Parathyroid Glands and Parathyroid Hormone.

                                   Parathyroid Glands and Parathyroid Hormone

                                               PKGhatak, MD

In 1880, Ivar Viktor Sandstrom, a Swedish medical student, identified parathyroid glands in humans. That was the last major discovery in human anatomy. His discovery remained unknown till 1891 when Eugene Gley of France established the endocrine nature of these glands. In 1925 J.B. Collip purified the hormone from these glands and it was known as Collip hormone. The molecular structure of this hormone was established by Potts in 1971. The hormone was called parathormone and now it is known as Parathyroid hormone, in short PTH.

Anatomy and Embryology

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In normal circumstances, a person has four Parathyroid glands. In rare circumstances, a person may have 8 or 16 parathyroid glands or none at all. Parathyroid glands are very small in size, about 6 cm x 3 cm, weighing about 50 mg each. They are mustard yellow in color. They are located in the neck, two on the left side and two on the right side, hiding behind the thyroid gland.  The two parathyroid glands that lie behind the upper pole of the thyroid gland are called superior parathyroid glands and similarly, those two behind the lower pole of the thyroid gland are known as inferior parathyroid glands. Both glands are supplied by the inferior thyroid artery.

These glands develop from the endodermal cells of the pharyngeal pouch. The inferior parathyroid glands develop from the dorsal wing of the 3^rd pharyngeal pouch; the thymus gland develops from the ventral wing of this pouch. By the 7^th week of fetal development, these glands lose their connection with the pharynx and begin to descend in the neck; the parathyroid glands stop descending when they reach the lower end of the thyroid gland; the thymus descends further to the chest cavity and lies in front of the heart. The superior parathyroid glands develop from the dorsal wing of the 4^th pharyngeal pouch and descend only a short distance to occupy their positions behind the upper part of the thyroid lobes.

In about 10 % of cases, supernumerary parathyroid is found due to fragmentation of glands during descent; in 3 % of cases, less than 4 glands are present. In about 20 % of cases, the ectopic location of the Parathyroid glands is seen. Thymus and inferior parathyroid glands descend together, any abnormalities of this process may lead to the positioning of inferior parathyroid glands in the lower part of the neck or further down in the chest, in front of the heart, behind the esophagus or paravertebral area, or within the thymus gland. Superior parathyroid glands descend with the thyroid gland and only for a short distance; as a result, abnormal positions of superior parathyroid glands are less scattered and located around the bifurcation of the common carotid artery or within the thyroid gland.

Chemistry and blood levels of the Parathyroid hormone.

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Parathyroid hormone (PTH) is a straight long chain polypeptide. PTH is produced by the chief cells of the parathyroid glands as a pro-pre-hormone containing 115 amino acids. It is immediately cleaved to a 90 amino acid pre-hormone. It is further cleaved to a linear protein containing 84 amino acids. In this form, it is stored in secretory granules. The Intact PTH or I-PTH (I-84) and PTH (I-34) - fragments are the biologically active parathyroid hormone. They have opposite effects on serum calcium and on the bone.  Biologically active PTH assay (BI PTH) is based on the sequential binding of amino acids I-4 of the PTH.

Normal serum levels of PTH are 10 - 65 pg/ml. It has a half-life of 4 minutes. Serum levels of BI-PTH are 6 - 40 pg/ml. BI-PTH levels are lowest at 2 AM.

Synthetic PTH N-terminal (I-11) has the same biological properties as native PTH (I-34).

Several factors can interfere with PTH blood level determination. Patients must fast in the morning before the blood sample is drawn. Milk and milk product consumption will give a false result. Patients taking lithium, rifampin, isoniazid, steroids, phenytoin and other anticonvulsant drugs, thiazide, furosemide, and phosphate laxative have falsely elevated PTH levels. Falsely low levels are seen in patients taking cimetidine and propranolol.

Pregnancy and lactation can give false results. Hypercholesterolemia and high triglycerides also give false low PTH levels.  Patients who had radioactive scans should delay PTH determination by one week.

In situations where serum calcium levels are high, PTH (I-84) is broken down at a faster rate and the PTH secretion rate is slower but PTH fragments- PTH (7-84) levels do not decrease.

PTH (I-84) and PTH (I-34) are broken down rapidly by a chemical process (proteolysis) by the liver and kidney. The rate of removal is accelerated by high serum calcium and decreased by lower serum calcium.   Peripheral tissues also remove biologically active PTH rapidly and the process is independent of serum calcium levels. C-terminal PTH (7-84) circulates in the blood longer and is filtered out by the kidneys. PTH (7-84) suppresses the actions of PTH (1-84) and PTH (1-34).                                                                                                                                                

Parathyroid Hormone Related Peptide. PTHrP.

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Cells of many organs and tissues are capable of producing PTH like the hormone PTHrP. Structurally the PTHrP is distinct from PTH and may contain 134 to 173 amino acids. PTHrP also breaks down into smaller fragments like normal PTH. In an experimental animal, PTHrP behaves almost as if PTH is derived from parathyroid glands. It is, however, not shown to be present in a significant amount in the blood of normal adults. Whether PTHrP has significant actions on local tissues at the site of production and then degraded locally is a conjecture at the moment, but when these cells turn malignant, they produce large quantities of PTHrP and are responsible for severely elevated serum calcium and may cause serious consequences.

Breast milk has a significant amount of PTHrP, it probably causes uterine contractions during lactation.  Placenta produces a significant amount of PTHrP and helps fetal bone development and growth.

In one area PTHrP differs from native PTH:   PTH binds to both PTH-R1 and PTH-R2 receptors, whereas PTHrP binds only to a PTH-R1 receptor.

Control of PTH secretion and Calcium sensor receptor.

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PTH is primarily responsible for keeping the ionized calcium levels of blood within a very narrow range of 1.1 to 1.3m.mol/L. Blood ionized calcium, on the other hand, controls PTH secretion by interacting with the Calcium sensor CaSR. CaSRs are located on the cells of the parathyroid glands.
 Calcitonin is produced by the C-cells of the thyroid gland, kidney, brain, pancreas, osteoblasts of bone, hemopoietic cells of bone marrow, squamous cells of the esophagus, gastrointestinal mucosa, and other tissues.   

PTH and PTHrP Receptors

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Biologically active Parathyroid hormone and Parathyroid related proteins both bind to the Parathyroid hormone receptor PTHR.  The C-terminal mid region PTH binds to a different receptor called the c-PHR receptor.

There are two distinct classes of PTH receptors known as PTH-R1 and PTH-R2. 

The biologically active PTH binds with both PTH-R1 and PTH-R2 receptors. The PTHrP binds with only the PTH-R1 receptor.
Immediate release of calcium in repose to hypocalcemia is the chief function. PTH receptors are present on osteoblasts but not on osteoclasts of bone. When short intermittent PTH stimulations occur an increase in the number of both osteoblast and osteoclast is seen and more trabecular bone is formed.
 The remodeling of bone takes place by PTH induces activation of the following processes-

1. Increased collagen synthesis.
2. Increased alkaline phosphatase activities.
3. Increased activities of various decarboxylases and glucose 6 phosphate dehydrogenase.
4. Increased synthesis of DNA. proteins, and phospholipids.
5. Increased calcium and phosphate transport.

In prolonged sustained PTH, stimulation of osteoclasts is stimulated by Cytokines released by osteoblasts and bone resorption takes place.

In the Kidney, the PTH acts on many sites and has many actions.

1. In proximal tubules, it suppresses phosphate and bicarbonate transport.
2.Activates Na +/ Ca2+ transport. ( + = ion)

3. In distal tubules, it stimulates Ca2 + transport. 
4. Activates 1- alpha-hydroxylase enzyme and converts vitamin 25(OH)D to active vitamin 1,25(OH)2D.

In the Gastrointestinal tract, PTH influences calcium absorption via activated vitamin D.

The final effect of these activities is the maintenance of a steady calcium environment and healthy bone.

Disorder of Parathyroid Hormone function.

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Various hereditary and acquired conditions can affect parathyroid function.   Renal failure is the most common clinical condition where hyperfunction of the parathyroid gland is seen. In this situation, the renal distal tubular conversion of vitamin D to active vitamin D is impaired and calcium absorption in the gut is poor. In addition, phosphate blood levels are high due to the failure of the kidney to eliminate phosphate in the urine. Serum calcium levels fall further due to the microscopic precipitation of calcium-phosphate in various tissues.   PTH (7-84) levels may reach 60% of blood PTH levels. PTH (7-84) interferes with the normal functions of biologically active PTH. Serum calcium is restored by the parathyroid gland by producing excessive amounts of PTH at the expense of bone calcium. The stimulation of PTH secretion remains high as long as the renal failure continues. Ultimately, parathyroid glands undergo hypertrophy and occasionally turn into an adenoma.

