Red Eye

                                                                    Red Eye

                                                     PKGhatak, MD

Eyes develop from the forebrain as an extension of the central nervous system but mystics believe eyes are portals to the soul. Some others claim they can judge a man whether is innocent or guilty by looking into his eyes. Poets, writers and musicians love to associate eyes with all the beautiful things in this universe. Eyes are really remarkable by any measure.

But the physicians see the eyes as specialized organs but like other organs, they are subject to infection and diseases.

The tiny blood vessels on the surface of the layer of the eye are colorless and the underlying layer is called the sclera, which is the white of the eye. In the center of the sclera is a transparent cornea through which light passes without distortion to the retina where the process of vision begins.

Eyes turn red due to congestion of conjunctival blood vessels or actual rupture of blood vessels. The oxygen of air binds with hemoglobin, separated by the thin layer, and so bleeding or congestion of the conjunctiva looks so red. Some call it bloodshot eyes, commonly seen in deprived students before examinations, or those who had too much to drink at a fraternity party.

Red eyes are common in conjunctivitis, keratitis (inflammation of the cornea), corneal scratches, foreign bodies in the eyes, glaucoma, subconjunctival hemorrhage, chemical burns, and certain systemic diseases.

Conjunctivitis is of three categories: acute, chronic, and a part of systemic diseases.

Acute conjunctivitis: conjunctivitis can develop acutely from viral or bacterial, parasitic infections, or from chemical irritation like tear gas or pepper spray. Allergic red eyes are a common occurrence in spring and fall. There are many other causes of red eye.

Viruses.

Many viruses can produce conjunctivitis and common among them are Enterovirus, coxsackie, adenovirus, herpes virus, rubella and measles viruses. Rare but locally endemic viruses like Dengue, Hantavirus and Ebola can produce conjunctivitis. Ophthalmic herpes zoster is a serious disease that requires careful medical management.

Adenovirus 8,19, and 37 produce a severe type of acute painful conjunctivitis known as Keratoconjunctivitis. Enterovirus 70 and coxsackievirus A24 produce hemorrhagic conjunctivitis in tropical and subtropical countries. Herpes simplex can cause blisters on the conjunctiva.

Bacterial conjunctivitis.

In adults, a severe form of infection is seen in Neisseria gonorrhea and N. meningitidis infection. Purulent discharges are loaded with bacteria and very contagious. The infection of the eyes spread very rapidly. Before the days of prenatal care, gonococcus eye infection in newborns took place during birth and was a major cause of infant blindness. Children are susceptible to H. influenzae, Streptococcus pneumonia, Staphylococcus and Moraxella conjunctivae.

Chlamydia trachomatis produces recurrent conjunctivitis, scarring of the inner aspect of eyelids and cornea. It is common in the poorest parts of the world. It is an important cause of blindness and it is preventable by the timely administration of antibiotics. Reiter's syndrome is also produced by Chlamydia in young adults. This is a combination of arthritis, conjunctivitis and urethritis.

Chronic Conjunctivitis.

When conjunctivitis persists over 4 weeks, it becomes chronic in nature and the eyelids are infected producing redness along the eyelashes and shedding of flake derbies and swelling of the eyelash margin. Common bacteria causing the chronic infection are Streptococcus and Moraxella.

Allergic conjunctivitis.

Besides pollen, other common causes of allergic conjunctivitis are mascara, contact lens and lens solution, animal dander, molds, mites and cigarette smoke.

Vernal keratoconjunctivitis is an IgE mediated allergic, self limited but recurrent episodes of inflammation of the cornea and conjunctiva.

Dry eyes.

It is commonly seen in the elderly from decreased tear formation. In others chronic inflammation due to autoimmune disease, Sjogren's syndrome, scleroderma, psoriasis and use of cholinergic drugs. The dryness of conjunctiva produces a gritty sensation and burning sensation and produces redness of the eyes.

Subconjunctival hemorrhage. 

It is common in the elderly, particularly those taking Aspirin and blood thinners. Vigorous rubbing of eyes, staining like cough or sneezing ruptures blood vessels of the conjunctiva. Usually, one eye is affected. The patient may be alarmed but it is a benign condition and the blood disappears in a few days.

Transitional causes of red eyes.

Crying spell. hot showers, emotional upset, trauma, eye drops, dust or eyelashes in the eye, frequent touching of eyes.

Parasitic conjunctivitis.

Loiasis.

Loa loa is a nematode, a parasitic worm. Larvae of loa loa enter the human flesh through bites of a female deer fly and mango fly, called Chrysops demidita and C. silacia. The mature worms migrate through the body and at times pass underneath the conjunctiva and produce severe conjunctivitis. WHO estimates about 10 million people suffer from Loiasis.

Acanthamoeba.

It is a protozoan present in soil and tap water. If tap water is used to clean contact lenses then the infection may occur.

Damodex folliculorum. 

It is a mite, lives under the eyelashes and eyebrows. Infestation produces itching, red eyes and shedding of dry skin. It usually becomes chronic.

Toxoplasmosis.

Toxoplasma gondii is a facultative intracellular parasite, infection is usually acquired congenitally and immunosuppressed people can get infected from cat litter. The infection is mainly located in the retina but may also infect the cornea and conjunctiva.

Myiasis.

 A fly that usually feeds on Caribou called Botfly, can bite humans and lay eggs in the wound. Hatched eggs, maggots, feed on living human tissues. Maggots develop into adult worms and migrate throughout the body.  In the eyes, adult worms cause severe conjunctival inflammation, glaucoma and detached retina.  

Systemic diseases.

The following diseases are often associated with eye involvement and the red eye is just a part of them.

 Systemic Lupus Erythematosus, Rheumatoid Arthritis, Scleroderma. Temporal Arteritis, Periarterites Nodosa, Sarcoidosis, Migraine,

Venous obstruction. Central retinal vein occlusion, Superior vena cava obstruction, constrictive pericarditis.

Graves' disease of the thyroid gland. Hyper-viscosity syndrome from multiple myeloma. Sickle cell disease. Serum sickness, Steven-Johnson syndrome, etc.

Glaucoma. Glaucoma is usually seen in the elderly but no group is immune from acquiring it, even a rare congenital form exists. In glaucoma, the hydrostatic pressure of the eyeball exceeds venous pressure resulting in damage of the retinal structure mainly in and around the Macula, a special area of acuity and color vision of the retina. This is a major cause of vision problems and blindness. Glaucoma is effectively treated before much damage has taken place.

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Trace Elements and Human Health

 

                                        Trace Elements and Human Health

                                           PKGhatak, MD

The elements making a human body are of three categories. Elements that are plentiful like carbon, oxygen, nitrogen, hydrogen, etc. These elements form covalent bonds and make up the tissue; the less plentiful elements are sodium. chloride, potassium, etc., which are responsible for maintaining osmotic pressure gradient between cellular and extracellular fluid and finally elements that are rare like zinc, copper, chromium, cobalt, selenium, magnesium, and molybdenum. These trace elements are bio-active substances or parts of many enzymes system responsible for various functions of the body.

In addition, elements found in human tissues are not parts of normal tissue or serve any useful purpose but accumulate in the body due to persistent exposure and often are harmful to the body, for example - lead, arsenic, mercury, etc.

