2016;63(3):993-999. doi:https://doi.org/10.1002/hep.28270 [AASLD]

55. Kaplowitz N. Idiosyncratic drug hepatotoxicity. Nat Rev Drug Discov. 2005;4(6):489-499. doi:10.1038/nrd1750 [PubMed] [Crosslink]

56. Devarbhavi H, Raj S, Aradya VH, et al. Drug-induced liver injury associated with Stevens-Johnson syndrome/toxic epidermal necrolysis: Patient characteristics, causes, and outcome in 36 cases. Hepatology. 2016;63(3):993-999. doi:10.1002/hep.28270 [PubMed][CrossRef]

57. Qu X, Donnelly R. Sex Hormone-Binding Globulin (SHBG) as an Early Biomarker and Therapeutic Target in Polycystic Ovary Syndrome. Int J Mol Sci. 2020;21(21):8191. Published 2020 Nov 1. doi:10.3390/ijms21218191. [PubMed]

58. Chakravarthy V, Ejaz S. Thyroxine-Binding Globulin Deficiency. [Updated 2023 Jul 4]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK544274/

59. Franklyn J, Shephard M. Evaluation of Thyroid Function in Health and Disease. In: Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, de Herder WW, Dhatariya K, Dungan K, Hofland J, Kalra S, Kaltsas G, Kapoor N, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, New M, Purnell J, Sahay R, Shah AS, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, editors. Endotext [Internet]. MDText.com, Inc.; South Dartmouth (MA): Sep 21, 2000. [PubMed]

60. Bruinstroop E, van der Spek AH, Boelen A. Role of hepatic deiodinases in thyroid hormone homeostasis and liver metabolism, inflammation, and fibrosis. Eur Thyroid J. 2023;12(3):e220211. Published 2023 Apr 13. doi:10.1530/ETJ-22-0211 [PubMed]

61. Hill, L. A., Bodnar, T. S., Weinberg, J., & Hammond, G. L. (2016). Corticosteroid-binding globulin is a biomarker of inflammation onset and severity in female rats. Journal of Endocrinology, 230(2), 215-225. Retrieved Oct 12, 2024, from https://doi.org/10.1530/JOE-16-0047

62. Feingold KR. Introduction to Lipids and Lipoproteins. [Updated 2024 Jan 14]. In: Feingold KR, Anawalt B, Blackman MR, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK305896/

63. Levitt DG, Levitt MD. Human serum albumin homeostasis: a new look at the roles of synthesis, catabolism, renal and gastrointestinal excretion, and the clinical value of serum albumin measurements. Int J Gen Med. 2016;9:229-55. [PMC free article] [PubMed]

64. Gatta A, Verardo A, Bolognesi M. Hypoalbuminemia. Intern Emerg Med. 2012 Oct;7 Suppl 3:S193-9. [PubMed]

65. Subbiah V, West HJ. Jaundice (Hyperbilirubinemia) in Cancer. JAMA Oncol. 2016;2(8):1103. doi:10.1001/jamaoncol.2016.1236 [PubMed] [Crossref]

66. Halliwell B., Gutteridge J.M. Role of free radicals and catalytic metal irons in human disease: An overview. Methods Enzymol. 1990;186:1–85. doi: 10.1016/0076-6879(90)86093-B. [PubMed] [CrossRef] [Google Scholar]

67. Tiedge M., Lortz S., Drinkgern J., Lenzen S. Relation between antioxidant enzyme gene expression and antioxidative defense status of insulin-producing cells. Diabetes. 1997;46:1733–1742. doi: 10.2337/diab.46.11.1733. [PubMed] [CrossRef] [Google Scholar]

68. Swaminathan S., Fonseca V.A., Alam M.G., Shah S.V. The role of iron in diabetes and its complications. Diabetes Care. 2007;30:1926–1933. doi: 10.2337/dc06-2625. [PubMed] [CrossRef] [Google Scholar]

69. Wilson J.G., Lindquist J.H., Grambow S.C., Crook E.D., Maher J.F. Potential role of increased iron stores in diabetes. Am. J. Med. Sci. 2003;325:332–339. doi: 10.1097/00000441-200306000-00004. [PubMed] [CrossRef] [Google Scholar]

70. De Valk B., Marx J.J. Iron, Atherosclerosis, and ischemic heart disease. Arch. Intern. Med. 1999;159:1542–1548. doi: 10.1001/archinte.159.14.1542. [PubMed] [CrossRef] [Google Scholar]

71. Furukawa S., Fujita T., Shimabukuro M., Iwaki M., Yamada Y., Nakajima Y., Nakayama O., Makishima M., Matsuda M., Shimomura I. Increased oxidative stress in obesity and its impact on metabolic syndrome. J. Clin. Investig. 2004;114:1752–1761. doi: 10.1172/JCI21625. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

72. Sies H. Oxidative stress: A concept in redox biology and medicine. Redox Biol. 2015;4:180–183. doi: 10.1016/j.redox.2015.01.002. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

73. National Kidney Foundation. Kidney Early Evaluation Program publications. National Kidney Foundation. Accessed September 7, 2024. [NKKF].

