Abnormal Genes and Cancer

    Abnormal Genes and cancer

    

          PKGhatak,MD  

                       

                                 

A Gene is a small part of a Chromosome and contains code for a specific cell function. At times, more than one gene can influence the same cell function. Chemically, the genes are Deoxyribose Nucleic Acids (DNA). There are four different nucleic acids - they are known as A, T, G & C. AT and GC always appear in pairs and are called Base Pairs. The three of these base pairs make a word of the coded instruction. A gene, on average, contains 17,000 Base Pairs and may contain as many as several million. Human chromosomes carry 3.2 billion base pairs and only 25,000 genes are known to code proteins. We have 23 pairs of chromosomes and we inherit one strand of the chromosome from each parent.

Believe it or not, every cell of our body has a defined time of existence: there is a time to be born, a time to achieve maturity, time to die and be replaced by a new cell. Different cell lines have different lifespans e.g., white blood cells live 5 days; red blood cells live 120 days and so on. Deaths of cells are programmed into the genes. If and when programmed cell death fails in one cell, this cell continues to live and multiply. This is the beginning of tumor growth and ultimately ends up in cancer formation.

In an individual, the cells are dividing regularly throughout life. During cell division, the chromosomes duplicate themselves and then separate and move to new cells. This is the critical time when things can go wrong.  Errors may appear in the spelling of coded words (Mutation), words may be dropped (Deletion), or attached to a different place (Translocation). The cells of an older person have divided many more times than a younger one and the elderly population is at higher risk of acquiring abnormal genes (Somatic Mutation). It explains the reason for the increased cancer rate in old age. Increasing concentrations of cancer causing chemicals in the environment, food additives, hormones, pesticides, cigarettes, ultraviolet rays of the sun, microwaves, x-rays, and virus infections, etc. either individually or collectively are constantly influencing the normal cell division at this critical juncture. Any minor or major dislocation of this process will lead to somatic mutations. Derailed repair of DNA is an additional cause of mutation.

To guard against these mishaps and to find defective genes, other genes are endowed with surveillance functions and are called Tumor- Suppressor Genes. However, there is no guarantee that mutation will not happen to these very tumor-suppressor genes. And when it happens, it is transmitted to the next generation of children.

A class of genes has the role of a caretaker function called Caretaker Genes. It looks after the entire population of chromosomes. The deficiency of these genes increases the rate of mutation in all genes. Another class of genes, called the Gatekeeper Gene, restrains the growth of individual cells and promotes cell differentiation.

A specific group of cells in our body is constantly keeping a vigil for such mutant cells (Surveillance cells). Once they detect a mutant cell they mark it with a protein, and Killer cells then move in and promptly remove these mutant cells from the body.

Somatic mutation or inherited defective gene/chromosome is the immediate cause of cancer. The development of cancer, however, is a failed multi-step process. A mutant cell has a growth advantage over its neighbors but it must escape from the surveillance cells before it can divide again. When mutant cells have gone through 5 to 10 generations of cumulative mutations then mutant cells have a chance to establish as a Malignant Phenotype (potential to cause cancer in this individual).

Oncogenes.

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These are cancer causing genes. They were first discovered in certain retrovirus induced cancer in chickens. Similar genes (homologous genes) are also present in human cells. But they are very tightly controlled by tumor-suppressors and caretaker genes.  To escape the scrutiny of tumor-suppressed-genes and caretaker-genes the oncogenes have to mutate first. There are 3 such mechanisms.

1. Translocation: A piece of a chromosome containing specific genes breaks away from its normal location and attaches to a different chromosome e.g. In chronic myelogenous leukemia. a piece of chromosome 9 is grafted to chromosome 22. This abnormality is better known as the Philadelphia chromosome of CML.

2. DNA Amplification: A certain part of base pairs of a gene appears repeatedly over and over again. This is often seen in Sarcoma and aggressive breast cancer.

3. Point mutation: One base pair mutation appears in several gene locations; often present in pancreatic cancer and colon cancer.