Trace elements and their functions.

The trace elements have similar dietary sources, digestion, absorption and transport systems. The elements differ mainly by the enzyme they form, even then many enzyme systems containing the trace elements participate in a sequence on the same substrate or metabolic process. This is particularly true with copper, zinc and manganese.

There are more than one standard daily requirement numbers - usual daily intake, recommended daily allowance, no adverse effects on a minimum dose, adverse effects on a dose and then various ratios. This also added confusion about the amount safe to take and should be good for the body.

Selenium.

Selenoproteins and selenium containing proteins are required for DNA synthesis, also needed for thyroid hormone production and metabolism. Selenium provides protection against infection.

Selenium exists in two forms: inorganic and organic forms. Most selenium in human tissues is incorporated non-specifically with the amino acid methionine. Skeletal muscle is the major site of selenium storage. Both selenocysteine and selenite are reduced to generate hydrogen selenide, which in turn is converted to selenophosphate for selenoprotein biosynthesis. Selenium is active as an anticancer agent; it prevents ischemic heart disease and selenium has vitamin E like effects on the body.

Daily requirement. 55 to 70 micrograms. Selenium containing food are Brazilian nuts, seafood, animal organs, cereals, shellfish and dairy products.

Chromium.

Chromium in nature exists as trivalent and hexavalent forms. Chromium is a part of the glucose transport protein. For organic processes, trivalent form is required and chromium is present in the enzyme system involved in the catabolism of fatty acids and carbohydrates. It is also required for the synthesis of cholesterol. It is also considered an antioxidant. Excess chromium is considered a risk factor for carcinoma of the lung, and premature atherosclerosis. Chromium poisoning produces GI upset, peptic ulcers, liver and kidney dysfunction and growth retardation in children. It is required for parenteral nutrition. The daily dietary requirement is 35 micrograms for adults.

Manganese.

It is one of the trace element constituents of superoxide dismutase, required for mitochondrial functions and integrity of the cell membrane. It is needed for carbohydrate, cholesterol and protein metabolism, sex hormone production and growth in children. Like many other trace elements, it is required for brain cell development, connective tissue, bones & joints and blood clotting.

Manganese is absorbed in the small intestine through an active transport system and, possibly by diffusion when oral intakes are high. After absorption, some manganese remains free, but most are bound to transferrin, albumin, and plasma protein alpha-2-macroglobulin. Manganese is taken up by the liver and other tissues. The daily requirement is 2 to 2.5 mg for adult males, women need lesser amounts. In poisoning from excess exposure in welding, the alloy industries and agriculture. Excess manganese in the body may produce neurological symptoms including Parkinson's disease. In iron deficiency anemia and liver cirrhosis, the adverse effects of Manganese develop more readily.  Leafy green vegetables, green tea, and whole grains are good dietary sources of chromium.

Molybdenum.

Molybdenum is required for processing DNA and other proteins. Molybdenum is a structural constituent of a cofactor and is required for the function of four enzymes- sulfite oxidase, xanthine oxidase, aldehyde oxidase, and mitochondrial amidoxime reducing component (mARC). These enzymes metabolize sulfur-containing amino acids and heterocyclic compounds including purines and pyrimidines. Xanthine oxidase, aldehyde oxidase, and mARC are involved in metabolizing drugs and toxins.

The kidneys are responsible for Molybdenum excretion. Molybdenum, in the form of molybdopterin, is stored in the liver, kidney, adrenal glands, and bones. Molybdenum deficiency is rare.

Serum levels of molybdenum range from 0.28 ng/mL to 1.17 ng/mL. Daily requirement – 45 to 50 micrograms.
Legumes are the richest sources of molybdenum. Other foods high in molybdenum include whole grains, nuts, and beef liver.

Cobalt.

Cobalt lies in the center of the vitamin B12 molecule. The role of B12 in humans is well known and discussed in an earlier blog (see vitamin B12 blog). Besides its role in RBC, cobalt is required for nerve cell formation, as a neurotransmitter, and for nerve impulse conduction. Food is the main source of cobalt but it can be absorbed through the skin from prolonged contact and by inhalation of contaminated air. Surgical implants containing cobalt can leach and can produce toxicity, produce chronic inflammation from increased production of IL-1 and IL-6 and TNF-alpha from the macrophages.

Toxicity to cobalt results from depression of cellular respiration because of the downregulation of the cytochrome P-450 enzyme. Other enzymes like catalase and aminolaevulinic synthetase involved in tissue respiration are also depressed by cobalt toxicity. Depresses Kreb cycle enzymes decrease energy and metabolism. Cobalt can replace zinc in enzymes like alcohol dehydrogenase and can increase alcohol toxicity. In toxic levels, cobalt interferes with Iodine and may result in thyroid goiter.

Copper.

Enzymes containing copper cuperoenzymes have various functions in the body.  Cuperoenzymes are needed in brain development, immune functions, angiogenesis, skin pigment production. Iron absorption and incorporation of iron into RBC is copper dependent. Copper is an important oxidase enzyme system. Ceruloplasmin, hephaestin and zyklopen are important among them. The iron transport protein - Ferroprotein, depends on these enzymes for a steady supply. Cytochrome C oxidase, required for so many cellular functions, is a copper-containing enzyme system. Copper, zinc superoxide dismutase (CuZnSOD), is an antioxidant enzyme. K562 cells, a human erythroleukemic cell line, can extract copper from ceruloplasmin and incorporate it into CuZnSOD.

Only a small amount of copper is present in the body, and is mainly present in the skeleton and skeletal muscles. The daily requirement of copper for adults is about 900 micrograms. The main dietary sources of copper are seafood, animal organs, nuts, beans and chocolate. A small amount of copper enters food during cooking in copper wares and vinegar, wine added during cooking accelerates copper leaching into food and may cause poisoning. Excess flux used in copper plumbing in the previous generation is another source of copper poisoning. Acute copper poisoning and suicide attempts using copper sulfate are common occurrences. Excess copper is harmful to the body. Copper produces liver disease - acute hepatitis and liver necrosis after ingestion of a large amount. Chronic copper poisoning is seen in an inherited autosomal recessive disease - Wilson disease, from accumulated copper in the liver producing liver cirrhosis, copper deposits on the cornea and other tissues containing ceruloplasmin. An X-linked recessive inherited disease - Menkes disease, (a similar inherited defect like Hemophilia A), is due to the ATP7A gene. Mutated genes produce defects in copper transport, leaving excess copper in the small intestine and renal tubules and at the same time, a deficiency of copper in hair, skeleton, blood vessels, structural abnormalities and nerve cells suffer from deficiency. 

Zinc. 

Zinc is involved in numerous aspects of cellular metabolism. Zinc is part of approximately 100 enzymes and it plays a role in immune function, protein synthesis, wound healing, DNA synthesis, and cell division, lymphocyte proliferation response to mitogen, Immune defects produce abnormal binding of nuclear factor kb and decrease in DNA, decreased production IL-2(interleukin 2) and killer T-Cells. Zn acts as an antioxidant. Zinc deficiency can impair macrophage and neutrophil functions, natural killer cell activity, and complement activity, and normal growth and development. Zinc is required for a proper sense of taste. Humans have no specialized zinc storage system.

