Total Protein: Diagnostic Significance and Clinical Insights

Authors: Payal Bhandari, M.D.

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




Total Protein 


Blood proteins help your body produce substances such as hormones, enzymes, and antibodies necessary to function. Total protein consists of two major types: Albumin and Globulins. Albumin is produced in the liver. Its primary function is to keep blood from leaking out of blood vessels and move minerals, vitamins, hormones, medicines, and other important substances throughout the body. Globulins are made by the immune system and the liver to help fight infection and move nutrients throughout the body. Abnormally low protein levels can indicate liver, gut, and/or kidney dysfunction linked to problems with digestion and absorption of certain types of proteins as well as malnutrition. Abnormally high protein levels can be a sign of inflammation, infection or bone marrow disorder.



Typical Adult Range


Ranges and thresholds can vary due to: 

(1) Lab-specific equipment, techniques, and chemicals, and 

(2) Patient demographics, including age, sex, and ethnicity.





Key Insights


Proteins are important for your body, helping to build tissues, transport substances, and support chemical reactions. Blood contains two main proteins: albumin and globulins. The body constantly breaks down and rebuilds proteins using amino acids, which come from food. The total protein test measures your protein levels and shows how well organs like the liver, kidneys, and small intestine are working. High protein levels may suggest digestive problems, while low levels may signal malnutrition or absorption issues. Monitoring protein levels can help detect health problems like cancer, infections, and heart disease.


What is the Total Protein Test? 

The total protein test measures two main proteins in the blood: albumin and globulins. Normal ranges for total protein can vary by lab, but they usually fall within a specific range. If the levels are too high or too low, it could indicate problems with the liver, kidneys, or small intestine, which affect protein processing. Checking total protein levels helps doctors understand a person’s overall health and nutrition, and can be used to diagnose and treat various health issues.


Amino Acids are the Building Blocks of Protein

Proteins make up much of the body, including collagen in bones, creatine in muscles, hemoglobin for oxygen transport, and enzymes that help chemical reactions. Proteins are also important for cell growth, healing, communication, and energy production (ATP).

Proteins are made from chains of amino acids. Each protein is unique based on the types and order of amino acids and how the chain interacts with itself and its surroundings. Amino acids have three parts: an amino group (-NH2), a carboxyl group (-COOH), and a side chain (R). There are hundreds of amino acids, but only twenty are essential for human protein building. Since the body can’t make these, they must come from food.


Figure 1. Proteins are repeating amino acid units arranged in unique patterns and connected by a peptide bond . Amino acids are made up of an amino group (-NH2), a carboxyl group (-COOH), and a differing side chain (R) that are connected by peptide bonds.



Figure 2: Proteins take on a myriad of forms and functions, such as cell signaling receptors, cell structure, transporters (e.g., for oxygen and carbon monoxide), and ion pumps and channels. 



Regulation of Protein Metabolism and Synthesis


The liver plays a key role in producing proteins, breaking down food for energy, and making important substances like hormones and enzymes. Its function and the amount of protein in the blood can be affected by things like diet, medications, drugs, lifestyle, stress, and health problems.


Cellular Respiration 

The body’s ability to make and use energy impacts how proteins are managed. Energy mainly comes from adenosine triphosphate (ATP), produced in cell mitochondria from food. Blood cells like red blood cells, platelets, and white blood cells don’t make ATP. Instead, they help tissues function and respond to damage when energy use is off, causing heat and reactive oxygen species (ROS).

When energy is low (like during fasting or intense exercise), or the brain needs more energy than the body, fat and muscle protein (like creatine) are broken down for fuel in a process called ketogenesis. Since the brain can’t use fat directly for energy, the fat must first be converted into glucose. Ketogenesis increases ATP from glucose, making the brain less reliant on carbs and proteins. It also helps stabilize protein metabolism, store fat, get rid of toxic proteins, and reduce ROS. Without ketogenesis, energy use and hormone balance are thrown off, which can lead to cell damage and genetic mutations.


                        


Figure 3: Cellular respiration is how cells turn food into energy. It produces molecules like ATP, NADH, and FADH, and releases carbon dioxide (CO2) as waste. The most energy is made in the mitochondria through the electron transport chain. Oxygen helps pull electrons, creating a proton gradient that makes ATP. Electrons move through carriers, losing energy until ATP is formed.


                          

Figure 4: Fat cells, liver, and muscle cells break down fatty acids, amino acids, glycerol, and other substances to control the production of glucose and ketones in the liver. Ketones provide an alternative energy source during long fasting, intense exercise, low insulin levels, high glucagon production, or when the brain needs more energy than the rest of the body. Ketone production generates much more energy (34 ATP) than glucose production (2 to 4 ATP). This process is strongly influenced by the body’s sleep-wake cycle.


Dietary Protein Metabolism 

Unlike fat, the body can’t store protein. Instead, it breaks down protein into amino acids, which are used to build new proteins. Each day, the body breaks down and builds about 250 grams of protein. Most of the protein we eat is not used for energy but is turned into glycogen and stored as fat.


Figure 5: Amino acids derived from food and muscle protein metabolism are placed into a “pool” and used to form new proteins and other nitrogen-containing compounds. 


When we chew food, bacteria in the mouth react with saliva. About 40% of the nitrates and nitrites in protein turn into nitric oxide, which helps keep arteries flexible, manage blood pressure, and protect blood vessels. The rest of the protein moves down the esophagus to the stomach, where stomach acid and the enzyme pepsin break it down into amino acids. This helps mix the food into chyme, which moves to the small intestine.

Bacteria like Veillonella, Neisseria, and Lactobacillus help in protein digestion by:

  • Releasing enzymes that break down proteins and create energy.

  • Producing nitric oxide.