In about 20% of cases, hyperthyroidism is associated with hyperparathyroidism.

Radiation therapy to the neck, radioactive Iodine treatment for Graves’ disease of the thyroid, and carelessly done thyroid surgery can lead to damage and destruction of the parathyroid glands. Under such conditions low PTH secretion and low serum calcium are present. This is called secondary hypoparathyroidism. Sarcoidosis, lymphoma, multiple myeloma, vitamin D toxicity, histiocytosis X    hemochromatosis, Wilson’s disease and low serum magnesium may also produce secondary hypoparathyroidism.

Familial hypocalciuric hypercalcemia –FHH is a hereditary disease of the calcium sensor receptors CaSR of the parathyroid glands and renal tubules. CaSR mistakenly senses low calcium when serum calcium is normal. Parathyroid glands respond by producing excess PTH.  This results in high serum calcium and excess urinary calcium loss.

A reverse condition is also present where CaSR senses high serum calcium in face of normal serum calcium. It results in decreased secretion of PTH and hypocalcemia. This condition is inherited as an autosomal dominant trait. And is known as ADHH-autosomal dominant hypocalcemic hypocalciuria.

Bartter’s syndrome V is a variant of this disorder. In addition to CaSR malfunction, other abnormalities of the ion-transport system result in excessive sodium, calcium and chloride loss in the urine. Low serum sodium leads to secondary hyperaldosteronism and hypokalemia and metabolic alkalosis. Renal calcification and renal stone formation are common.  

In rare autoimmune diseases, antibodies are directed against CaSR. Stimulation of CaSR by antibodies leads to suppression of PTH secretion and low serum calcium. In the Polyglandular autoimmune type, 1 deficiency adrenal glands and ovaries are affected in addition to parathyroid glands. Vitiligo, alopecia, pernicious anemia and mucocutaneous candida infection are present. The defect lies on chromosome 21.

Jensen’s disease is a rare autosomal dominant inherited disease of the PTH-R1 receptor. PTH-R1 is upregulated and excessive PTH-R1 actions are seen in bones and kidneys. Calcium is mobilized from bone and blood calcium level rises. In children, this condition leads to short-limb- dwarfism and in adults bone changes resemble hyperparathyroidism.

In DiGeorge syndrome, there is a defective development of the 3^rd pharyngeal pouch. In this condition both the thymus and parathyroid glands are rudimentary. Abnormal development of bones and arteries derived from the 3^rd pharyngeal pouch takes place. This condition is transmitted by autosomal dominant inheritance and due to a mutation on chromosome 10. Sporadic cases of DiGeorge syndrome are due to other chromosomal abnormalities like Kenny-Caffey syndrome, Sanjad-Sakate syndrome.

In hereditary mitochondrial disorders like Kearns-Sayre syndrome and MELAS syndrome, hypofunction of the parathyroid is associated with other metabolic defects.

Hypoparathyroidism, in the previous generation, was classified as Primary Hypoparathyroidism, Pseudohypoparathyroidism and Pseudo-pseudohypoparathyroidism.  Current progress in molecular biology has simplified many such disease entities, and they are now known by more clear terms. But some Hypoparathyroidism remains to be defined in those terms and this class of disorder is called Primary hypoparathyroidism. Primary hypothyroidism may be due to a failure of the gland to synthesize PTH or fail to secrete bio-active PTH. 

Symptoms of hypoparathyroidism vary depending on whether the condition is of acute onset or chronic.
In an acute situation, hypocalcemia produces muscle cramps, tetany, carpopedal spasm, and abnormal sensation around the mouth, hand, and feet. Serious cardiac arrhythmias may develop.
In a chronic situation, Parkinson's disease, like rigidity and extrapyramidal movements like athetosis and chorea, are present and associated with calcification of the Basal ganglia of the brain.  Increased intracranial pressure and papilledema, alopecia, cataract and candida infection may be present.

In pseudohypoparathyroidism (PHP) the defect is in the end-organ -PTH response. Hyperplasia of the parathyroid glands with the increase in PTH secretion takes place in association with clinical features of hypoparathyroidism. This is an inherited disorder due to an abnormality of chromosome 20. In PHP the PTH fails to activate the guanyl-nucleotide binding protein complex, as a result, the intracellular cyclic AMP fails to increase. the kidney 

Tumors and Malignancy of Parathyroid glands.

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Multiple endocrine neoplasias (MEN) are associated with tumors of the parathyroid gland. In general, all inherited malignant diseases are due to overexpression of proto-oncogenes and / loss of function of tumor suppressor genes.

In MEN1 hyperparathyroidism is associated with tumors of the pituitary and pancreas. Patients present with symptoms of excessive gastric secretion and recurrent gastric ulcers. Mutations of tumor-suppressor genes on chromosome 11q13 are seen.

In MEN2A hyperparathyroidism is associated with medullary carcinoma of the thyroid gland and pheochromocytoma of the adrenal glands.
In MEN2B in addition to features of MEN2A, multiple neuromas are present and hyperparathyroidism is absent in some cases.
Other hereditary cancers involve parathyroid glands only, not in association with other endocrine organs.
Certain malignant tumors of various organs produce PTHrP and the presenting symptoms are due to hypercalcemia and hyperparathyroidism.

Primary Hyperparathyroidism is due to inappropriate excessive PTH secretion, and most often due to a benign adenoma and occasionally hyperplasia of one of the parathyroid glands.
Symptoms are variable: in many cases patients are healthy and serum calcium is minimally elevated; in others, recurrent renal stones, peptic ulcers, recurrent pancreatitis, mental changes, cardiac rhythm abnormalities and demineralization of bone are seen.   Parathyroid adenoma in primary hyperparathyroidism is almost always benign and very rarely progresses to carcinoma.

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Emphysema

                                                                             Emphysema

                                                                    PKGhatak, MD

Emphysema is a Greek word, it means inflation or blown with puffed cheeks. In medicine, emphysema is classified under chronic obstructive lung disease. The underlying structural problem in emphysema is the fragmentation of elastic tissues. In the normal lung, elastic tissues are abundant in the walls of small air sacs called alveoli.

To demonstrate the fragmentation of elastic tissue: Take two identical balloons. Blow one to its full capacity and hold it for a minute, then release the air. The balloon will collapse but will not return to its original size. The balloon will appear larger and flabbier compared with the other. In the process of inflation, some of the elastic fibers of the balloon were stretched beyond their limits and fractured. When the air was released, the elastic recoil could not bring the balloon back to the original size and appeared flabby. Emphysematous lungs are like that flabby balloon.

An alveolus (air sac) is the structural and functional unit of the lung. Each lung has about 300 million alveoli. Each alveolus is about 250 microns across and lined with one layer of cells and is connected with a tiny airway through which air enters and leaves as one breathes in and out. These airways are the terminal branches of the main airway called bronchus. Alveoli are supported and kept separated by walls made up of connective tissue. Blood enters the lungs by the pulmonary artery, it branches repeatedly and the arterial branches follow the bronchial branches very closely. At the very end, the pulmonary artery becomes a capillary- just one cell in thickness and lies in apposition with the liner cells of the alveolus. Blood picks up oxygen and releases carbon dioxide easily across this thin membrane. As a consequence of loss of elasticity, alveoli lose support and one alveolus joins with its adjacent alveoli and becomes a larger alveolus. Mathematics tells us the sum of the surface area of two equal sized spheres is much larger than the surface area of a larger sphere made of two such spheres. The final effect of these changes results in a reduction of the total surface area of the lungs and is a major cause of oxygen deprivation. The carbon dioxide, however, diffuses 40 times faster than oxygen and no retention of carbon dioxide takes place in this stage of the disease.

As we inhale (inspiration) the diaphragm descends and the chest wall moves outwards, creating more room in the chest cavity and the intrathoracic pressure falls. This pressure difference drives outside air into the lungs via the nose and air reaches the alveoli. Exhalation (expiration) is a passive process: muscle contraction, which was holding the chest wall in an expanded condition, is terminated and the lungs return to the original state by the recoil of the elastic tissues. The pressure inside the chest cavity rises just above the outside pressure and the air from the lungs is forced out. Elastic tissues and their distribution around the terminal branches of the airways are essential in holding these tiny airways open during expiration.  In fact, airways not only become shorter but also wider because of radial pull generated by elastic recoil during expiration. In emphysema, loss of elastic recoil leads to obstruction of air movement during expiration. Thus, emphysema is also an obstructive airway disease. And because the process takes a long time to develop, it is called chronic. Nowadays, the term chronic obstructive airway diseases of the lung (COLD) is replaced by COPD, the word “lung” is replaced by pulmonary.