74. United States Renal Data System. 2022 USRDS Annual Data Report: Epidemiology of kidney disease in the United States. National Institutes of Health [NIH], National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2022.

75. Levey AS, Eckardt KU, Tsukamoto Y, et al. Definition and classification of chronic kidney disease: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2005;67(6):2089-2100 [PubMed] [Google Scholar]

76. Jiang R., Ma J., Ascherio A., Stampfer M.J., Willett W.C., Hu F.B. Dietary iron intake and blood donations in relation to risk of type 2 diabetes in men: A prospective cohort study. Am. J. Clin. Nutr. 2004;79:70–75. [PubMed] [Google Scholar]

77. Zhao Z., Li S., Liu G., Yan F., Ma X., Huang Z., Tian H. Body iron stores and heme-iron intake in relation to risk of type 2 diabetes: A systematic review and meta-analysis. PLoS One. 2012;7:e41641. [PMC free article] [PubMed] [Google Scholar]

78. Jehn M.L., Guallar E., Clark J.M., Couper D., Duncan B.B., Ballantyne C.M., Hoogeveen R.C., Harris Z.L., Pankow J.S. A prospective study of plasma ferritin level and incident diabetes: The Atherosclerosis Risk in Communities (ARIC) Study. Am. J. Epidemiol. 2007;165:1047–1054. doi: 10.1093/aje/kwk093. [PubMed] [CrossRef] [Google Scholar]

79. Qiu C., Zhang C., Gelaye B., Enquobahrie D.A., Frederick I.O., Williams M.A. Gestational diabetes mellitus in relation to maternal dietary heme iron and nonheme iron intake. Diabetes Care. 2011;34:1564–1569. doi: 10.2337/dc11-0135. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

80. Ascherio A., Hennekens C.H., Buring J.E., Master C., Stampfer M.J., Willett W.C. Trans-fatty acids intake and risk of myocardial infarction. Circulation. 1994;89:94–101. doi: 10.1161/01.CIR.89.1.94. [PubMed] [CrossRef] [Google Scholar]

81. Snowdon D.A., Phillips R.L., Fraser G.E. Meat consumption and fatal ischemic heart disease. Prev. Med. 1984;13:490–500. doi: 10.1016/0091-7435(84)90017-3. [PubMed] [CrossRef] [Google Scholar]

82. Kleinbongard P., Dejam A., Lauer T., Jax T., Kerber S., Gharini P., Balzer J., Zotz R.B., Scharf R.E., Willers R., et al. Plasma nitrite concentrations reflect the degree of endothelial dysfunction in humans. Free Radic. Biol. Med. 2006;40:295–302. doi: 10.1016/j.freeradbiomed.2005.08.025. [PubMed] [CrossRef] [Google Scholar]

83. Mannisto S., Kontto J., Kataja-Tuomola M., Albanes D., Virtamo J. High processed meat consumption is a risk factor of type 2 diabetes in the α-tocopherol, β-carotene cancer prevention study. Br. J. Nutr. 2010;103:1817–1822. doi: 10.1017/S0007114510000073. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

84. Piskin E, Cianciosi D,  Gulec S, Tomas M, Capanoglu E. Iron Absorption: Factors, Limitations, and Improvement Methods. ACS Omega. 2022 Jun 21; 7(24): 20441–20456. doi: 10.1021/acsomega.2c01833 [PMC]

85. Boldt D. H. New Perspectives on Iron: An Introduction. Am. J. Med. Sci. 1999, 318 (4), 207. 10.1097/00000441-199910000-00001. [PubMed]

86. Smirnoff N. Ascorbic Acid Metabolism and Functions: A Comparison of Plants and Mammals. Free Radic. Biol. Med. 2018, 122, 116–129. 10.1016/j.freeradbiomed.2018.03.033. [PubMed]

87. Cory H, Passarelli S, Szeto J, Tamez M, Mattei J. The Role of Polyphenols in Human Health and Food Systems: A Mini-Review. Front Nutr. 2018;5:87. Published 2018 Sep 21. doi:10.3389/fnut.2018.00087 [PubMed]

88. Zhang H, Tsao R. Dietary polyphenols, oxidative stress and antioxidant and anti-inflammatory effects. Curr Opin Food Sci. (2016) 8:33–42. 10.1016/j.cofs.2016.02.002 [CrossRef] [Google Scholar]

89. Hart J. J.; Tako E.; Kochian L. V.; Glahn R. P. Identification of Black Bean (Phaseolus Vulgaris L.) Polyphenols That Inhibit and Promote Iron Uptake by Caco-2 Cells. J. Agric. Food Chem. 2015, 63 (25), 5950–5956. 10.1021/acs.jafc.5b00531. [PubMed]

90. Naghedi-Baghdar, H., Nematy, M., Kooshyar, M. M., Taghipour, A., Sajadi Tabassi, S. A., Shokri, S., Javan, R., & Nazari, S. M. (2018). Effect of a functional food (vegetable soup) on blood rheology in patients with polycythemia. Avicenna journal of phytomedicine, 8(5), 389–398. [PubMed]