When one copy of mutated oncogenes overrides the effect of its other normal copy and the disease is manifested in the person carrying the mutated genes. This mode of inheritance is known as Autosomal Dominant Inheritance. When one copy of the mutated gene does not cause cancer but needs both copies of genes to be mutated then this type of inheritance is called the Autosomal Recessive Mode of transmission. One mutated copy is usually inherited; the other may be due to somatic mutation.

Hereditary cancer.

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Every normal person has many mutated genes and these mutations are generally harmless.  Somatic mutations of genes, for the most part, are not transmitted to the next generation. The hereditary cause of cancer is not more than 5 to 10 % of all cancers. Only about 100 hereditary cancers are known. We read in the newspaper about the finding of a new gene for particular cancer. It does not mean that the gene itself is the cause of cancer. The abnormal gene should be considered as one of the risk factors.

Genes are named according to their functions or association with a specific disease.

To specify the location of genetic mutations on chromosomes, numbers and letters are used like astronomers assign letters and numbers to designate points of light in the dark night sky. To give an example: a 11q 13.1 number signifies chromosome # 11, q is the long arm of this chromosome and 13.1 is the band location. Bands are detected when chromosomes are stained with dyes for microscopic examination. (p stands for the short arm of chromosomes and q for the long arm).

 Here are some of the well known hereditary cancers: -

1. Hereditary Adenomatous Polyposis Colon Cancer: The disease is due to APC gene mutation, located on 5q21, a dominant mode of inheritance. Patients develop multiple colon polyps, some or many of them eventually turn cancerous.

2. Hereditary Non-adenomatous Colon Cancer: Also known as Lynch syndrome due to MHS2, MHL1, PMS2 gene mutations, located on any of these positions – 3p21.3, 7p12.2p16, a dominant mode of inheritance.

3. Multiple Endocrine Neoplasia 2a - MEN 2a: Due to RET gene mutation, located on 10q11.2.  Patients have medullary thyroid cancer, pheochromocytoma and parathyroid overactivity.

4. Hereditary Breast/ Ovarian Cancer 1: Due to oncogene mutation of BRCA1gene, located on   17q21; dominant mode of inheritance. Carrier of BRCA1gene has an 80% risk of breast cancer and 60% risk of ovarian cancer; and has some increased risk of colon, pancreatic, and uterine cancers.

5. Hereditary Breast/Ovarian Cancer 2: Due to oncogene mutation of the BRCA2 gene, located on 13q12.3, a dominant mode of inheritance.  Female carriers in addition to the risk of breast and ovarian cancers also are at risk of cancer of the colon, stomach, gallbladder, bile duct, and melanoma. Male members have a risk of breast, colon, and prostate cancers.

5. Hereditary Prostate Cancer: Due to mutation of oncogene HPC1, location 1q24-25, a dominant mode of inheritance. Carriers of this mutation develop cancer in age 30s - 40s, this cancer is aggressive in nature.

6. Cancers due to Oncogene Translocation:

 Cancers of blood cell lines and lymphatic tissues are strongly associated with such defects. Examples are- Chronic myelogenous leukemia, Mantle cell lymphoma, Follicular lymphoma, Ewing’s tumor, T-cell leukemia, Burkett’s lymphoma.

Cells carry out functions according to instructions coded in the genes like applications run on computer software programs. When software programs are corrupted by hackers or computer viruses, they create havoc. Similar processes are at work in cells having cancer enhancing mutations.

Every day scientists and researchers are adding more knowledge in genetics and cancer research, and progress in recent years has been astounding. Your interest in this subject will encourage more research.  

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Fat Cells (Adipocytes)

Adipocytes

PKGhatak,MD

 Fat gets bad press all the time. It began with epidemiological studies linking the increased rate of heart attacks with elevated blood levels of fat and cholesterol.

If fat is that bad - why do we have fat cells in our body in the first place?

 You must have seen the painting of the smiling face of the Mona Lisa. Now think - if she was skinny like the present day supermodels would her smile be as captivating!

Underneath the skin, there is a layer of fatty tissue that protects the body against the elements - acting as a thermal insulator.  A human body has many empty spaces, big or small, all are nicely packed with fatty tissue. Without packing, the kidneys, liver, spleen, and other abdominal organs will have a hard time staying in their respective places and work.