What are the causes of Emphysema.

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1. The elastic tissue is made of a protein called elastin. Throughout our lives, elastin is laid down and removed continuously in the lungs. For removal, elastin is digested by an enzyme called Elastase produced locally by white blood cells, neutrophils and tissue macrophages.  When the digestion is complete, the action of elastase is stopped by another enzyme called alpha-1-Antitrypsin (a-1AT). The a-1AT belongs to a family of enzymes called Serpina-1. The long arm of chromosome 14 at the 32.1 locus contains the genetic code for the production of serpina-1. The mode of inheritance of this gene is by autosomal codominance, meaning that both genes are active in an individual, and determine the genetic trait. The normal allele (a pair - one from each parent) of this gene is designated as MM based on the appearance of the band in the middle of the gel used in electrophoresis.  More than 120 mutations in this gene are known. The normal phenotype is MM and an individual with MM allele has a normal blood level of a-1AT, whereas the ZZ phenotype has a profound deficiency.  SS phenotype has a moderate deficiency. Antitrypsin is produced in the liver and transported to the lungs via blood.  The normal blood levels of antitrypsin are 150 to 350 mg /dL. The blood levels of antitrypsin vary depending on the inheritance of the various combinations of these alleles.  In ZZ phenotype people, the digestive action of elastase on the elastic tissues proceeds uninhibited and they become candidates for an early onset of emphysema.

It is estimated that 1 in 3,000 people in the USA may be a carrier of the mutation of this gene but the hereditary cause of emphysema accounts for only 1 to 2 % of the vast number of emphysema patients.

2. Cigarette smoke.

Oxidants in cigarette smoke inactivate deacetylase-2 of the macrophages. Then a chain of chemical events follows resulting in the release of elastase and activation of other serine proteinases in the lung   Cigarette smokers and secondhand smokers are at high risk of developing emphysema. Damage to the elastic matrix is greatest in a-1AT deficient individuals. Early and rapidly progressive emphysema is seen in these individuals.

3. Kitchen smoke.

Widespread use of wood, coal, and coke burning stoves in kitchens of poor countries is a major cause of emphysema and chronic bronchitis in women.

4. Chronic bronchitis and Asthma.

Many experts believe chronic bronchitis and emphysema in advanced stages become indistinguishable from each other. Other experts consider asthma also in this group. There is no doubt that considerable overlap exists in the pathophysiology of these three entities.

5. Coal dust.
People exposed to coal dust develop marked emphysema in the lower lobes of the lungs, even though the coal is inert. The coal dust is picked up by macrophages when dust particles reach the lungs and are carried to the walls of the alveoli. Here, macrophages release enzyme elastase and collagenase and the destruction of the lungs begins.

Silica dust and silica crystals inhaled by mine workers in various mining related industries suffer from COPD and more severe changes are seen in people who also smoke cigarettes.

6. Air pollution.

Ozone in the air is particularly harmful. Sulfurdioxide and nitrogen dioxide damage lung tissue directly.

Cotton dust inhalation causes lung damage. Cadmium fumes exposure is a known cause of emphysema and bronchitis.

7. Allergy and hypersensitivity.

Airway hypersensitivity is an important factor in the genesis of asthma.  Poorly controlled asthma over time may progress to produce alveolar damage and loss of alveolar surface area.

8. Repeated infection.

In adults, repeated inflammation or infections of the lungs may produce loss of lung surface area and especially in growing children.

9. Congenital abnormalities of collagen tissue formation due to gene abnormalities are associated with emphysema as seen in Cutes Laxa and Ehlers-Danlos syndrome. Some tall and thin young men for some unknown reason develop sudden rupture lungs because of emphysematous changes of the top of the lung or just underneath the pleura. An enzyme Lysyl oxidase is responsible for cross linkage of elastin. In individuals deficient in this enzyme, emphysema develops.
These are rare examples of pulmonary emphysema. Cigarette smoking is the most harmful agent in the development of emphysema. Emphysema does not damage all the segments of the lungs uniformly; in some cases, the upper lobes are damaged; in other cases, the lower lobes are preferentially damaged. Even in a given lobe, the changes may dominate in the middle or in the periphery leaving other parts relatively normal.

Symptoms

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There may not be any symptoms at the beginning; some years later, patients may complain of shortness of breath on heavy work, gradually in later years with light work and finally, patients will be short of breath even at rest. Those who have associated bronchitis will notice a chronic cough and increased sputum production. They may experience more than their usual share of seasonal cold and chest infections. At an advanced stage of the disease, they will develop heart failure and respiratory failure and many will die prematurely.

 Diagnosis.

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A history of cigarette smoking, the family history of chronic lung disease, and physical signs of inflated lungs with decreased breath sounds will be enough to suspect pulmonary emphysema. A simple breathing test and chest radiographs are all that are required to make a diagnosis. Subsequently, all emphysema patients should have complete pulmonary function tests, oximetry, and serum alpha-1-antitrypsin levels determined. A CT scan of the chest delineates structural changes in the lungs in addition to the heart, blood vessels, ribs, vertebrae and the diaphragm and the stomach.  Then they may be categorized as early, moderately-advanced, and far-advanced stages of the disease along with long-term health outlooks due to the presence of associated diseases.

Treatment.

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It is never too late to give up smoking. All available facilities should be explored in helping patients with smoking cessation.

Yearly influenza vaccination is mandatory, so also pneumonia vaccination initially and repeated once 5 years later. Vaccination for shingles should be offered to elderly patients.

Those who have an oxygen saturation of 87% or below at rest, should use oxygen on a 24-hour basis; those who develop hypoxemia with physical activities should use oxygen when they undertake those activities and also during sleep. Patients having obstructive sleep apnea in addition to emphysema should use appropriate breathing devices during sleep. Oxygen is the only agent that delays or even prevents the progression of pulmonary hypertension and heart failure, improves the quality of patients’ lives and extends abilities to stay engaged in the workplace.

Patients deficient in alpha-1 antitrypsin should be considered for antitrypsin therapy; given by injection weekly. The cost of antitrypsin is about $100,000. / Year

Medications-
Two groups of medications are generally helpful- 

[A] bronchodilators

[B] steroids.

[A] Bronchodilators are many but can be mentioned here under three headings.

1. Anticholine: Atropine like synthetic compounds are administered by inhalation either from a can or by a handheld nebulizer. It counteracts the effects of acetylcholine. Acetylcholine produces bronchial smooth muscle constriction when released at the neuromuscular junction by stimulation of the vagus nerve in the lung. People having prostate hypertrophy or glaucoma should not use this medication without specific instructions from their physicians.

2. Beta agonists: Adrenaline-like chemical compounds stimulate beta receptors of the bronchial smooth muscles and produce dilation of the airways. These agents can be taken orally or by inhalation like the anticholinergic. This medication may increase blood pressure and heart rate and may cause cardiac arrhythmias. To minimize the side effects, inhalation is a preferred method of administration.

3. Xanthine compounds: Caffeine-like chemicals i.e. Theophylline was used extensively in the past, administered orally, intramuscularly, or intravenously. It is hardly used nowadays because of gastrointestinal and cardiac side effects. It inhibits enzyme phosphodiesterase and thereby produces dilatation of bronchial muscles. It increases the force of muscle contractions of the diaphragm and chest wall muscles by enhancing calcium uptake by muscles; delays the onset of fatigue and improves the functional capacity of muscles.

[B] Steroid.  Corticosteroid, like many synthetic steroid hormones, is extensively used in medicine. The corticosteroid has a direct anti-inflammatory effect when delivered locally or in the entire body when given orally or intravenously. The steroid also helps to stabilize macrophage and mast cell membranes and thereby prevents the release of chemicals that initiate and prolong inflammatory and allergic reactions. The steroid has a long list of significant side effects.

In emphysema, it is used mostly as an inhaler. Since it encourages fungal growth in the mouth and tongue known as thrush or oral candidiasis, the patient should rinse the mouth with warm water 5- 10  minutes after its use.

Emphysema patients will develop one or more major complications several years later. At that time, patients will require hospitalization and proper treatment.