The daily requirement of zinc is 9 to 12 mg, excess intake can interfere with copper absorption and anemia.

Zinc deficiency is usually common in India, mostly in breast milk-fed children.  Frequent infections, diarrhea and growth retardation and hypogonadism are presenting symptoms. Excess Zinc in the elderly is not a rare occurrence in these days of megavitamins and heavy doses of mineral intake. It appears that many elders believe - " if 1 microgram is good then 1 gm will be better." Excess Zinc interferes with iron and copper abortion and incorporation of iron in the RBC, and copper-containing enzymes.  Zinc substitution of other trace elements in enzymes results in a poor functioning immune system, and frequent infection.

The gene SLC39A4 defect, either acquired or inherited as autosomal recessive mode, results in a lack of absorption of zinc from the small intestine. The disease is characterized by pustular dermatitis around the mouth and anus, diarrhea, nail dystrophy, and poor health. This condition is known as Acrodermatitis enteropathica.

The buzzword of this generation is Anti Oxidant. Nutritional supplements and various chemicals marketed as antioxidants are sought after substances. It is better to be prudent and a bit skeptical before ingesting chemicals that could poison the brain, liver and kidneys.

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Penicillin Allergy

                                                               Penicillin Allergy

                                                        PKGhatak, MD

Penicillin was the first antibiotic that came into the medical field and it proved far superior to sulfonamides. On the battlefields, Penicillin was the only antibiotic available for the treatment of wound infections.

Soon, Penicillin was prescribed on a wider scale for the public. Reports of allergic reactions and anaphylaxis began to surface, making doctors take a careful history of penicillin allergy before prescribing penicillin.

10 % of patients reported being allergic to penicillin G, penicillin related compounds, and cephalosporins. At present, true penicillin allergy is seen in 3 % of users, and the rest of the reactions are nonallergic minor symptoms.

Molecular basis of Penicillin allergy.

Penicillin is a Dipeptide. The structure of penicillin consists of a beta-lactam ring, a thiazolidine ring, and a side chain of 6 amino acids. The allergenic property of penicillin lies within the β-lactam ring. Penicillin is a Hepten. It binds readily with plasma protein and becomes antigenic in susceptible individuals.

Why do certain people develop a Penicillin allergy:

The adaptive immune system produces IgM (Ig = immunoglobulin) and IgG classes of antibodies; IgA class antibodies in the GI, Respiratory, and Genitourinary tracts. IgE( immunoglobulin E) antibody is produced in the regional lymph nodes draining the location where the offending organism entered the body. However, the antigen must have these characteristics:

1. The antigen must be a small molecule of protein; if the antigen is not a protein, then it must be a Hapten. A hapten binds readily with a protein and becomes an antigen.

2. The antigen must be soluble so that the Dendritic cells can recognize it as a foreign substance.

3. The molecule of antigen has to be small. 

The plasma cells, in the lymph node genome center, switch IgE antibody production under the influence of CD4 and Th2 (thymic 2) cells. A low dose exposure of Penicillin on the Th2 cells produces Interleukin IL-4 and IL-13. Those two Interleukins are the molecular switch for IgM and IgG production. If penicillin exposure is large, then Th1 cells are activated. Th1 cells produce IFN gamma (interferon-gamma), IFN gamma acts as a brake on Th2 cells, and Th2 cells stop producing IgM and IgG antibodies.

Penicillin-induced Hypersensitivities are in two categories. 1. Immediate,

 2. Delayed.

 The reactions are also referred to as Type I to 4 Hypersensitive Reactions.

Immediate Reaction.

Type I. - Immunoglobulin E-mediated immediate reaction, occurs minutes to hours after exposure to the antigen.

Delayed Reaction.

Type II. -  Immunoglobulins IgM and IgG mediated Cytotoxic reaction, occurs 72 hours after exposure.

Type III. - Immune Complex reaction occurs 10 to 12 days after exposure.

Type IV. - Cell-mediated Delayed reaction occurs 4  days after exposure.

Special features of IgE.

IgE differs from other Ig classes of antibody in being locally produced and most abundant in local tissue. IgE has a high affinity for the skin resident Mast cells, FCεRI receptors. IgE also binds to some degree to eosinophils and basophils. Repeat exposure to the antigen releases pre-formed Bradykinins, Histamine, and other enzymes locally. That produces allergic symptoms. In Anaphylaxis, the mast cells, eosinophils, and basophils all empty preformed enzymes simultaneously, producing swelling of the mucosa of the tongue, pharynx, upper airway, obstruction, hypotension, hypoxemia, and cardiovascular collapse.

Detecting IgE in Allergy and Anaphylaxis.

The tests are in two groups, namely, Skin Tests and Blood Tests. The skin tests are the Scratch test, Intradermal test, and Patch test. The first two tests are for detecting IgE antibody against Penicillin, and the Patch test is for detecting delayed skin reaction to Penicillin. The scratch test is performed on the forearm. A drop of a standard solution of penicilloyl-polylysine or undegraded penicillin is applied to the skin. A fine needle is used to lightly scratch the skin through the liquid. In 15 to 20 minutes, a wheal should appear if the person is allergic to penicillin. The wheal is measured with a ruler. The degree of sensitivity is proportional to the diameter of the wheal.

The specificity and sensitivity of the scratch test can be improved by injecting the same penicillin solution between the layers of the skin. And the resultant wheal is measured the same way the scratch test is done.

The patch test is described later under delayed hypersensitivity reaction.

A skin test is generally considered a standard test for allergies. This test, however, has considerable risk. It may precipitate a severe allergic reaction or anaphylaxis.

That risk is totally eliminated by performing a blood test. A modified RAST       (radio-allergo-sorbent test) blood test - CAP RAST or  CAP FEIA (fluorescence enzyme immune test). Blood is collected from the patient. At the laboratory, tiny discs coated with penicillin are mixed with serum. After a certain time, when the IgE antibodies bind with the antigen is complete and the unbound IgE is washed away. The bound IgE is quantified by fluorescent enzyme immunoassay.

The blood test has a significant false positive result, but a negative result is confirmation of the absence of penicillin allergy.

Type II Penicillin Hypersensitivity.

Penicillin molecule at times binds with the normal cells' surface receptors. This new molecule is perceived by the immune cells as foreign. Antibodies of class IgM and IgG are generated. The antibodies attack the penicillin-bound normal tissue or the extracellular matrix. This triggers the activation of complement, producing matrix destruction and loss of function. Examples of type II hypersensitivity are acquired hemolytic anemia, Thrombocytopenia, and Leukopenia.

Type III penicillin Hypersensitivity.

In type III hypersensitivity, the IgG antibody is combined with penicillin. These antigen-antibody complexes are deposited in tissues. The immune cells are activated against this complex. The immune inflammatory reaction causes tissue damage and loss of function. Examples are Serum sickness (fever, arthralgia, urticaria, lymphadenopathy, and glomerulonephritis), Vasculitis (multiple organ involvement – hepatitis, nephritis, pneumonitis, skin lesions, etc.). Interstitial nephritis.