In starved conditions, Fat cells (adipocytes) release a breakdown product fat called Fatty Acids which provide needed energy to the body. When excess energy (food) is ingested, the excess energy is turned into Triglyceride (fat) and stored in adipocytes.  As fat accumulates, the adipocytes bulge with fat. Fat cells may enlarge four times the original size and then divide; thereby, increase the absolute number of fat cells. On the other hand, in prolonged fasting, fat cells shrink in size but do not decrease in number. Adipocytes, when stretched with loaded fat, release a hormone called Leptin. Leptin acts directly on the appetite center and via the vagus nerve. It decreases appetite and increases the rate of metabolism. Besides leptin, adipocytes also produce a BP regulating chemical called Angiotensinogen, a vascular protective protein called Adiponectin, a blood clotting inhibitory factor known as Plasminogen Activator Inhibitor I, a complement called Adiposin or factor D, and cytokines called Interleukin IL6, and Tumor Necrosis Factor Alpha.  These chemicals help to regulate BP, blood sugar, blood lipids, the integrity of blood vessels, healthy body weight and the immune system.

When body weight increases, leptin production also increases but it does not depress hunger.  Probably because, the secretory products of adipocytes have a rate-limiting production or are made inactive by another substance like Resistin - produced by obese adipocytes. Resistin increases insulin resistance and high blood sugar.

Adipose tissue is a loose connective tissue. It contains adipocytes, preadipocytes, and macrophages and has a rich supply of blood vessels and nerve fibers.

Fat cells (Adipocytes) belong to the Fibroblast Family of Cells of connective tissue origin. Other members of this prominent family are myofibroblasts, smooth muscle cells, osteocytes, osteoblasts, chondrocytes, and fibroblasts. Because of the common origin, these cells share the capacity to differentiate into one another.

An adult has 30 billion adipocytes in the body - about 30 lbs. in weight.
Adipocytes are two different kinds of Adipocytes: White Adipocytes and Brown Adipocytes.

 In adults, most adipocytes are white adipocytes (white fat cells). White fat cells store fat inside the cell as a single large globule; chemically it is a triglyceride. (One molecule of Glycerol combined with 3 molecules of fatty acids). The nucleus of the cells is pushed to one side and the cytoplasm of the cell appears as a thin rim when seen under the microscope. Once loaded with an excessive amount of fat, the white fat cells will divide and increase in numbers.  An adult person turnover 10% of fat cells every year. Preadipocytes, in the connective tissue, generate new adipocytes. In situations of need, the connective tissue fibroblasts transform into adipocytes. And this is not a one-way phenomenon, under appropriate circumstances, adipocytes can transform into fibroblasts and fibrocytes.

The brown fat cells are also known as Baby Fat Cells, they are loaded with mitochondria that give them the brown color.  20% of adipocytes in newborn babies are brown fat cells. Brown fat cell numbers decrease with age. In adults, brown fat cells are found in the lower neck and around the main blood vessels of the chest. Hibernating animals have more brown fat cells. The fat in the brown adipocytes is present as drops of various sizes throughout the cell cytoplasm and the nucleus is somewhat out of the center but not pushed to the periphery.  Brown fat cells generate heat by a process known as Uncoupled Respiration and Thermogenesis. This is achieved due to the presence of a unique mitochondrial protein. Simply, it means when exposed to cold the Norepinephrine stimulates fat breakdown in both the white and brown fat cells. But brown fat cells burn fatty acids and glycerol and generate body heat. While the white fat cells release fatty acids into circulation. Brown fat cells are closer, in origin, to skeletal muscles than to white fat cells. In experimental animals, white fat cells can be switched into brown fat cells. Many studies are currently underway to turn human white fat cells into brown fat cells.