At some point in the progression of emphysema, certain patients may benefit from surgical treatment.  A markedly diseased lobe or lobes, when they interfere with normal functions of other relatively healthy lobes of the lung, may be removed surgically. Also, lung transplantation is an option available for a select group of patients. But it is worth mentioning here that the transplantation of a lung requires a technically superior surgical team and the risk of infection is greater. The survival rate following lung transplantation is 65% in 1 year, and 40% in 5 years.

Pulmonary emphysema is a long drawn debilitating disease. It is the right time, just now, to quit smoking.
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  Edited 2020.     

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Phosphorus

                                                                 Phosphorus

                                                       PKGhatak, MD

An adult has about 1gm of Phosphorus (phosphate levels are expressed in terms of phosphorus) in the body, of which 80% is in the tissues and the rest is in the fluid of the extracellular space. The intracellular phosphate is chemically bound to the bones, cell wall, mitochondria, various intermediate products of glucose, fat and proteins metabolism, enzymes, and are integral parts of DNA and RNA, high energy compounds like ATP, ADP; 80 % of which is bound to calcium in the bones in the form hydroxyapatite. The tissue-bound phosphate is called Organic Phosphate, in short Organophosphate. In medical practice, organophosphates are not measured.

Extracellular phosphate is Inorganic Phosphate. It is present as Dihydrogen phosphate (H2PO4) and Monohydrogen Phosphate (HPO4) in a ratio of 4:1 at a pH of 7.4. Normal blood levels of phosphate vary with age, time of the day, food intake, and pH of the blood. It is higher in children and pregnancy. The normal range of blood phosphates, expressed as phosphorus, is 3.5 to 4.5 mg/dl. To convert it to mmol/L – multiply the phosphate value by 0.323.

Phosphorus and Calcium are like twin brothers – always together; and also have sibling rivalry. When the product of blood phosphate and calcium goes over 70 (phosphate in mg/dl multiplied by calcium in mg/dl), soft tissue calcification, mostly in the eyes, heart, lungs, and skin may occur. To prevent this from happening, the one having a lower concentration in the blood is prevented from getting into the blood from the gut or eliminated by the kidneys by the other one, like a stronger eagle chick pushing the weaker ones out of the nest. When blood calcium levels are low, more phosphate is lost in the urine and phosphate concentration is brought to par with calcium like a true twin.

Red meat, milk and beans are good sources of phosphorus. A normal diet contains about 1.5 gm of phosphate, 80 % of it is absorbed from the gut and the rest is eliminated in the stool. Most of the phosphate is absorbed in the jejunum, then the duodenum and ileum. Absorption in the gut is a passive process, more phosphate is in the food and has a slow transient time, more phosphate is absorbed. Increasing the Sodium load in the diet produces more phosphate absorption. Vitamin D and its analogs increase phosphate absorption. Antacids containing aluminum bind with phosphate in the gut and make it unavailable for absorption. 90% of phosphate in the blood is free, and the rest is bound to protein. Phosphate concentrations in the blood and cells are about the same and phosphate moves in and out of cells easily, depending upon the pH of the blood.

Kidneys:

In 24 hours, about 1.5 gm of phosphate is filtered by the kidneys; 90% of filtered phosphate is reabsorbed in the proximal tubules by a passive process and is dependent on the Sodium transport system. Some reabsorption of filtered phosphate takes place in the distal tubules. Parathyroid hormone and growth hormone depress phosphate resorption.

Phosphate controlling Hormones: 
Parathyroid hormone, Fibroblast Growth Factor-13 (FGF-23) and Calcitriol (active vitamin D3).

The parathyroid hormone produced by the parathyroid glands prevents the reabsorption of filtered Phosphate in proximal renal tubules.
Fibroblast growth factor-23 is a peptide hormone produced in bones by Osteocytes and Osteoblasts when the serum phosphate level is high. It depresses phosphate reabsorption in proximal renal tubules like parathormone. FGF-23 lowers serum calcitriol levels by decreasing the conversion of D2 to D3 and increases the degradation of D3 by stimulating the 24-hydroxylase enzyme.
Calcitriol (active D3). It mobilizes calcium and phosphate from bone by increasing Osteoclasts activities. It also increases the abortion of dietary calcium and phosphates in the small intestine. Calcitriol activities in the small intestine are over and above its action on osteoclasts and in the end bone loss of calcium does not take place.

Role of Inorganic phosphate:
It has a vital role in maintaining normal functions of cells of the entire body including red cells, white blood cells, platelets, oxygen transport system and blood pH. It maintains the bone structure and its stability, muscle functions and transmembrane resting potential.

High blood Phosphate is called Hyperphosphatemia.

Failure to eliminate phosphate via urine is the most important cause. Any disruption of the balance between the phosphate absorption in the gut and elimination by the kidneys will have a profound effect on the blood levels of phosphate. 
Renal causes of hyperphosphatemia are - a low GFR as seen in renal failure.
Increased phosphate reabsorption due to hypoparathyroidism, hyperthyroidism, acromegaly, juvenile hypogonadism, insulin, growth hormone.
Vitamin D, high serum calcium, and magnesium increase phosphate absorption.

Phosphate levels are high in situations of increased phosphate load, as seen in excessive use of laxatives containing phosphate, a diet containing high phosphate, transfusion of old red cells due to hemolysis. Rapid tissue breakdown releases plenty of phosphates - examples are lymphomas, tissue necrosis due to ischemia, gangrene and crush injury. High levels are also present in extracellular and intracellular volume contraction, magnesium deficiency and familial intermittent hyperphosphatemia.

Conditions where Phosphate levels are low – (Hypophosphatemia).

1. Hyperventilation, respiratory alkalosis and metabolic alkalosis - due to the movement of phosphate from the blood into the cells.

2. GI loss. Due to diarrhea, and vomiting.

3. Renal loss. Due to excess parathormone and renal failure. In congenital conditions like Fanconi syndrome, Wilson's disease, and glycogen storage disease.

4. Vitamin D deficiency.

5. Multiple myeloma, heavy metal poisoning, amyloidosis, renal transplant, vitamin D resistant rickets, a rapid expansion of blood volume by saline and bicarbonate, early stages of acute tubular necrosis and use of potent diuretics.

6. Alcoholism. Due to multiple factors.

7. Starvation.

8. IV hyperalimentation

In a clinical situation of significant hypophosphatemia, the urine should be phosphate free. If phosphate is present in the urine, then the cause is renal.

Treatment of hypophosphatemia.
Generally, patients are very sick and require IV phosphate replacement along with treatment of the underlying cause. Since low blood levels do not reflect the true value of the total body phosphate content, frequent blood level determination is required to correct hypophosphatemia.

Treatment of hyperphosphatemia.
Restricting phosphate intake, use of phosphate-binding antacids, alkalization of urine and correcting the underlying cause often is not enough and hemodialysis may be required at times. However, dialysis is also not very satisfactory in removing excess phosphate from the body.

 

Phosphate in organic form is an essential part of the cell membrane, DNA and RNA of nuclei and RNA of the mitochondria of all nucleated cells of the body. Red Blood Cells must have adequate levels of 2, 3 diphosphoglycerates to deliver oxygen to tissues. All cellular enzymatic reactions require phosphate and organic compounds. Energy generation, ATP formation is phosphate dependent. Additionally, phosphate is the second most important buffer and calcium pyrophosphate provides bone and teeth stability and strength. 

Updated 2020

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Calcium

                                                                Calcium

                                                     PKGhatak, MD

We have about 4 lbs. of calcium in our body, almost entirely in bones and teeth. Blood levels of calcium are 8.5 to 10.5 mg/dl; 50% of blood calcium is in ionized form, and the rest is bound with serum albumin and immunoglobulin. The intracellular calcium concentration is 400 ng/dl. We lose about 250 mg of calcium daily in urine, feces, and sweat. We consume about 500 mg of calcium daily in food.

Calcium not only provides strength and stability to bones but also is the immediate source of ionized calcium in the blood. Calcium is essential for muscle functions, heartbeats, nerve conduction, clotting of blood, secretion of all glands, and vascular wall contraction and relaxation.

Bones and Calcium.

---------------------

The calcium in bone is a loosely bound crystalline hydroxyapatite form of calcium phosphate. Both deposition and resorption of calcium in bone are under the direct influence of parathyroid hormone (PTH). Bone is active living tissue and the daily turnover of calcium between blood and bone is around 250 to 500 mg/day. After reaching midlife, we begin to lose bone calcium about 1% a year.  If for any reason the blood level of ionized calcium drops, even slightly, calcium is mobilized from the bone. The calcium sensors are located on the parathyroid glands; the effect of stimulation of these sensors is the immediate release of the preformed PTH hormone.  PTH receptors are present on osteoblast cells but not on osteoclasts. The action of PTH on osteoblasts is to promote calcium deposition and release cytokines which in turn activate osteoclasts, thereby increasing the resorption of calcium from bone. Only in cases of prolonged calcium deficiency does the osteoclast activity predominate. Short intermittent administration of PTH increases bone density.