Type IV penicillin Hypersensitivity.

Penicillin ointments, creams, and drops were used to treat wounds. Penicillin sensitized the skin's immune cells. Sensitized immune cells produce inflammation in the skin area and the condition is called contact dermatitis. This preexposure to penicillin produced penicillin resistant bacteria. Now, this practice is abandoned, and contact dermatitis due to penicillin has greatly disappeared. Examples of delayed reactions are - Contact dermatitis, morbilliform skin eruptions, Stevens-Johnson Syndrome (SJS), and a more severe form of SJS, Toxic Epidermal Necrosis (TEN).

Footnote:

Skin test for Type IV reaction. A small piece of sterile dressing soaked with penicillin solution is applied to the back of the patient and kept in place by an occlusive dressing for 4 days. When the dressing is removed and the presence of skin lesions is noted.

Stevens-Johnson Syndrome: Flue like symptoms, rapidly spreading skin lesions which quickly turn into blisters. Mouth, lips, and throat swell and become painful and bleed easily, and becomes fatigued. Shedding of layers of skin and rapid deterioration of the condition, an emergency situation develops.

edited June 2025.

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Insulin Resistance.

                                                    Insulin Resistance

                                               PKGhatak, MD

Insulin is an essential hormone for glucose utilization. In the absence of Insulin, blood sugar is elevated and the body is unable to generate an adequate amount of energy and many other metabolic processes are derailed. Unless Insulin is administered, death is inevitable. This is called Type I Diabetes mellitus (DM1). Type I diabetes is not a part of today's insulin resistance discussion.

In Type II Diabetes mellitus (DM2) the Insulin is either structurally abnormal or due to the presence of circulating antibodies making Insulin less effective. In this condition, the blood sugar is high and Insulin levels are high to high normal. A recent study from Japan showed DM2 might result from an increased renal insulin clearance and high sugar is due to relative insulin deficiency. WHO reported that    Covid-19 can destroy beta cells of the pancreas as documented in long covid.

An outline of Insulin activities.

Chemically Insulin is a polypeptide. Polypeptide hormones are prone to structural abnormalities due to minor defects in the cleavage of the long chain amino acids, which make the polypeptides. Some other non-insulin polypeptides have Insulin-like actions. Notable among them are Insulin-like growth factor I and II (IGF1 and IGF2).

Insulin Carrier Proteins:

Insulin molecules are transported by carrier proteins to cells. The cell surface contains receptors for Insulin. Insulin receptors are made up of two units - an A unit and a B unit. The distribution of A and B units is not uniform in the tissues. The binding of insulin with a specific receptor A or B determines the metabolic path the glucose molecule takes inside the cell. Moreover, when Insulin binds with one unit, then the other unit becomes inactive. In the Liver, however, Insulin binds with both units A and B. As a result, Insulin in the liver makes multiple metabolic paths unlike in other tissues. Insulin, on binding with the cell receptors, facilitates Glucose entry inside the cell and also stimulates the hexokinase pathway for the utilization of glucose and ATP generation.

Transport of Glucose molecules in and out of cells:

The glucose transport proteins belong to two groups. One is energy-independent Glucose transport proteins (GTP 1 to 13) and the second one is Sodium-Glucose Linked Transporters (SGLTs) and this requires energy expenditure.

GTP 1. This transporter helps a low-level glucose entry into all cells for tissue respiration.

GTP 2. This transporter is bidirectional. In the intestine, renal tubules and beta cells of the pancreas GTP 2 ferries glucose in and out of cells under the concentration gradient.

GTP 3. This transporter is most active in the nerve cells of the brain and spinal cord.

GTP 4. It is most prevalent in cardiac and skeletal muscles.

Energy dependent SGLT.

Energy is used for Sodium, Potassium, and H ion exchanges to maintain Intracellular pH and blood/cytosol Na and K concentration gradients.

During this process, Glucose enters the cell when a relative Na+ ion (sodium ion) deficiency develops. In high plasma glucose concentration, the process is reversed. In post digestion, glucose absorption in the small intestine and renal tubular conservation of filtered glucose are examples of SGLT1 transport.

Besides these sites, three other sites - Liver, Muscles and White Fat Cells (WFC) are the main focus of Insulin resistance and require attention.

Liver: The liver is the prime metabolic workshop. 1. Glucose is metabolized via tricarboxylic acid cycle, 2. Excess glucose is converted to glycogen, 3. Glucose is generated from fatty acids and amino acids and 4. Glycogen is broken down to glucose. All these metabolic processes are enzyme driven and take place in cellular mitochondria and endoplasmic reticulum (EPR).

Muscles: 1. Glucose is utilized in the muscles as fuel, 2. Excess glucose is stored as glycogen, and 3. glucose is generated from glycogen.

White fat cells (adipocytes): 1. Fatty acids are stored as fat molecules. 2. And fat provides energy when needed by turning back into fatty acids and glycerol.

Just as these organs differ the way glucose is utilized, similarly when Insulin resistance develops, these organs are affected in different ways and the degree of effects are variable.

Clinical entities associated with Insulin resistance.

1. Metabolic syndrome. This entry consists of hypertension, fatty liver, hyperlipidemia, high blood sugar and abdominal obesity.

2. Polycystic ovary syndrome.

3. Pre-diabetic stage.

4. Lipodystrophy.

5. Non-alcoholic fatty liver disease.

Mechanism of intracellular Insulin resistance in Type II Diabetes mellitus.

1. Structural abnormality of Insulin.

2. Presence of circulating Insulin antibodies.

3. Inherited mutation of genes expressing Glucose transport proteins and glucose receptors of cells.

4. Acquired mutation of genes expressing glucose transport proteins and glucose receptors. 

5. Stress and Inflammation.

Stress.

Stress. Excess accumulation of lipids inside the cells diverts the metabolic path from the tricarboxylic cycle to the utilization of fat. This puts an extra burden on mitochondria and the endoplasmic reticulum.

Inflammation

Inflammation. Inside the cell cytoplasm, various inflammatory cytokines like IL-6, IL-10, and TNF-alpha1 accumulate. Obesity is now considered as a chronic inflammatory condition of fatty tissue.

 6. Molecules of intermediate products of metabolism like bioactive lipids, diacetyl- ceramide, acyl carnitine produce mitochondrial stress and inflammatory cytokines. 

7. Glucagon or ACTH, glucocorticoids secreting tumors

8.  Endocrine abnormality. - Hyperthyroidism, Gigantism and Acromegaly. Cushing disease.

9. Growth hormone of the anterior pituitary is antagonistic to Insulin in the skeletal muscles and liver.

10. Medication. - A common cause of high blood sugar is chronic use of systemic steroids used in immunosuppression following organ transplants and asthma and certain hematological malignancies. Other drugs may elevate sugar are Hydrochlorothiazide, Statins, Beta blockers, Amiodarone, Niacin, Antipsychotic drugs and Prostaglandin E1.

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Immune Reaction

                                                              Immune Reaction

                                                     PKGhatak, MD

While reading any medical journal one usually encounters various descriptions of tissue response to injuries, infections, and illnesses, described as reactions. Immune reactions are the body's attempts to stamp out or control infection, cancer and diseases in an orderly fashion by the use of specialized cells and biochemical molecules.