The fatty tissue used to be considered storage and packing material but is now considered an important chemical factory. When the method of turning white fat cells into brown fat cells in humans will be achieved and subsequently marketed as a drug, then the fat will be the darling of the pharmaceutical companies. Such a drug is expected to bring in $30 billion/year and will be the drug of choice for obesity.
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Carcinoid and other Neuroendocrine Tumors

Carcinoid and other Neuroendocrine Tumors  

                                         

             PKGhatak,MD

 Definition:                                             

Carcinoid means a tumor having some but not all the features of cancer when examined under a microscope. Neuroendocrine implies a cell destined to become a nerve cell ends up as a hormone producing cell.
                                             

Even though it is known that not all of these peptide producing tumors are derived from the primitive-nerve cell, this name is still in use because of certain advantages. Neuroendocrine tumors, including carcinoids, are special tumors for several interesting reasons. Some tumors produce the same hormone/peptide even when they are located in different organs; tumors located in one organ secrete two or more hormones. Carcinoid and other neuroendocrine tumors are identical pathologically whether they are benign or malignant. Only their biological behavior makes a tumor benign or malignant. The diagnosis is often delayed because of its small size and widespread distribution. Advances in molecular biochemistry and genetics have outpaced clinical medicine, as a result, the chemical signatures and effects of these hormones on the human body are better defined than clinical diagnosis and treatment.

A simplified look in embryology is essential to comprehend the wide distribution of neuroendocrine tumors in various organs and tissues.
In a very early stage of embryo development, a sheet of cells differentiates into outer, inner and middle layers. The outer and inner layers fold into two separate tubes. The outer tube is called Neural Tube from which the brain and spinal cord develop and the inner tube is known as the Primitive Gut from it the entire gastrointestinal tract, liver, pancreas, bronchial tree and other structures develop. These two tubes lie next to each other. Some of the cells at the line of fusion of neural tube spread out like tiny wings, one on each side, called the neural crest. These cells have the potential to form many varied functions. Some of the cells of the neural crest attach to the developing primitive gut and find their way to different locations in the G-I tract and related organs.   These cells secrete potent hormones. Since these endocrine cells originated from the neural crest, they are called neuroendocrine cells.

Carcinoid Syndrome and Carcinoid tumors:

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All carcinoid tumors are capable of producing hormones and peptides but may secrete only in small quantities into circulation and tumors may remain silent for a long time. Whereas, those carcinoid tumors secrete large quantities of hormones/peptides cause severe symptoms in patients.

A patient is diagnosed as having Carcinoid Syndrome when he presents with a specific group of symptoms due to excess Serotonin.

Serotonin is produced normally in the body from an amino acid Tryptophan. The first step of this 2-step process is the conversion of tryptophan to 5-Hydroxytryptophan (5HTP), in the next step 5HTP is converted to 5-Hydroxytryptamine which is known as Serotonin (5HT). It is an amine and belongs to other potent amines like Epinephrine, Norepinephrine, and Dopamine.  5HT is stored in the cells in the secretory granules till it is released into circulation. Serotonin is taken up and stored in the platelets. In a normal situation, only about 1% of tryptophan is converted to serotonin. In carcinoid syndrome, 60% of tryptophan is diverted to 5HT production. As a result, Niacin (vitamin B3) which is also derived from Tryptophan, becomes deficient in the body and deficiency of niacin produces a condition known as Pellagra. The symptoms of pellagra are beefy red tongue, red edematous skin rash, hypersensitive to sunlight, diarrhea, and dementia.

The normal blood 5HT levels are 0.1 to 0.3 mcg/ml. In carcinoid syndrome, 5HT blood levels are 0.5 to 2.7 mcg/ml. Serotonin is degraded to 5-Hydoxyindoleacetic acid (5HIAA) and is eliminated from the body in the urine. About 75 to 700 mg of 5HIAA is excreted in the urine in 24 hours. (In normal people the range is 2 to 8mg/day). In addition, both blood and urine levels of 5HTP are usually mildly elevated.

The symptoms of carcinoid syndrome are sudden onset of flushing of the face, neck, trunk, and arms associated with a sensation of warmth or itching; profuse watery diarrhea accompanied by abdominal pain; wheezing; and cardiac problems.  These symptoms may last only a few minutes to several hours. Once symptoms are resolved by medical therapy or spontaneously, the patient remains symptom free.  Ingestion of food rich in serotonin or taking drugs that elevate blood serotonin levels may precipitate symptoms. Cardiac symptoms appear at a later stage and are due to the deposition of fibrin on the inner laying cells of the right ventricle, valves and intraventricular septum leading to valvular stenosis and incompetence and right sided heart failure.