Gut and Calcium.

-------------------

The digestion of food by gastric acid liberates calcium from food. The released calcium is absorbed in the small intestine, mostly under the influence of active vitamin D and also about 20% directly without vitamin D. If a meal contains a large amount of calcium, a higher proportion of calcium will not be absorbed; on the other hand, if calcium content is adequate, and meals are taken two or three times a day, a much higher portion of calcium will be absorbed from the gut. The daily absorption of calcium in the gut is about 400 mg.

Calcium present in the gastrointestinal secretions is not available for absorption and about 150 mg a day is lost in the stool. This is an obligatory loss and must be replaced in the diet.

Kidney and Calcium

----------------------

The kidneys filter about 10 grams of calcium a day, of which only 100 mg is lost in the 24 hour urine. 65% of the filtered calcium is reabsorbed in the proximal tubules; 20% in the cortical thick part of the ascending loop of Henley (cTAL) by the influence of locally present calcium sensors (CaSR), the remaining 10% in the distal convoluted tubules (DCT) under the influence of PTH. In cTAL Thiazide diuretic promotes   Na+ secretion and absorbs Ca+, resulting in lowering calcium in the urine. Furosemide prevents calcium reabsorption in DTC. 

Blood and Calcium.

--------------------

The ionized calcium level in blood is tightly regulated by calcium sensors located on the parathyroid glands. Any fall of ionized calcium will be normalized within minutes by the PTH action of osteoclasts of the bone. A sustained low level of calcium increases PTH production. PTH increases calcium reabsorption by the kidney and increases the absorption of calcium in the gut by the activation of vitamin D by PTH.  As ionized calcium and vitamin D levels raise the PTH level, it returns to normal.

Tissues and Calcium

------------------------

All cells have calcium in the cell sap, called intracellular calcium. The normal levels are 1.1 to 1.3 mmol/L. Compared with blood level this is about 10, 0000 times lower. There is a tendency for calcium to move from the blood into the cells. The cellular entry and exit of calcium are very closely regulated and take place along calcium channels. Various hormones, proteins, metabolites and nerve impulses modulate calcium movement across the cells.

Food rich in Calcium.

------------------------

Milk and milk products are a good source of dietary calcium.    Leafy vegetables like turnip greens, kale, Chinese cabbage, spinach, nuts, beans, broccoli and soy products contain varying amounts of calcium. A good plant source of calcium does not automatically mean all the calcium will be absorbed. The phytic acid present in beans, nuts, and whole grains, bread binds with calcium and calcium is lost in the stool. The oxalic acid present in rhubarb, spinach, and collard greens must be avoided by people who have had kidney stones. In the malabsorption of fat, the undigested fatty acids bind with calcium in the gut and are not absorbed.  Our daily intake of calcium in food is between 500 to 1000 mg.

Calcium fortified food.  

--------------------------

Only orange juice and soy products are regularly fortified with calcium, and some brands of cereals also contain added calcium. Products made of whole grain though contain a modest amount of calcium is a good source of calcium because of the amount consumed.

High and Low Intake of Calcium.

-----------------------------------

About 5 to 20% of the calcium in the food is absorbed in the small intestine directly without the assistance of vitamin D. In other words, this path of absorption is not regulated. A 20% of 4gm calcium supplement will result in 800 mg of calcium absorption and overwhelm the regulatory system and will produce calcium toxicity and lead to kidney stones and kidney failure among other symptoms if continued for weeks.

A diet deficient in calcium leads to overproduction of PTH, bone demineralization, osteopenia, bone fractures, cardiac arrhythmias, muscle weakness, muscle cramps and other symptoms.

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Vitamin D

                                                                         Vitamin D

                                                                PKGhatak,MD

Vitamin D is a fat soluble vitamin. It is also a hormone.

Cholecalciferol, known as Vitamin D3, is vitamin D for vertebrates. Vitamin D2 is Ergocalciferol, and it is vitamin D for invertebrates, aquatic plants, and fungi.

Our daily requirement of vitamin D has recently been raised to 600 IU or 15 mcg a day from 400 IU. The important dietary sources of vitamin D are fish, milk, eggs, meat, and field mushrooms. In the USA   milk, cereals, and margarine are fortified with vitamin D. A serving of 3 oz fish supplies 200 to 400 IU, 15 ml of cod liver oil 1400 IU, a large egg about 40 IU, and beef 3 oz 15 IU of vitamin D. For strict vegetarians (vegans) sunlight exposed or ultraviolet B light exposed mushrooms, and yeasts are the only source of vitamin D.

Cholecalciferol - vitamin D3, however, is not an active vitamin. Vitamin D3 is taken up by the liver cells and converted to Calcidiol {25(OH) D}. It is stored in the liver cells, where it combines with alpha globulin and is released into the blood when required. Calcidiol is a weak vitamin D. When it reaches the Proximal Tubular cells of the Kidney, the calcidiol is converted to Calcitriol {1,25(OH)2D} by the action of Parathyroid Hormone (PTH). Low blood levels of phosphates also stimulate the activation of vitamin 1,25(OH)2D.  Calcitriol is the active hormone/vitamin D3. It circulates in the blood bound to a protein called vitamin D binding protein (VDBP).  The active vitamin attaches to the receptor vitamin (VDR) on the nucleus of cells of the small intestine, bone, heart, gonads, prostate, brain, and other tissues; and in turn, produces specific proteins for specific functions.

Cholecalciferol is produced by the cells of the deeper layers of the Skin from a normally present cholesterol derivative  - 7-dehydrocholesterol, when exposed to the ultraviolet B (UVB) light of sun rays. In tropical countries, people exposed to the sun even for a short time can produce their daily requirements of vitamin D.   However, as vitamin D accumulates in the skin, this process slows down and excess vitamin D is broken down. In temperate regions, there is not enough UVB light in sun rays for the skin to produce sufficient quantities of vitamin D; moreover, sun-blocking lotions and melanin pigment of the skin block UVB light. Window glass blocks UVB and indoor sun exposure has no effect on vitamin D production. Calcitriol must be supplied to the body with food.

White blood cells and macrophages are also capable of producing calcitriol for its use locally.

Vitamin D3 is manufactured for commercial use by UVB exposure of wool fat; D2 is produced by the same process on yeasts. Liver and fat cells store vitamin D as 25(OH)D. An obese person has more stored vitamin D than a thin individual. Recently questions have been raised about whether vitamin D2 can be fully converted to D3 in humans. Excess vitamin D is secreted in bile and reabsorbed in the terminal ileum.  1,25(OH)2D is broken down in various tissues by enzymes.

The vitamin D receptors (VDR) in different tissues differ in their response to 1,25(OH)2D. The receptors of the cells of the small intestine are the most active.  These activated receptors promote specific protein production by target genes which in turn combine with calcium in the intestine and carry calcium across the cells to the portal circulation and to the liver. Vitamin D also promotes phosphate absorption in the small intestine. In the proximal tubular cells of the kidney under the influence of PTH, the 1,25(OH)2D activates the VDR and thereby promotes calcium reabsorption. In bone, the 1,25(OH)2D has multiple actions by activating several genes. In osteoblasts, it promotes calcium deposition, increases bone matrix proteins and type 1 collagen production and bone growth.  Osteoclasts are activated by cytokines released by osteoblasts by the action of PTH and help bone resorption and increase serum calcium.

In parathyroid glands calcium bound VDR, depresses cell proliferation thereby lowers PTH production. It also has antiproliferative effects on keratinocytes of the skin and cancerous cells of the prostate and breast.

It should be understood that there is more than one cause of decreased vitamin D activities in humans. The most common cause of deficiency is dietary; other causes are: advanced liver disease and renal failure, diseases of the small intestine, malabsorption syndrome, and lack of exposure to sun rays, hypoparathyroidism and congenital abnormality of genes. Drugs that interfere with vitamin D are Barbiturates, Phenytoin, Ketoconazole, INH, and Rifampin.