Our body is pre-programmed to respond by a set pattern of actions called Innate or inherited immune reaction. And by a separate set of actions, from experience gained from encounters with the offending agents, called Acquired Immune reaction.

Innate reaction.

The skin, surface layer of the nose, mouth, GI, Respiratory and Genitourinary tracts are the physical barriers to invaders. Once that defense is breached, then the responsibilities fall on the surveillance cells for finding the invaders or cancer cells. These immune cells are Dendritic cells. They recognize the molecular patterns of the invaders' surface membrane, and they attach themselves to it, like a key fits a lock, and release the chemicals, called Cytokines. In response to cytokines, neutrophils, monocytes, eosinophils, phagocytes and complements gather at the site. And a series of actions and reactions take place in the local area resulting in increased blood flow, redness, swelling, temperature elevation and temporary loss of function.

The complement pathway of action is described as the Classical Pathway. Other pathways are also present, these are Alternate Pathway, and Mannose-Lectin Pathway. These pathways are activated by yeasts, viruses and certain bacteria.

The end result of this action is that the invasion is checked, the invaders are paralyzed and eaten alive by the macrophages and the dead bodies are removed from the area in order for healing to take place.

Adaptive Immune Reaction:

Acquisition of adaptive immunity is a learned process. During the first encounter with a pathogen, a signature part of the pathogen - usually, a protein molecule called antigen is recognized by the dendritic cells and the information is passed in succession to lymphocytes of various designations like B-cells, T-cells and ultimately to antibody producing B-lymphocytes. B-cells produce immunoglobulin, specific for that antigen, which combines with that antigen and neutralizes the pathogen. This antigen remains in memory in a subset of B -B-cells in the regional lymph nodes, but the memory is short-lived. Some memory B-cells move to the bone marrow and there retain memory permanently. 

Like innate immunity, adaptive immunity also consists of a cellular component and a Humoral component.

Adaptive immunity has a wide range of actions on pathogens and can be obtained in various ways.

Classification of adaptive immunity.

A. Natural

1. Passive immunity. A developing child in the mother's womb gets antibodies from the mother's blood via the placenta, and in some cases also from breast milk.

2. Active immunity is acquired from prior infection by that pathogen.

B. Artificial.

1. Active. Use of a vaccine to generate antibodies, which protects an individual for a while depending on the nature of the pathogen.

2. Passive. By giving IV antibodies, obtained from recovered patients or generated in animals by inoculating the animal, or obtained in the laboratory by the cell culture methods.

Abnormal Immune reaction.

Not every attempt to generate an adequate number of immune cells and antibodies against a pathogen will go smoothly. In some cases, the defect may lie in abnormal genes in a family or gene mutation of the individual. The response may be either excessive called Hypersensitivity reactions or cross reacts with normal body cells called Autoimmune diseases.

A. Hypersensitivity.

1. Immediate. The reaction happens within 24 hours after exposure to an allergen (pathogen).

Immediate hypersensitivity is of 3 different types.

Type I hypersensitivity reaction.

Also known as Immediate immune reaction, Allergy, Anaphylaxis and Atopy. The body produces Immunoglobulin E (IgE) instead of Immunoglobulin M or G (IgM, IgG). The circulating IgE binds with the Mast cell receptors. When sensitized mast cells encounter the same pathogen again (like pollen, bee stings, peanuts, etc.), the encounter causes the mast cell to release the preformed granules containing Histamine, and other enzymes at the site, and the consequence of that is the dilated blood vessels, fluid escaping locally. Nasal discharge, cough, paroxysm, and itching are produced depending on whether it occurs in the nose, lungs, or skin respectively.

Anaphylaxis.

Anaphylaxis is an excessive amount of cytokines released in a minute after exposure resulting in a drop in blood pressure, severe tightness in the chest, low blood oxygen, and cardiovascular collapse.

Type II hypersensitivity reaction.

In type II reaction, the IgM and IgG antibodies are involved. Examples of clinical conditions are Acquired hemolytic anemia, Rheumatic heart disease, Good Posture syndrome, Myasthenia gravis, Pemphigus Vulgaris, etc. 

Type III hypersensitive reaction.

Type III reaction is known as Immune complex mediated reactions. Here IgG, complement and neutrophils are involved. Clinical examples are Serum sickness, Rheumatoid arthritis, Lupus erythematosus, Glomerulonephritis, Hypersensitive pneumonitis, etc.

B. Delayed reaction.

The delayed hypersensitive reaction is also known as Type IV reaction, Cytotoxic or Cell mediated hypersensitive reaction. The reaction starts at 48 to 72 hours after exposure.

In type IV reaction, Thymic Th1 and Th17 cells are participants. Clinical examples are Contact dermatitis, poison ivy, Chronic transplant rejection, Multiple sclerosis, Celiac disease, Hashimoto thyroiditis, Granuloma annulare, etc.

Autoimmune disease.

The acquisition of knowledge by the immune cells that are foreign is gained in the developing T cells in the thymus in the developing embryo, and the learning process continues at a slow pace during the rest of life.

                                         [https://humihealth.blogspot.com/2021/08/thymus.html]

The mutated genes, either inherited or acquired gene mutation, result in misdirected immune attacks against the own normal tissue or organ.

Clinical examples are Crohn's disease, Acquired hemophiliac anemia, Aplastic anemia, Thrombotic thrombocytopenic purpura (TTP), SLE, Multiple sclerosis, Rheumatoid arthritis, Type1 Diabetes mellitus. Pernicious anemia, etc.

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Interleukin- 6

                                                          Interleukin- 6 (IL-6)

                                                 PKGhatak, MD

Interleukins are secreted primarily by immunocytes. Interleukins (ILs) are hormones like chemicals, function as an inflammatory promoter but also act as anti-inflammatory agents. In the biological system, pro and anti, inflammatory agents are neither good nor bad. Both are required to fight infections, autoimmune diseases, cancers, and at the same time must be available for repairs of diseased or damaged tissues.

Interleukin 6 (IL-6) is the main Interleukin in the pathogenesis of COVID-19 virus inflammatory reactions. In a previous blog, dated July 2020, a general outline of Interleukin was presented. In this article, a more detailed mechanism of action of IL-6 in inflammation is discussed.

Cells capable of secreting IL-6. IL-6 producing cells are Macrophages, endothelial cells of blood vessels, epithelial cells of the gut, and T & B cells (lymphocytes).

Normal serum levels of IL-6 are 0 pmg/ml to 1.8 pmg/ml.(pmg=picomiligram)

How activation of immunocytes occurs.

Bacterial glycoprotein fits the pattern of the Pathogen Associated Molecular Pattern (PAMP) Receptors. Other receptors are Toll Like Receptors (TL) are activated by bacterial lipopolysaccharide [Toll is a german word meaning stunning]. Once these antigens bind with the appropriate receptor IL-6 is produced. Immunocytes can also be activated by cellular metabolic changes, hypoxia, viral infection, activated nuclear factor (NF) k-B (killer B-cells), and NF-IL6 composites.