A life-threatening situation known as a Carcinoid Crisis may occur in patients who excrete large quantities, over 200mg/day, of urinary 5HIAA.  Patients develop intense flushing, diarrhea, dehydration, hypotension, respiratory distress, cardiac rate disturbances, and death. Carcinoid crisis may happen spontaneously; often at the time of a biopsy or surgery or anesthesia.

Carcinoid tumors, like other tumors of neurological origin, produce a protein called Chromogranin and an enzyme Enolase. In carcinoids, chromogranin and enolase blood levels are high and are useful in the diagnosis but not diagnostic (normal 225ng /ml).

The incidence of Carcinoid syndrome is about 8 cases per year per million population and the incidence of carcinoid tumors is about 50 in one million population per year in the USA. Carcinoid syndrome is most frequently seen in small intestinal carcinoids and tumors are usually small and multiple.  Carcinoids also occur in the stomach, pancreas, bronchial tree, Meckel’s diverticulum, colon, rectum, appendix, ovary, and testis.  Carcinoid tumors of the appendix, colon, and rectum usually produce pain and intestinal obstruction. Carcinoid syndrome is seen in a third of the colon carcinoids and very rarely in carcinoids of the rectum and appendix. Once the tumor metastasizes to the liver it may produce carcinoid syndrome due to the direct discharge of serotonin into the bloodstream. This is also the case in ovarian carcinoid and retroperitoneal carcinoids though the incidence of carcinoid is rare in these locations.

Bronchial Carcinoid:

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Bronchial carcinoid is the second most common cause of carcinoid syndrome, even though carcinoid tumors account for less than 1% of all lung tumors. There are two subtypes – central and peripheral carcinoids. The central carcinoid tumors are located in the trachea, main bronchus, and its main branches. These tumors are slow growing and patients present with a cough and hemoptysis. Tumors are easily detected by bronchoscopy as small, fleshy, cherry red vascular tumors. Treatment can start early and patients have a better prognosis. The tumor in a later stage metastasizes to the liver.  Peripheral carcinoids are aggressive tumors that metastasize early in the regional lymph nodes and bone. Patients present with a cough, pneumonia and other signs of bronchial obstruction. CT scan of the chest detects the tumor and bronchoscopic biopsy is diagnostic.

There are certain special features of bronchial carcinoid syndrome.  Asthma attacks are common and generally last longer. Flushing is associated with increased tearing, sweating, and salivation. The flushed upper part of the body appears red in color and the flushing is intense. Diarrhea and other symptoms are like small bowel carcinoids.

Bronchial carcinoids often produce ACTH (adrenocorticotropic hormone) and growth hormone besides serotonin. Excess ACTH produces Cushing’s syndrome which is easy to diagnose by these features: central obesity, moon face, buffalo hump, wasting of muscles of upper and lower extremities, dark pigmentation, high BP, and diabetes mellitus. Acromegaly is produced by excess growth hormone-like-peptides by carcinoids. Acromegaly is also easy to recognize by very distinct clinical features: wide hands and feet, coarse facial features, protruding prominent lower jaw, large tongue, deep voice, hypertension, and cardiomegaly.

  

Somatostatin Receptors and Octeroid  Scan :

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Carcinoid tumors and other neuroendocrine tumors have receptors called Somatostatin receptors on the cell surface. There are 5 subtypes of somatostatin receptors 1 to 5(ss1 to ss5). The ss2 and ss5 bind with somatostatin most avidly. They also bind with a synthetic analog of somatostatin called Octreotide. Radioactive tagged octreotide scintigraphy (scan) is useful in localizing carcinoid tumors since ss2 and ss5 receptors are abundant in carcinoids.

Diagnosis of Carcinoid Syndrome:

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When a patient presents with symptoms of carcinoid syndrome or carcinoid crisis the clinical diagnosis is not difficult. An elevated blood level of chromogranin, 5HT and 5HPT and 24-hour urine 5HIAA should confirm the diagnosis. Localizing a small carcinoid tumor is difficult.