91. Kennedy M. How much water you’re actually supposed to drink each day – and why 8 cups isn’t right for everyone. Business Insider. December 14, 2021. [Website]

92. Ballard H. S. (1997). The hematological complications of alcoholism. Alcohol health and research world, 21(1), 42–52. [PubMed]

93. Bradley CS, Erickson BA, Messersmith EE, et al. Evidence of the Impact of Diet, Fluid Intake, Caffeine, Alcohol and Tobacco on Lower Urinary Tract Symptoms: A Systematic Review. J Urol. 2017;198(5):1010-1020. doi:10.1016/j.juro.2017.04.097 [PubMed] [PMC Full Text] [Full Text]

94. Polhuis KCMM, Wijnen AHC, Sierksma A, Calame W, Tieland M. The Diuretic Action of Weak and Strong Alcoholic Beverages in Elderly Men: A Randomized Diet-Controlled Crossover Trial. Nutrients. 2017;9(7):660. Published 2017 Jun 28. doi:10.3390/nu9070660 [PubMed]

95. Intermittent Fasting: What is it, and how does it work? (2024, June 20). Johns Hopkins Medicine. [Full Text]

96. Rochon J, Bales CW, Ravussin E, et al. Design and conduct of the CALERIE study: comprehensive assessment of the long term effects of reducing intake of energy. J Gerontol A Biol Sci Med Sci 2011;66:97-108. [PubMed] [PMC]

97. Most J, Gilmore LA, Smith SR, Han H, Ravussin E, Redman LM. Significant improvement in cardiometabolic health in healthy nonobese individuals during caloric restriction-induced weight loss and weight loss maintenance. Am J Physiol Endocrinol Metab 2018;314:E396-E405. [PubMed] [APS] [PMC]

98. Martin CK, Bhapkar M, Pittas AG, et al. Effect of calorie restriction on mood, quality of life, sleep, and sexual function in healthy nonobese adults: the CALERIE 2 randomized clinical trial. JAMA Intern Med 2016;176:743-52. [PubMed] [JAMA] [PMC]

99. Heilbronn LK, de Jonge L, Frisard MI, et al. Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: a randomized controlled trial. JAMA 2006;295:1539-48. [PubMed] [JAMA] [PMC]

100. Ravussin E, Redman LM, Rochon J, et al. A 2-year randomized controlled trial of human caloric restriction: feasibility and effects on predictors of health span and longevity. J Gerontol A Biol Sci Med Sci 2015;70:1097-104. [PubMed] [Oxford Academic] [PMC]

101. Kristi Wempen, R.D.N. “Are You Getting Too Much Protein?” Mayo Clinic Health System, Mayo Clinic Health System, 14 Dec. 2023. [Full Text]

102. Gremese, Elisa, et al. “Serum Albumin Levels: A Biomarker to Be Repurposed in Different Disease Settings in Clinical Practice.” MDPI, Multidisciplinary Digital Publishing Institute, 17 Sept. 2023, [Free Full Text]

103. Hirshkowitz M, Whiton K, Albert SM, et al. National Sleep Foundation’s sleep time duration recommendations: methodology and results summary. Sleep Health. 2015;1(1):40-43. doi:10.1016/j.sleh.2014.12.010 [PubMed] [Elsevier]

104. Hamasaki H. The Effects of Mindfulness on Glycemic Control in People with Diabetes: An Overview of Systematic Reviews and Meta-Analyses. Medicines (Basel). 2023;10(9):53. Published 2023 Sep 7. doi:10.3390/medicines10090053 [PubMed]

105. Pascoe MC, Thompson DR, Jenkins ZM, Ski CF. Mindfulness mediates the physiological markers of stress: Systematic review and meta-analysis. J Psychiatr Res. 2017;95:156-178. doi:10.1016/j.jpsychires.2017.08.004 [PubMed] [Elsevier]

106. Nephrol I, Gupta R, Maheshwari V (2014) Impact of smoking on microalbuminuria and albumin creatinine ratio in non-diabetic normotensive  smokers. 24(2):92-96 [PubMed] doi: 10.4103/0971-4065.127893

107. Rutledge S, Asgharpour A (2020) Smoking and Liver Disease. 16(12): 617-625 [PubMed]

108. University of California, San Francisco Health. Albumin blood (serum) tests. [Google]

109. Immanuel, S., Bororing, S. R., & Dharma, R. S. (2006). The effect of aerobic exercise on blood and plasma viscosity on cardiac health club participants. Acta medica Indonesiana, 38(4), 185–188. [PubMed] [Free Full Text PDF]

110. El-Sayed M. S. (1998). Effects of exercise and training on blood rheology. Sports medicine (Auckland, N.Z.), 26(5), 281–292. https://doi.org/10.2165/00007256-199826050-00001 [PubMed] [Springer]

111. Kilic-Toprak, E., Ardic, F., Erken, G., Unver-Kocak, F., Kucukatay, V., & Bor-Kucukatay, M. (2012). Hemorheological responses to progressive resistance exercise training in healthy young males. Medical science monitor : international medical journal of experimental and clinical research, 18(6), CR351–CR360. https://doi.org/10.12659/msm.882878 [PubMed] [ISI] [PubMed]