A general outline of IL-6 effects in the body.

1. IL-6 promotes inflammation. 2. Anti-inflammation. 3. Pathogen clearance. 4. New blood cell formation(hemopoiesis) 5. Reset the metabolic rate of the body. 6. Modification of lipid metabolism. 7. Neural differentiation increased substance-P generation and myelin sheath break-up.

Nature of IL-6.

IL-6 is a small protein molecule containing 212 amino acid residues. IL-6 molecule attaches to its target cells by two pathways. One is by attaching with the universal glycoprotein g130 surface receptors, the other by the IL-6R receptors. The IL-6R receptors are present in very limited cell lines – in hepatocytes, macrophages, B-cells and a subset of T-cells.

IL-6 must first bind with IL-6R present on the cell surface, then this composite allows the IL-6 to bind with g130 receptors. As a result, IL-6 R limits IL-6 activities to limited tissues. This is the Classical Path of Activation of immunocytes and the effect on the body is Anti-inflammatory.

Role of Metalloprotease in Cytokines production.

Activated metalloprotease strips IL-6R from the cell surface membrane. The free IL-6 receptors easily bind with IL-6. Then these composites can easily bind and activate a number of cells in different tissues.

This pathway leads to the unregulated production of cytokines and other mediators. This pathway of immunocyte activation is seen in cancers, autoimmune diseases, arteritis (inflammation of the smooth muscular layer of blood vessels), muscles of the GI tract, heart muscles, brain cells and other tissues. This path of activation of immunocytes is Pro-inflammatory.

IL-6 induced acute inflammation.

IL-6 acts through intermediate cytokines like TNF (tissue necrosis factor), PGE (prostaglandins E) and other interleukins (IL).

Acute phase inflammatory reactants.

Most of the acute phase reactants (APR) are produced and released by hepatocytes. The liver secretes increasing amounts of C-Reactive Protein, hepcidin, and haptoglobin. Fibrinogen, serum amyloid proteins from IL-6 stimulation.

Macrophage.

Macrophages are of 3 types - resident tissue macrophages (RTMs), monocyte-derived macrophages (MDMs), and transitioning MDMs in the tissue.

Macrophages express a number of proinflammatory chemokines and cytokines, including IL-1β, IL-6, IL-8, CXCL10, and TNFα. And a macrophage subset termed Macro_c2-CCL3L1, which specifically expressed CCL8, CXCL10/11, and IL-6, and a monocyte subset termed Mono_c1-CD14-CCL3, which abundantly expressed IL-1β, CCL20, CXCL2, CXCL3, CCL3, CCL4, and TNF alpha.

Macrophage hyperactivation.

Hyperstimulated macrophages produce Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome. Hemophagocytosis (i.e., engulfment of erythrocytes by activated macrophages), systemic inflammation, fever, cytopenia, hyperferritinemia, and hyperlipidemia, which can be due to inherited defects in cytotoxic T-cell function or triggered secondary to infection or rheumatological disorders.

This hyperactive IL-6 is seen often in covid related bilateral interstitial pneumonia and multisystem failure and deaths.

 IL-6 plays an important function in both innate and acquired immunity - first to limit infection, and invasion of harmful pathogens, toxins, venom, and cancers. Then in the second phase, it helps to heal the tissue by removing debris and dead pathogens, followed by the formation of collagen fibers, new cells and new blood vessel growth.  In the initial stage of infection, treatment should promote inflammation and not limit it. In macrophage induced hyperactive stage, intervention should be directed to stop cytokines or neutralize cytokines in limiting tissue damage. If interventions are not properly timed, then such interventions do more harm than good. For example, at the beginning of the COVID infection and symptoms, if drugs are used to kill the virus, or antibody infusion to neutralize the virus, then these interventions are beneficial. Medications and biological agents that limit acute inflammatory reactions are detrimental when used in this phase of infection.

In any discussion of COVID, specially in newspapers and social media, there is hardly any attention paid to what and when such interventions were done. Such discussions are useless and harmful.

Role of IL-6 in a few select organs.

Brain.

IL-6 crosses the blood-brain barrier. IL-6 induces PGE2 (prostaglandin E2) in the Hypothalamus. (Hypothalamus acts as the Thermostat of the body temperature). In response, the skeletal muscles generate body heat by non-shivering thermogenesis, catabolism of fatty acids and depletion of body fat.  It also improves glucose utilization by increasing GLP-1 (glucagon like peptide) and Amylin secretion from the pancreas.

Lungs.

In normal circumstances, IL-6 helps to maintain the integrity of lung elastic tissues, alveolar membrane, maintain pulmonary BP, and preserve pulmonary microcirculation. In overactive IL-6, the proinflammatory effects override the anti-inflammatory functions and produce the following changes -

 IL-6 induced cytokines damage pneumocytes II and damages endothelial cells of the pulmonary capillaries. It produces alveolar and interstitial edema and micro atelectasis. Pulmonary hypertension develops due to platelet microemboli. Gas exchanges are hampered and hypoxia develops.

Liver.

Increased production of the acute phase reactants is already mentioned. The liver also reduces the production and release of Fibronectin and Transferrin into circulation.

GI tract.

Increased hepcidin blocks the action of Ferroproteins (normally carry iron from the gut to bone marrow for RBC production) leading to anemia of infection.

On other viruses.

Enterovirus 71. It causes Hand- Foot - Mouth disease in humans. Under IL6 stimulation enterovirus 71 invades the brain and produces encephalitis.

Herpes virus increases its virulence and produces Kaposi sarcoma.

IL6 is implicated in the following diseases.

Diabetes mellitus, Alzheimer's disease. Amyloidosis, Rheumatoid arthritis, Lupus erythematosus, Multiple myeloma, Bechet disease, Multiple sclerosis, Neuromyelitis Optica, Prostatic cancer.

Interleukin 6 is an important Cytokine and possesses a multitude of functional potentials. The covid pandemic has brought IL-6 cytokine to the general public domain. Covid discussions are commonplace in social media and everyone has an opinion with or without the basic knowledge of Interleukins, specially IL-6.

Covid vaccine is as sure a preventive measure as one can possibly create but the vaccines are kept in warehouses while unvaccinated people are engaged in endless debate over the use of antiviral drugs and biological immunosuppressive, and Immunopotentiation therapies.

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Lactic Dehydrogease. (LDH)

                                                 Lactic Dehydrogenase (LDH)

                                               PKGhatak, MD

Lactic Dehydrogenase is an enzyme present in all tissues. LDH catalyzes, in a reversible reaction, lactate to pyruvate. LDH transfers 2 electrons and one hydrogen ion to NAD and in the process generates 2 molecules of ATP per molecule of glucose. LDH is an intracellular enzyme and consists of 5 isoenzymes. The individual organ contains one predominant isoenzyme and also small but variable quantities of other isoenzymes. Tissues are capable of producing any isoenzymes given the proper substrate concentration, pH, and oxygen supply.