  • Metabolizing vitamins.

  • Breaking down fiber into short-chain fatty acids like acetate, propionate, and butyrate.

  • Stimulating the pancreas to release enzymes and neutralize stomach acid, protecting the gut lining.

Figure 6: Plant-based proteins contain nitrates and nitrites, which healthy bacteria turn into nitric oxide (NO) in the mouth, small intestine, and skin. This helps improve blood flow, lower blood pressure, and protect tissues. NO keeps arteries flexible, helps nerve cells communicate, and reduces inflammation, infection, and cancer.


                               

Figure 7: When you eat protein, bacteria, stomach acid (HCl), and enzymes break it down into amino acids, nitrates, and nitrites, which go to the liver and organs. Chemicals from the pancreas and small intestine protect the gut lining from damage. Without this, harmful substances can leak into the bloodstream, causing “leaky gut syndrome.”



Healthy gut bacteria, digestive enzymes, and hydrochloric acid (HCl) are essential for making nitric oxide and properly digesting food. If these are lacking, undigested food particles (like proteins, fats, and carbs) can enter the bloodstream. White blood cells treat these particles as invaders and attack them by releasing inflammatory proteins (cytokines, chemokines, and antibodies) and reactive oxygen species (ROS, or heat). This heat can damage cells. To stop bleeding, platelets and smooth muscle cells help clear the damage, create scar tissue, and form new blood vessels, a process called atherosclerosis.


          

Figure 8: High protein levels in the blood can lead to undigested food and tissue debris that block blood flow, preventing red blood cells from oxygenating tissues. Atherosclerosis is an inflammation that causes fat and scar tissue buildup in blood vessels, raising blood pressure and disrupting blood flow. If untreated, it can harden and thicken blood vessels, damaging organs like the heart, pancreas, and legs.



Stress from factors like trauma, surgery, or illness can change how the body uses energy. The body relies more on glucose and stops producing ketones. Stress hormones like cortisol break down muscle and raise blood acidity, making it harder to burn fat and causing fat storage. For example, lack of sleep increases cortisol, which breaks down glucose and releases insulin for energy. Chronic stress can damage the pancreas, raise blood sugar, and reduce oxygen delivery to tissues, harming cells. The body uses glucose to protect against low oxygen and thyroid hormones to help with protein and cell production.

The thyroid and liver are key for regulating body functions. T4, an inactive thyroid hormone, is converted to active T3, which helps fight inflammation and protect cells. Monitoring thyroid and liver function is important for overall health and treatment.

Clinical Significance of Monitoring Total Protein Blood Levels

Non-alcoholic fatty liver disease (NAFLD) is a common cause of abnormal protein levels in the blood. It ranges from fat buildup in the liver to more serious conditions like NASH, fibrosis, and cirrhosis. NAFLD is linked to insulin resistance and diabetes. Extra fat in the liver reduces protein production and increases harmful molecules (ROS), which damage gut bacteria. This causes digestion problems, poor nutrient absorption, and inflammation, raising blood protein levels.


Figure 9: Chronic liver damage can cause abnormal protein levels in the blood. Inflammation redirects nutrients to heal the liver, instead of supporting normal body functions. This leads to scar tissue, clots, and eventually liver failure.

 

Figure 10: A healthy gut microbiota is key for digestion and metabolism. When good bacteria decrease (dysbiosis), it disrupts metabolism, reduces energy, and causes inflammation, raising harmful proteins in the blood.



High Total Protein Blood Level

High total protein levels (hyperproteinemia) can occur when the body focuses on repairing damage and preventing bleeding. This can cause the immune system to attack the body’s own tissues and activate infections in the gut. If not treated, high protein levels may lead to autoimmune diseases, infections, heart problems, cancer, and organ failure. Inflammation can worsen from dehydration, medications, poor diet, stress, or other health issues. Hormones from pregnancy or treatments like steroids can also increase inflammation and protein levels.


Low Total Protein Blood Levels 

Low total protein levels (hypoproteinemia) usually suggest the liver is working well. But in advanced liver disease, like cirrhosis, long-term problems with protein production can lower these levels. Other factors, such as heavy use of substances like nicotine or alcohol, prolonged fasting, a diet low in plant proteins, or gut imbalances, can also decrease protein levels. This can lead to dehydration, disrupting water, minerals, vitamins, and hormones, and affect metabolism and waste removal. Low protein levels can cause swelling and increase inflammation in the body.


Prevalence & Significance of Abnormal Protein Blood Levels  

 High or low total protein blood levels are linked to liver problems, protein metabolism, and nitric oxide. Liver diseases are increasing worldwide, with NAFLD (non-alcoholic fatty liver disease) being the leading cause. NAFLD occurs when the liver struggles to process excess fat and protein. If it leads to liver damage, it becomes NASH, a more serious condition. About 25% of people in the U.S. have NAFLD.

NAFLD and liver biomarkers, like total protein, are influenced by factors like environment, ethnicity, and genetics. Hispanic Americans, especially those of Mexican descent, have a higher risk of NAFLD. In short, total protein levels are affected by lifestyle, ethnicity, and genetics. While we can’t change genetics, improving lifestyle can help protect liver health.


Conclusion 

Total protein is an important marker of overall health and nutrition. Proteins are essential for many body functions. For example, albumin, the main protein in blood vessels, helps control fluid balance, blood pressure, blood flow, and nutrient transport. Extremely high or low protein levels can signal serious health issues, such as heart disease, autoimmune disorders, infections, cancer, or organ failure. To maintain healthy protein levels, it’s important to stay hydrated, eat a plant-based diet, try intermittent fasting or a low-calorie intake, exercise regularly, manage stress, and adjust medications as needed. Regularly checking protein levels can help identify health problems and guide treatment.


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