Normal blood levels of vitamin D are 15 to 25 ng/ml or 37 to 62 nmol/L.   Laboratory reports vitamin D results as 25(OH)D. About 90% of vitamin D in the blood is bound to VDBP, free D [1,25(OH)2D] vitamin is 0.03%, and the rest is combined with serum albumin

The free active vitamin D3 remains normal in face of vitamin deficiency because the renal distal tubular cells are still capable of turning out adequate quantities of active vitamin D3[1,25(OH)2D3] by acting on the dwindling store of vitamin 25(OH)D3. 

Symptoms of vitamin D deficiency in adults are non-specific, the weakness of muscles of the shoulders, hips, and thighs may be the only symptoms. When deficiency persists in thinning of bones (osteopenia), loss of mineralization of bone (osteomalacia) may be detected by X-ray and bone densitometry respectively.   When vitamin D deficiency persists for months, the Parathyroid glands become overactive and produce excess Parathyroid Hormone (PTH) in order to maintain a steady normal blood level of calcium. Due to the increase in PTH, phosphates loss continues through the kidney and bones become more demineralized and become soft. Bowing of these softened bones occurs under the weight of the body and fractures may result. At this stage, if treatment for osteomalacia is started with Bisphosphonates, (Fosamax) which prevents PTH action on osteoclasts,  an acute hypocalcemia may develop, and it may manifest as tetany or laryngospasm. The treatment should be directed to correct vitamin D and calcium deficiencies first.

In children, vitamin deficiency leads to rickets, growth retardation and hypocalcemia tetany.

A short summary of the action of vitamin D.

1. Increases serum calcium levels by (a) increased calcium and phosphate absorption,(b) increased release of calcium from the bones by stimulating osteoclastic activities, and (c) increased renal reabsorption of filtered calcium in the renal tubules.

2. If adequate estrogen, growth hormone, and thyroid hormone are present, vitamin D promotes new matrix formation.

When mega dose vitamin D is taken, it may bypass normal controlled vitamin D absorption in the gut, instead, combine with lipoproteins and is carried directly to macrophages in arterial plaques and promote calcification of plaques. When blood levels of vitamin D are high, vitamin 25(OH) D may displace 1,25(OH)2 D from the vitamin D binding protein thereby increasing free 1,25 (OH)2D levels. Active vitamin D [1,25(OH)2] directly attaches to the vitamin D receptors and thereby calcium blood levels increase further.  A high dose of vitamin D therapy (40,000 IU) over several months may lead to high serum calcium, large urine output, increased frequency of urination, kidney stones, kidney failure and calcification of the kidney and other tissues.  
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Hunger & Obesity

                                                     Hunger and Obesity

                                                  PKGhatak, MD

One cannot escape from the fact that the present generation is getting heavier and fatter, despite cable channels broadcasting continuously healthy cooking, diet, and exercise, the print media are not far behind. 

Why then is the opposite happening!

Maybe we are asking the wrong questions. We should be asking what makes us feel hungry.

Hunger is a sensation registered in the brain as a strong desire for food. As we fill up our stomachs with food and drinks, the hunger goes away and again returns after an interval.

The nerve center for hunger, the Appetite Center, is located in the Hypothalamus. The stomach and small intestine are connected to the appetite center. The hypothalamus, in turn, is connected with other parts of the brain, and the input reaches the conscious level in the cerebral cortex.

 A full stomach sends signals to the brain through the vagus nerve. The appetite shuts down.  Alcohol speeds up stomach emptying, and fat delays emptying.

  

 In starved conditions, the fat cells provide needed energy. Eating extra food makes adipocytes bulge with fat.  Leptin, a hormone, decreases appetite and increases energy expenditure (EEx).  Adipocytes also produce blood pressure regulating Angiotensinogen, a vascular protective protein called Adiponectin, a blood clotting inhibitor known as Plasminogen activator inhibitor 1, a complement called Adiposin or factor D, and cytokines - Interleukin IL6 and Tumor necrosis factor alpha. The net effect of these chemicals on the body is to help regulate BP, blood sugar, blood lipids, blood vessels’ health, healthy body weight, and a competent immune system.

The appetite center is under the influence of several hormones and chemicals. Cortisol depresses appetite. Glucagon secreted from the pancreas has a similar effect. Growth hormones and Gonadal hormones also regulate appetite.  A gut peptide, Ghrelin, is produced by the stomach, which speeds up stomach emptying. Peptide YY and cholecystokinin are produced and have a similar effect to ghrelin. 

High blood sugar and Ketones depress the appetite.

It may sound strange, but it is true that as the person gains weight, the mean energy expenditure (EEx) increases.  As EEx increases, the person feels hungry because of stimulation of the appetite center. The reverse is also true: with weight loss, the EEx falls and the appetite center is depressed.

Non-Exercise-Activity-Thermogenesis (NEAT) regulates energy expenditure of activities of daily living. The basal metabolic rate (BMR) accounts for 70% of EEx,  only 5 to 10% of EEx is required for voluntary activities, including work, exercise, etc. A person can burn at most 400 kcal/ hour by intense exercise, and marathon runners can burn 1200 kcal/hr.

To lose 1lb of flesh, one has to burn 2,500 kcal.  It is not difficult to understand why losing the extra fat by exercising is difficult.

Hypothalamus produces and releases many peptides known collectively as hypothalamic peptides; by the actions of these, it maintains a balance between appetite, fat storage, and energy expenditure. Important peptides in this group are neuropeptide Y, Agouti-related peptide, alpha melanocyte-stimulating hormone, and melanocyte-concentrating hormone. An interaction between hypothalamic peptides and neural pathways via Serotonin, Catecholamine, and endocannabinoid receptors in various target tissues is ultimately responsible for maintaining steady body weight.

Appetite supressing drugs are coming to the market in increasing numbers, but none are safe for long-term use. These drugs act directly on the appetite center by increasing the production and release of a chemical group called monoamine. The pharmacological actions of norepinephrine, serotonin, and dopamine are enhanced by monoamine. These drugs may increase the risk of heart disease and high BP, as well as insomnia and nervousness.

The newer anti diabetic II oral drug, SGTP-2, and a weekly injection of Glucagon-Like Peptide-1 Inhibitors ( GLP-1) work in different sectors of metabolism and have a different safety profile.

 Body mass index (BMI), height-weight nomograms, the thickness of skin fold of arms, and waist-hip ratio are helpful to identify obese individuals, but not all agree on a particular standard. An underwater determination of weight-volume ratio is an accurate measurement of obesity, but it is not a practical method.

 A normal BMI is 20 to 25 kg/m2. A person is considered overweight if the number is between 26 and 29, and over 30 is considered obese. An increase in the waist-hip ratio of over 0.9 in women and 1.0 in men is taken as obesity.

The cause of obesity is unknown. Several factors have been implicated: heredity, environment, cultural habits, a viral infection of the GI tract, and sleep deprivation. 

Several endocrine disorders like Cushing's syndrome, Hypothyroidism, Insulinoma, Hypogonadism and mental retardation also produce obesity.

 Obesity increases the risk of heart disease, diabetes, high cholesterol, high BP, arthritis, and disturbances in sex-hormone-related diseases.

The body’s own regulating system of appetite, energy storage, and energy expenditure must be derailed before weight gain starts. If the process is allowed to progress unchecked for years, the person will be overweight or even obese.

 

edited May 2025

 

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Hepatitis

                                                                Hepatitis

                                                     PKGhatak, MD                                                         

          

                                                 

Yellow Fever is now classified under acute viral hemorrhagic fever but it is viral hepatitis.  The methodology used in the investigation of yellow fever outbreaks opened the doors for all future studies in the epidemiology of viral hepatitis. 

In colonial America, outbreaks of Yellow Fever were frequent.  In 1904, the USA took over the construction of the Panama Canal from the French and thousands of US workers went there to work. Over 5000 workers died of yellow fever and malaria during canal construction. Carlos Findlay of Cuba theorized that man-to-man transmission of yellow fever did not occur and in 1881 he identified a mosquito - Ades egypti, which was responsible for the spread of the disease. Walter Reed confirmed Findlay’s observation and Reed’s research proved that the yellow fever virus infected jungle monkeys and the monkey acted as a natural reservoir of the virus. When men entered their domain, the mosquitoes attacked men and infected mosquitoes transmitted the yellow fever virus to men.  For his work, Carlos Findlay was nominated seven times for the Nobel Prize in Medicine; he, however, did not get the prize. Max Theiler of South Africa won the Nobel Prize in 1951 for discovering an effective vaccine.   

In present-day medical journals, you will find discussions on viral hepatitis; they are mostly on hepatitis C (HCV) and occasionally also other forms of viral hepatitis. The cable news and newspapers will whip up your anxiety, from time to time, with reports of outbreaks of a few cases of Infectious Hepatitis, also called HAV or hepatitis A virus infection. Compared with Yellow fever, Infectious Hepatitis is a relatively mild disease and fatality is rare.