LDH concentration is higher in the RBC, liver, heart, brain, lungs, kidneys and bones. Any disease or infection that damages any organ will release LDH in the blood and the serum level of LDH rises - twice or many times higher than normal. LHD is an anaerobic enzyme that belongs to the oxidoreductase group.  LDH is present both in the cell cytoplasm (Cytosol) and in mitochondria. The mitochondrial LDH is called mL-LDH (mitochondrial Levo LDH). The mL-LDH facilitates the oxidation of lactate to pyruvate. The RBC has no mitochondria and lacks mL-LDH as a result, unable to metabolize lactate further.

Action of LDH.

The chemical reaction of LDH is as follows -

CH3 CHOH COOH+ NAD + LDH = converted to CH3 CO COOH + NADH + H+ and in reverse action -

Pyruvate + NADH + H+ in presence of LDH = Lactate + NAD +. (See footnote 2 Cori cycle)

Pyruvate then enters the Krebs cycle (see footnote 1) and generates 36 ATP molecules during its full utilization in the generating energy. Excess accumulation of NADH is the triggering point of the reverse action and produces lactate.

Blood levels of LDA.

Serum LDH level is higher than plasma level because clotting of blood releases LDH.

Normal serum level if LDH

Newborn	135 to 750 units/L. In CSF < 70 units / L
Children up to 12 years	180 to 435 units/L
12 to 18 years	122 to 222 units/L
Adults	140 to 280 units/L
CSF LDH in adults	Less than 40 units/L

Falsely elevated LDH.

Following general anesthesia, Aspirin use, alcohol, and procainamide may elevate LDH levels.

Falsely low LDH.

Vitamin C use.

LDH isoenzymes and structure;

LDH has 5 isoenzymes - 1 to 5. And each LDH molecule is a combination of two units, H and M units. H stands for heart and M for skeletal muscle.

LDH isoenzymes and composition

Name	Units	Higher levels in
LDH1	4 H units	Heart
LDH 2	3 H units + 1 M unit	RBC, Spleen, Bone marrow.
LDH 3	2 H units + 2 M units	Lungs
LDH 4	1 H unit + 3 M units	Kidneys
LDH 5	4 M units	Skeletal muscles, Liver.

All tissues have the above 5 isoenzymes in variable amounts. The H Unit binds faster with the substrate but has a slow rate of metabolic activities.

Two chromosomes, 11 and 12, encode LDH. The genes of the two chromosomes are designated as LHD- A, B, C, D genes. LDH-A.B.C genes encode L- LDH (Levo LDH) isomer and LDH-D gene encodes d-LDH isomer. Levo isomers are required in Lactate utilization and the Krebs cycle

Congenital absence of LDH.

The encoding genes for LHD are 4 in number, designated as A, B, C, & D. The mode of inheritance is autosomal recessive. LDH deficiency is very rare, Japan reported most cases; the incidence in Japan is 1 per million people. And known as congenital LDH – A and LDH- B deficiencies.

Deficiency in LDH-A results in absent LDH 5. Patients present with easy fatigability, muscle cramps and pain, myoglobinuria, and renal failure.

LDH -B deficiency causes LDH- 1 deficiency. The heart muscles are capable of generating energy from using other sources and patients show no effects from this deficiency.

Covid-19 and LDH.

In every study published on COVID-19 virus infected hospitalized patients, the serum LDH is universally elevated. NIH calculated that an elevated LDH increases a 6-fold increase in serious illness and a 16-fold increase in mortality. In multisystem failure, all LDH isoenzymes are elevated, the higher the number, the worse is the outcome. In platelet microthrombi and interstitial pneumonia, LDH3 is very high. Accumulation of lactate in tissue increases the H ion concentration and a fall in the pH, Low pH enhances macrophage metalloprotease and initiates new blood vessel growth in the inflammatory tissues.

LDH activity in the specific organ/tissue.

Muscle.

Muscular activities utilize oxygen, and in a sustained activity like in a marathon run, a severe hypoxic condition is created. Since oxygen is the final electron acceptor, the ATP generation stops but the muscles continue to function by creating ATP through NAD+. The serum levels of LDH 5 are high in muscular dystrophy, HIV infection, crush injury and rhabdomyolysis. The damaged muscles release myoglobin and kidney damage is common in significant myoglobinuria.

Brain.

In normal conditions, the brain uses lactate to generate 30% of its energy needs. In anoxia, the brain can raise it to 60%. Excess lactate enters the CSF. CSF lactate levels are used for diagnosis of anoxic brain injury, and bacterial meningitis but LDH usually remains normal in viral meningitis. The CSF LDH levels are very high in subarachnoid bleeding, and high in metastatic carcinoma, CNS lymphoma, and Leukemic infiltration to the brain.

Heart.

In myocardial infarction (MI), the LDH level rises within 24 hours and stays up for 4 days then returns to a normal level. A normal heart generates LDH2. In MI the LDH1 rises over the LDH2. The elevated LDH1/LGD2 ratio is helpful in the diagnosis of MI.

Pleural effusion.

In inflammatory pleural effusion, the ratio of LDH of pleural fluid and serum LDH is >0.6.

Liver.

In cirrhosis of the liver and hepatitis, the LDH2 is proportionally higher than LDH4. In toxic hepatitis, LDH is 10 times the normal serum LDH.

Lungs.

In microvascular pulmonary embolism, LDH3 is very high, so also in pulmonary emboli and infarction, necrotizing pneumonia.

B12 deficiency and macrocytic anemia.

LDH levels are high, and the levels fall with adequate therapy.

Cancer.

All cancer cells produce excess LDH and high serum levels reflect the aggressiveness of cancer. Many cancer cells are capable of copying mitochondrial mL-LDH and use it to generate extra energy for cancer growth. This is known as the Warburg effect (see footnote 3).

Malignant melanoma metastases are associated with very high serum LDH levels, usually over 50 times the normal value. Leukemia. Lymphoma, Multiple myeloma, testicular and ovarian cancers also produce high serum LDH.

When treatment of cancer is effective the LDH level falls. The LDH level is used as a serum marker for monitoring cancer recurrence.

In colorectal, esophageal, nasopharyngeal, prostrate, germ cell cancers and malignant melanoma, the LDH levels over 1000 units/L signify a poor prognosis.

An interesting side note.

Malaria parasites lack the tricarboxylic acid cycle and depend on LDH for energy generation. Attempts are now being made to block LDH in malaria parasites and if successful it will help to control malaria.

Footnotes-

1. Krebs cycle is also called the tricarboxylic cycle. Two carbon compounds generated from the metabolism of glucose, fatty acids, and glucogenic amino acids combine with the enzyme CoA and form Acetyl CoA. Acetyl CoA combines with Oxaloacetate to form Citric acid and enters a cycle that runs strep wise, in reversible actions, and generates ATP, CO2, and H20.

2. Cori Cycle.

The Cori cycle explains the steps in the conversion of lactate to Glucose. The newly formed glucose (neoglucogenesis) is added to the blood to keep blood sugar within the range.

3. Warburg Effect.

This is a biochemical process of speeding the rate of glucose conversion to lactate in aerobic conditions. Cancer cells use this to generate extra energy.

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Pulmonary Function Tests.