Routine X-Rays, CT scans, Sonograms, Endoscopy and MRI often fail to detect the tumor/ tumors.   The Octreotide scan is positive in 90 to 100 % of cases under this circumstance. It is a sensitive scan but not specific for carcinoids or other neuroendocrine tumors because the octreotide scans are also positive in granulomas like TB, sarcoid, lymphoma, wound infection and thyroid goiter.

Positron emission scans with 18F-fluoro-DOPA and 11C-5HPT scans are more sensitive scans but may not be widely available.

Once the localization of the tumor is made by an octreotide scan then a biopsy of the tumor is performed to confirm the diagnosis.

Gastric carcinoid:

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The incidence of Gastric Carcinoid is increasing.   The rise of gastric carcinoid is parallel with the increase in long term use of a potent gastric acid suppressing drug known as Proton-Pump-Inhibitor called Pantoprazole. Pantoprazole suppresses gastric acid but increases Gastrin (a hormone of the stomach) secretion. Gastrin stimulates carcinoid cellular growth and hyperplasia. High gastrin levels were seen in atrophic gastritis and pernicious anemia are also associated with an increased incidence of carcinoids. It is suspected that pantoprazole may be just one of several factors involved in the transformation of normal neuroendocrine cells into carcinoid tumors of the stomach. In MEN1 (multiple endocrine neoplasia 1) and Zollinger-Ellison syndrome, the gastrin levels are high and carcinoid tumors are part of the syndrome.  These two types of carcinoid tumors, associated with high serum gastrin levels, are multiple in number, less than 1 cm in size, invade only the submucosal layer of the stomach, and 25% of cases metastasize to the liver. A third type of gastric carcinoid not associated with high gastrin is an aggressive, large, solitary tumor and produces carcinoid syndrome, and over 60% of cases metastasize to the liver.

Some gastric carcinoids lack the DOPA-decarboxylase enzyme. Under normal conditions, this enzyme is required to convert 5HTP to 5PT.  Deficiency of this enzyme leads to accumulation of 5HTP in blood and the blood 5PT remains low or normal and urinary 5HIAA remains slightly above normal.  Kidneys can convert 5HPT to 5TP, and as a result, urinary 5TP is elevated. 

Other peptides and Hormones secreted by Carcinoid tumors:

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Many Carcinoids may not produce excess 5HT but generally, produce a number of other peptides and hormones. One tumor may produce several peptides and or hormones e.g.: -   adrenocorticotropic hormone (ACTH), insulin, calcitonin, glucagon, prostaglandins, vasoactive peptide (VAP), substance P, gastrin, ghrelin, motilin, alpha- subunit of growth hormone and others. Further discussion of these peptides/hormones will not be attempted here.

 Other Neuroendocrine Tumors:

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Of the non-carcinoid neuroendocrine tumors, pancreatic tumors are more prevalent. Other common sites are the small intestine, stomach, biliary tract, liver, ovary, and omentum. As in carcinoids these tumors may or may not secrete hormones but are capable of producing several hormones/chemicals in small quantities.

Those tumors that secrete hormones cause severe symptoms in patients but often are too small for a quick localization and treatment; whereas those do not secrete hormones grow to a large size before producing abdominal pain and by that time many tumors have metastasized and consequently the result of treatment is poor. In both instances, the usual time between the onset of symptoms and diagnosis is 5 years.

The diagnosis is strongly suggested by demonstrating elevated levels of hormone; localization of the tumor requires scanning and other methods and the final diagnosis is by a biopsy or removal of the tumor.

Only a few of these tumors will be mentioned briefly here:

Insulinoma:

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These tumors are located in the pancreas; usually multiple, and small less than 1cm in size, and only 10% are malignant. They produce insulin and proinsulin in excess amounts. The patient presents with very low fasting blood sugar levels - usually 45 mg/dl.  Because of hypoglycemia patients develop confusion, agitation, disorientation visual disturbances, and coma.

A diagnosis requires the presence of high plasma insulin, proinsulin and C-peptide levels besides severe low blood sugar in a fasting state.