The story is quite different in South Asia where Hepatitis A infection is endemic. The poorer the country, the more prevalent the disease is and the government statistics are either non-existent or simply unreliable.

Hepatitis A.
---------------

It is transmitted from man to man by the fecal-oral route and is highly contagious.

When a person is infected with the virus, initially he has no symptoms but the virus keeps on multiplying in their body. He sheds the virus in his stool. Contaminated water and food are the primary mode of spread of hepatitis A, sexual contact and sharing needles among IV drug users also spread the disease. Even when patients recover from the infection, they would continue to shed the virus for another 2-3 weeks. In South Asian countries, the monsoon rain often inundates the cultivated fields; overflow sewer water also ends up in fields and contaminates the produce. People eating raw vegetables, shellfish, or fresh fruits are infected. The rich and affluent middle class often employ 2 -3 domestic help as cooks, kitchen help, etc., they are poor and live in appalling unsanitary conditions. They have no knowledge of fecal-oral transmission of hepatitis, and hardly ever wash their hands with soap and water after visiting toilets. This mode of spread of a disease is called the fecal-oral route of transmission. You may not know that people working in restaurants in many South Asian countries are not required to carry food-handler certificates. Consequently, you are at risk when you eat out. If you have neglected HAV vaccination, check your vaccine status before you leave home.

Infected people when recovering from HAV infection carry a lifelong immunity; others can protect themselves by taking the HAV vaccine.

Hepatitis B.
-------------

People infected with this virus carry the virus in all of their body fluids, including saliva.

Transfusion of contaminated blood or blood products, sharing infected needles and sexual intercourse are the usual modes of transmission of HBV (hepatitis B virus). Late in pregnancy, the mother may pass the virus to the unborn child and also may infect during childbirth. Breastfeeding does not add any risk.  Since mandatory screening for hepatitis was instituted in donated blood and blood products, the HBV by transfusion is nearly eliminated. All newborns are vaccinated for HBV and adults are going to be covered for HBV vaccination by the new health care bill. HBV is still a problem for HIV infected people. The new cases of HBV infection are decreasing rapidly; hopefully, it will be eliminated in the near future.

Hepatitis C.
---------------

It is a blood-borne infection like HBV; however, the virus is less virulent.
The mode of transmission is usually by sharing IV needles and transfusion of contaminated blood and blood products and by sexual contact. Transmission during the perinatal period (late pregnancy and childbirth) is very rare. Breastfeeding does not increase the risk of transmission to a child.

This disease is a major concern of the present time, not because it is a deadly disease, but because the illness is so benign initially that the infected persons may be completely symptom-free. The majority of the infected people will recover spontaneously. Only a minority will have major complications. Carriers of this virus can be identified by antibody testing and polymerase chain reaction (PCR) tests. Several years after the initial infection, patients may present with cirrhosis of the liver or cancer of the liver. The treatment of HCV is expensive, requires medication administered by injections or oral antiviral tablets, given over twelve weeks, in certain cases, liver transplant is the only option. Since HBV infection is declining, HCV infection has come more and more into focus. There is no vaccine against HCV.

Hepatitis D.
-------------

HDV is a deadly virus but it either co-infects people at the time of HBV infection or infects people who are suffering from HBV disease; by itself, it is unable to infect healthy individuals.

There is no HDV vaccine.

Hepatitis E.
--------------

This virus is a waterborne disease and spreads by contaminated drinking water. It is rarely transmitted from person to person. It infects younger adults in general, often those immune to HAV. It is suspected that pigs are the natural reservoir of this virus.

The vaccine for Hepatitis E is available only in China.

Hepatitis F.
-------------

This virus may cause hepatitis in rhesus monkeys but has not been proven to cause any human disease. This virus is delisted as a cause of human viral hepatitis.

Hepatitis G.
--------------

This is also known as GBV-C, named after G. Baker. It is an infectious virus to humans but probably does not cause human illness. It is transmitted by the oral route and sexual contacts in HIV infected people.

It is thought that co-infection with the BG-C virus may actually slow the progression of HIV infection.

Several other viruses may also damage the liver, but the liver is not their primary target, and will not be discussed here.

Hepatitis means inflammation of the liver, not necessarily infection only. Many other agents including poisons, drugs, parasites, and our own misdirected immune system may seriously damage the liver.

Let us look at this aspect a bit closely:

1. Lupus hepatitis: (SLE) For some poorly understood reasons, some individuals may start directing the body's defense system against their own normal tissues and organs. In SLE liver damage is a significant finding.

2. Poisoning: By consuming poisonous mushrooms, many people may end up in acute liver failure. Habitual drinking of African bush tea, a known hepatic poison, may lead to serious liver problems. Industrial poisoning by Carbon tetrachloride, a dry-cleaning agent, is a well-known hepatotoxin; so also, many other deadly gases are used in warfare. Suicidal attempts with ingestion of Copper Sulfate is common in some Asia countries, hepatic narcosis is not unusual in many such cases. Chronic Iron overload (in Hemochromatosis, repeated Red Cell transfusions) may lead to hepatic cirrhosis and liver cancer. A high dose of Paracetamol (Tylenol) may cause Liver failure.

3. Drug reaction: Many medications have significant adverse effects on the liver, and may produce reversible or irreversible damage to the liver. Some of the drugs are listed here.

Anti-Cholesterol: - Ezetimide, Statins.Fenofibrate, Gemfibrozil

Anti-TB: - Isoniazide, Refampin, Pyrazinamide,

Antibiotics: - Tetracyclines, Oxycyclins, Chloramphenicol, Telithromycin, Trovafloxacin, Sulfanomide, Nitrofurantoin,  

Anti-Retroviral: - Abacavir, Nevirapine, Tipranivir,

Anti-Seizure-: Carbamazipine, Valproic acid, Phenytoin, Lamotrigine, Felbamate

Vitamins: - Vitamin A, Niacin

Ant- Diabetic: - Troglitazone, Pioglitazone, Rosiglitazone

Antifungal: - Ketokenazole, Itracoazole, Voriconazole

Antidepressant: - Duloxatine, Premoline, Nefazodone

Arthritis: - Aspirin, Declofenec, Rofecoxib. Leflonamide, Bromofenac, Benoxaprofen, Methtrexate, Phenylbutazone, Parafon forte.

Anti-Parkinson: - Methyldopa, Tolcapone

Anti- Cancer: Flutamide, Interferon beta1b, Imuran, Imatinib, Isotretinoin

Anesthetic: - Halothane

Acne: - Isotretinoin

Heart: - quinidine, Amiodarone

Asthma: - Zileuton, Zafirlukast,

Alzheimer’s disease: - Tacrine

Hyperthyroid: - Propylthiouracil, Methimazole

Diuretic: - Tienic Acid.

4. Parasitic diseases: Liver flukes (schistosomiasis) infect men when they eat uncooked fish. A bite of sand fly spreads Leishmaniasis (Kalazar). It is a chronic debilitating disease with hepatic enlargement. Amoebic liver abscess by Entamoeba histolytica in tropical countries is not uncommon. Humans acquire amoebic infection via the fecal-oral route and from the gut, the amoeba travels to the liver via the portal vein. By eating improperly cooked pork, men acquire Echinococcus infection and may develop multi-loculated Hydatid cysts in the liver. Mosquitoes transmit Malaria. There are several families of malaria parasites; in some chronic stages of malaria, liver enlargement and dysfunction are common.

5. Leptospirosis: Liver necrosis is a common finding in its hepatic form. The disease spreads via the contamination of water by rats’ urine.

6. Q Fever: Drinking milk contaminated with   Rickettsia may cause serious liver damage.

7. Fungal infection: In disseminated Histoplasmosis liver damage is inevitable.

8. Bacterial infection of the liver is very unusual; however, an infection may spread to the liver from infected gallstones and bile ducts.

9. Alcohol: It is a curse of our civilization. So many people are addicted to this potent liver poison and heading for chronic liver diseases and serious health & social consequences. Alcoholics are less likely to recover when they contract other forms of hepatitis.

This is not a complete list. But if you are reading it, please pay attention and do not get into trouble.

 

edited 2020

 

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Wheezing

                                                                     Wheezing

                                                             PKGhatak, MD

Wheezing is a common symptom of asthma but asthma is not the only cause of wheezing. As more and more people are developing asthma. You need to pay attention if you begin to wheeze for the first time in your life.