 

                                               Pulmonary Function Tests

                                             PKGhatak, MD

Pulmonary Function Tests (PFTs) are aptly named; these tests delineate the functional status of the lungs and allow one to track the progression of a disease or improvement. The tests are also sensitive in the early stages of a pulmonary disease, when other tests, such as chest X-rays, CT scans, and blood tests, are likely to be normal. The PFTs are an integral part of good management of asthma, where patients themselves can adjust medications on a day-to-day basis. Tests are simple enough and can be repeated frequently.

A complete PFT is performed in a pulmonary lab by a technician and consists of several tests requiring maximum effort of the patient and a brief period is allowed for the patient to recover, but in one visit. 

From the patient's side, the patient is required to breathe in and out, as best he/she can, into a mouthpiece attached to a machine. And there is no need for a blood sample or any injections.

The electronic machines are amazingly efficient and fast, and can spit out numbers instantly. If the report is delayed, that is likely due to the time taken to interpret those numbers by an expert.

Why PFTs are needed:

1. It is an essential test to monitor a lung disease from day to day.

2. Patients use this device to detect early warning signs of trouble and seek proper help ahead of the problem begins

3. In certain pulmonary diseases, the functional state is more important than just a diagnosis. An example is asthma.

4. An essential tool for detecting very early cases of asthma. And then categorize asthma according to severity, in order to prescribe appropriate medications and dose adjustments.

5.PFTs are sensitive tests utilized in detecting the cause when the breathlessness of patient is the only symptom.

6. These tests differentiate obstructive lung diseases from those diseases that prevent the lung from expanding fully to its capacity (restrictive lung disease).

Normal breathing.

We breathe 12 times a minute, one cycle takes about 5 seconds, which includes two phases, inhalation and expiration. If one listens with a stethoscope, the movement of air during inhalation makes a gentle sound, whereas expiration is very short, and only in the early part of expiration is audible. That is due to the fact that the elastic recoil of the lungs and the chest wall does all the work during expiration.

Let's take a look at this test result together. Note that there is a small oval graph within the larger one, and a horizontal line runs across the graphs. The horizontal line is the baseline. The lower half of the graph represents the movement of air into the lungs, and the upper part represents air moving out of the lungs. For the lower half, the pen inscribes from Right to Left. The pen inscribes on the upper part from Left to Right.

The smaller graph depicts the air moving in and out of the lungs during normal breathing.

The larger graph is inscribed when the patient took in as much air in his lungs as possible and then forced out air as fast as he could and continued to push out air from his lungs with the constant cheering of the technician. This graph represents Forced vital capacity, or simply the Vital Capacity.

The horizontal line within the graphs represents the Volume of air in Liters, the vertical line depicts the Flow Rate of air in Liters per Second.

The difference between the two graphs is the Reserve Volume of the lungs, both in the inspiratory and expiratory phases.

FEV1.

The amount of air that expired under maximum efforts in the First second is known as the forced expired volume in the first one second (FEV1). A normal person can expel 80 % or more in the first second. In obstruction of the airway (COPD), the FEV1 is less than 75%. In asthma, the FEV1 should return to a normal level after a brief inhalation of a bronchodilator. In suspected cases of asthma, the initial EFV1 may be normal but the FEV1 will fall below 80% after a Methacholine challenge test, also known as Bronchial Provocation Test

The results of the PFT are reported with the actual patient's performance numbers and also as a percentage of his performance when compared with a normal person with his age/ sex/ethnic background/ height/ and ideal weight for the age and height.

Methacholine Challenge test.

A forced vital capacity is recorded first. Only if PFT is normal, then the methacholine challenge test is performed; because this test is a test to document hyperactive airways, if that is already demonstrable, then there is no point in doing the test.

The subject is asked to breathe in and out normally, a nebulizing solution starting with a dose of 1 to 3 micrograms of methacholine and observing and documenting changes in flow rates of the forceful expiration. The test is continued with an increased dose of methacholine till the maximum dose is given or a reduction of flow rate is observed. 

A decrease of 20% of FEV1 is necessary to call a test positive.

Total Lung Capacity.

After a maximum expiratory effort, a significant amount of air is still left in the lungs because the lungs cannot be squeezed further, as the chest wall will not yield because of rigidity. The amount of air that will not be expelled is called Residual Volume.

On adding the residual volume to the forced vital capacity volume, the Total Lung Capacity (TLC) number is obtained.

Direct measurement of TLC.

To determine the TLC, a known amount of inert gas, Helium (harmless, non-absorbable, not soluble in water or blood), is used. A mixture of oxygen and helium is inhaled from a closed system and the subject is allowed to breathe in and out within the closed system to ensure the proper distribution of helium in the lungs. Then the expired air is analyzed for the final concentration of the helium gas. Knowing the initial gas concentration and the final gas concentration of helium, the volume of the Total Air present in the lungs is easily calculated.

In emphysema, the reserve volume increases at the expense of inspiratory reserve volume and the TLC also increases due to the loss of the elastic tissue and the chest expands outwards, commonly referred to as a Barrel Chest.

In chest wall deformities, e.g., Kyphoscoliosis, and in pulmonary fibrosis, the TLC and the FVC are reduced.

Diffusion Capacity.

The diffusion capacity of the lung is also known as the transfer factor, DLCO (diffusion of carbon monoxide), TLCO. The diffusion capacity is a measure of the health of the delicate tissue at the junction of air sacs (alveoli) and pulmonary capillaries, where the oxygen molecules from the alveoli move across the membrane and bind with the Hemoglobin in the RBCs.

In a biological system, multiple factors are at play, so also in DLCO. One has to accept that under the condition of the test, just one factor is variable. After the result is obtained, a correction is made, if necessary. As an example, significant anemia will appear as decreased DLCO due to less hemoglobin available to bind oxygen and not due to a damaged membrane.

To test DLCO, the subject exhales forcefully first, then inhales a known amount of a mixture of oxygen, nitrogen, helium and carbon monoxide (CO) from a closed system, and holds breath for 10 seconds. The expired air is sampled at the mid portion of expiration and analyzed by a rapid CO analyzer. The amount of CO transferred is calculated and expressed in CO mmol/min/k Pa or SI units. And a ratio of the expected normal value.

DLCO is reduced in pulmonary emphysema, pulmonary fibrosis, loss of lung tissue from lung surgery, or other diseases. Also, damage to the pulmonary capillaries from platelet microthrombi, Pulmonary embolism, poison gases, radiation, etc.

Very Useful gadgets developed from PFT.

Peak Flow Meter.

A peak flow meter is easy to use, and the inexpensive gadget is an integral part of asthma management.

A maker on a tube records the highest flow generated with forceful expiration. A sudden fall in the Peak Flow indicates fatigue is setting in, a sustained asthma attack - also called Status Asthmaticus. Patients are well coached to seek medical attention right away.

Vitalograph.

A simple vital capacity measuring device uses a rubber bag to collect expired air and a pen records the volume and flow rates on graph paper. Patients with neurological conditions like Guillain-Barré syndrome, ascending paralysis, or ALS and their caregivers are taught to use the gadget and call their doctors when they detect deterioration. The use of these devices prevents time intervention and avoids ER trips.

Volumetric Incentive Spirometer.

This device is a simpler gadget than a vitalograph, but basically performs the same function.

edited: June 2025.

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