Glocagonoma:

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It is also a pancreatic tumor. It produces glucagon in excessive amounts.  In normal circumstances, glucagon prevents hypoglycemia by raising blood sugar.  Patients with glucagonoma often develop a distinct skin rash around the mouth or groin or buttocks, other presenting symptoms of glucagonoma are diarrhea, weight loss, diabetes and recurrent thromboembolism.

This tumor is usually single, large 5 to 10 cm in diameter, located in the tail of the pancreas, 75% are malignant and metastasize to the liver. Diagnosis is made by the presence of high plasma levels of glucagon, over 1000ng/L. (normal less than 100 ng/L).

Gastrinoma:
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This tumor secretes gastrin in large amounts. Gastrin stimulates hydrochloric acid secretion by the parietal cells of the stomach. The patient develops severe, multiple peptic ulcers, often in unusual places, and these ulcers are registrant to treatment. Patients also have abdominal pain and diarrhea. This condition is better known as Zollinger-Ellison syndrome. The tumor usually is located in the duodenum; the next common sites are the pancreas, bile ducts, stomach, liver, and ovary. Diagnosis is made by demonstrating a basal gastrin level of over 1000ng/L, (normal 100 ng/L) and a high basal gastric acid secretion rate. Gastric pH remains below 2. In borderline cases, the Secretin Stimulation Test showing an increase in gastrin level 200ng/L over the basal gastrin level is considered diagnostic. This tumor is often malignant and metastases to the liver, bone and lymph nodes. Gastrinoma associated with MEN1 is located in the duodenum and multiple in number. 

Somatostatinoma Syndrome.

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Somatostatin is a neurotransmitter for the central nervous system and an inhibitor of all hormones in the gastrointestinal tract. It reduces gastric acid production, decreases pancreatic secretion, and decreases intestinal absorption of food. 

Tumors producing somatostatin are usually found in the head of the pancreas and small intestine. The tumor is large, about 5 cm in diameter, and often single. The liver is the main site of metastasis.

Patients present with diabetes mellitus, gallbladder disease, diarrhea and fat malabsorption.

Diagnosis requires demonstrating a high blood level of somatostatin.

Vipoma.

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Vaso-intestinal-peptide (VIP) producing tumor is called vipoma. VIP is also a neurotransmitter. It is a potent vasodilator and increases chloride secretion in the small intestine and stimulates smooth muscle contractions. Tumors are usually located in the tail of the pancreas and are usually single and large in size, and metastasize to the liver.

The presenting symptoms are watery diarrhea - over a liter a day, severe hypokalemia and vasomotor collapse. This condition is commonly known as pancreatic cholera.

Non-Functional Neuroendocrine tumors.

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The pancreas is the usual location of these tumors. The tumors are often single and over 5 cm in size, located in the head of the pancreas. Even tumors known as non-secretors, they produce very small amounts of several chemicals like chromogranin, growth hormone, and other peptides.

The patient presents with abdominal pain, jaundice, spontaneous bleeding and weight loss.

Diagnosis is often made very late in the disease and requires a biopsy.  Liver metastasis is common.

There are many other tumors under this category. In addition, some of these tumors are present as a part of groups e.g., in Multiple Endocrine Neoplasm (MENS I) and other such conditions.
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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 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, steroid, phenytoin and other anticonvulsant drugs, thiazide, furosemide, 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 triglyceride 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 that 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 cells of 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 osteoclasts are stimulated by Cytokines released by osteoblasts and bone resorption takes place.

In 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 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 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 parathyroidism 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.
There are other hereditary cancers that 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-1Anti Trypsin (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 begin.

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 nitogendioxide 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, this enzyme develops emphysema.
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-1antitrypsin levels determined. A CT scan of the chest delineates structural changes in the lungs in addition to the heart, blood vessels, ribs and vertebra and the diaphragm and 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 is 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 anticholine. 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 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 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. Increase 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, direction depends 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 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 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 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 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.

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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 blood level of ionizes 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.

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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

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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 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.

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The ionized calcium level in blood is tightly regulated by calcium sensors located on 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 increased 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 returns to normal.

Tissues and Calcium

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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.

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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 green 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.  

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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.

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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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