What makes one wheeze?

When airways of the lungs (nose, throat, voice box, windpipe, bronchus and its smaller branches) become narrower relative to the airflow, the flow of air becomes turbulent and makes a sound. The sound then gets magnified in the chest because the air in the lungs acts as a resonator.

The airway has three layers, the innermost layer is moist and rich in blood supply, and the middle layer has smooth muscles laid down in a circular fashion and the outer layer has connective tissues.

Inflammation or infection of the airway makes the inner wall swell up making the passageway narrower; contraction of muscles of the middle layer narrows the airway. Any growth or swelling next to the outer layer of the airway can produce narrowing by compression of the airway.

When a person breathes with a narrowed airway, wheezing is heard; at the same time, the person feels it is difficult to breathe because he has to work harder to breathe. When one is exhausted from labored breathing, airflow diminishes so much that only a faint sound of airflow is hard and wheezing disappears. It is now an emergency, without medical help, life is in danger.

Asthma is an inflammatory disease of the bronchus and its branches, resulting in swelling of the inner layer, at the same time, the muscle layer contracts, making airways still narrower. There are several effective medications available to treat asthma.

What about other causes of wheezing.

When heart muscles become weak and fail to pump blood adequately through the lungs the liquid part of blood sips out from the blood vessels into the lungs, constricting the airways from outside and also swelling the inner layer making it narrower.

Any foreign body lodged in the airway, any growth or accumulated secretion in the airway can make one wheeze. In addition, there are several other diseases, not so common, involving the airway and may produce wheezing.

The common cold and hay fever in a certain group of people can produce wheezing. Newborn infants and children have narrower airways, to begin with; as a result, any viral infection can produce wheezing.

In essence: if one begins to wheeze for the first time, it must be checked out by a physician.

 

edited 2020.

 

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Sinister Headache

                                                         Sinister Headache

                                                     PKGhatak, MD

Any abnormal condition in the head and neck area may cause a headache. The cause of this type of headache is easily identifiable and effectively treated. There are, however, more serious forms of headaches. We will consider a few of them here.

 

The brain tissue itself is insensitive to pain, but its coverings (meninges) at the base of the skull are very sensitive. Arteries and veins of certain parts of the brain are also sensitive to pain. Bacterial meningitis is probably the most life threatening and very rapidly progressing infection.

An 18-year-old youngster gets up in the morning with a mild frontal headache and malaise, which he attributes to drinks he had the night before. Later in the day, he has chills and fever; the headache becomes intense and throbbing in character.  He develops nausea and vomiting. In an hour he becomes dizzy; pink colored skin rashes begin to appear over his wrists and ankles. Unless he is taken to a hospital at that moment, it may be too late to save him. This is an example of meningococcal meningitis.

Besides this bacterium, other bacteria may also cause meningitis but the progression of meningitis in those cases may not be that explosive and skin rashes do not develop.

A variety of common and not so common viruses can cause meningitis. In general, sore throat, runny nose, and cough begin first; a day or two later headaches become most troublesome and persist even after taking potent headache pills. A low-grade fever continues and a stiff neck develops. Only a spinal tap and examination of the CSF (cerebrospinal fluid) will differentiate viral meningitis from bacterial meningitis. Coxsackie, Echo, Herpes simplex, E-B virus, and Adenovirus are commonly responsible for viral meningitis. From time to time TV news and newspapers scare people with reports of West Nile virus encephalitis, Western Equine encephalitis, St. Louis encephalitis, Japanese B encephalitis, and other forms of encephalitis. Viral Encephalitis is an infection of the brain tissue and is often associated with meningitis. Depending on the type of virus, the illness may go on for days or a week before a correct diagnosis is made. A headache, fever, and neck rigidity are common symptoms; lethargy, mental confusion, and altered consciousness characterize encephalitis. Various neurological signs and seizures are common, however, most of the neurological defects will resolve with treatment over a period of time.

 

The most intense and worst type of headache is seen in subarachnoid hemorrhage. A ruptured intracranial aneurysm is often the cause. Typically, the person has an episode of a short, sudden severe headache, which may subside in time. Then the most painful, intense headache starts, followed by loss of consciousness within a short period. There may or may not be warning signs of the presence of a berry sized aneurysm at the base of the brain; pain following a rupture may be the only presentation. An immediate surgical procedure is required to save the life. 

A stroke, as a result of bleeding inside the brain tissue, may produce a severe headache because accumulated blood stretches the meninges and blood vessels; often, a headache may precede the bleed for hours or a few days, but associated paralysis is the predominant presenting symptom. A headache from stroke, as a result of thrombosis of an artery or blood clot emboli, may or may not be present.

 

A person having high Blood Pressure often complains of a dull headache over the back of the head or forehead, often the headache has a throbbing character, at times a headache is associated with dizziness. A headache subsides with the control of BP.

People fear a headache may be a sign of brain tumors but often headache is not a presenting symptom. When a headache is present, it is deep seated, dull aching and becomes worse with coughing and straining at stool.

A persistent and constant throbbing headache over one side of the temple, or in rare cases on both sides, may result from Temporal arteritis, also called Giant Cell Arteritis. The pain is located on the face, jaw, or side of the neck. The scalp becomes very painful to touch. At times, it is associated with visual impairment or the onset of sudden blindness. Urgent treatment is required when vision is affected.

 

A fall or injury to the head will cause pain and headache but if vomiting, confusion, and altered consciousness are absent and no neurological signs are present, then brain injury is unlikely. A subdural hematoma may result from a fall in old people; it could even develop several weeks later. A persistent headache may be the only symptom, later incontinence of the bladder, unsteadiness on the feet, walking difficulties, and drowsiness may develop.

Infection from nasal sinuses or inner ears may spread inside the skull to the brain tissue and may end up in an abscess formation. Persistent fever is associated with a headache and various neurological signs are present depending on the location of the abscess. Nausea, vomiting, drowsiness, mental confusion, and lethargy are common.

The 5^th cranial nerve carries sensation from the face, forehead, and anterior part of the scalp. Herpes zoster infection (commonly called shingles) at the ganglion of this nerve can cause a severe headache and pain in the affected area. At times a headache precedes the appearance of the typical vesicles on the skin. The vesicles appear in bunches like grapes. Without the presence of skin lesions, the diagnosis can be difficult. Early initiation of treatment with antiviral drugs may shorten the duration and severity of the illness. Neuralgia of the scalp and forehead from other causes often makes life miserable for the patients and may be difficult to treat effectively.

Post-spinal tap headache is another painful condition. It is localized on the back of the head, often dull and pulsatile in character. It is worse when the person gets up from the bed and assumes an upright posture and the headache is relieved on lying down. When there is a significant loss of CSF from the puncture site, the problem is a complex one, and a surgical repair of the torn dura is required to seal the leak.  

Migraine, Cluster headache, and Histamine cephalgia are also important in this group, but most people are aware of them, and they will not be highlighted here. 

 

edited 2020.

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Varicose Veins

                                                                 Varicose veins

                                                        PKGhatak, MD

Inside the veins, at certain intervals, there are valves. Valves prevent blood from moving downwards to the dependent parts of the body and legs. Valves break up the blood column in short segments, thereby lowering the pressure within the veins. Blood flows by gravity from the head and neck to the right atrium of the heart. The pressure generated by skeletal muscle contractions and smooth muscle contractions of the vein wall creates the pressure gradient that propels blood from the dependent parts of the body toward the heart. The pressure inside the veins is very low, but higher than the right atrial pressure, which is generally 1 to 3 cm of water.

You can easily see the healthy veins on the back of your hands. If you follow a long vein of your legs, you will notice small bulges along the walls. These are valves. 

When standing in one spot for long hours, blood tends to remain stagnant in the legs. The blood column exerts pressure on the valves. After many years in sedentary workers, the valves become lax and unable to hold back blood, and become incompetent. These veins become tortuous and darker in color, and the condition is called varicose veins. Often, there is also a genetic predisposition for varicosity, but the precise mode of inheritance is not known.

Incompetent veins cause fatigue of the legs and may cause a sense of fullness and pain in the legs when walking for some time. In older people, loss of muscle, the veins become easily visible, and if the valves are incompetent, the stagnant blood thins out the skin, and ulcers and clots develop.  This is called venous thrombosis. Though many other factors favor blood clotting in the leg veins but prolonged immobility in the elderly is the main cause of venous clots.

It is a good idea to remain active even if you have a job requiring standing for long hours. You must walk around every so often to help blood circulate better in your legs, thereby preventing varicose veins.

 

edited May 2025.

 

 

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