Friday, September 1, 2017

The Spleen

                                   







The spleen is the most underappreciated organ in human body. Even people gave it a bad rap like “to vent one’s spleen”- meaning vent anger; sadness and melancholy were associated with the spleen. Greek and Chinese were more generous with the spleen- they associated spleen with good-heartedness and strong will power.  Medical books describe spleen as the headquarters of the Reticulo-Endothelial System. What is that?—you know lymph nodes and lymphatics; the spleen is rich in both.

Spleen is not a good looking organ. It is a kind of mottled purplish gray in color, about 3 inches from side to side and 4 inches vertically and 2inches in thickness. It weighs less than 1/2 pound. It is hidden under the left ribcage, way deep inside the abdomen, resting below the diaphragm. The top of the left kidney is resting on it, the tail of the pancreas is touching it and the stomach is smoothly gliding over it.

If you imagine shrinking yourself to a tiny size like a RBC (red blood cell) and enter the spleen you will immediately find yourself lost in an area like bogs in Louisiana. Pools of blood are everywhere and there are islands of cells of various sizes all along the lakes, channels, and streams. In the central part it has a kind of white appearance and as you travel further away towards the distal end you see it is turning to a red color.
In the white area where Lymphocytes are manufactured and the red area where the cells are checking everything that enters the spleen like airport security officers do by scanning, patting and strip searching. What are they doing?- removing deformed or broken RBCs, bacteria, parasites and other disease causing agents that are marked by a coat of protein; then giving them to macrophages which eat them alive. The disease fighting antibodies are produced by B- lymphocytes and spleen is the site- like a  factory. It is also a source of T-lymphocytes
Human spleen has lost its ability, in the course of evolution, to inject a fresh supply of RBC in the circulation in time of need like the sudden spurt of physical activities e.g   hunting or racing. Dogs and horses are able to do that.  In human the spleen stores a good quantity of Platelets and some White Blood Cells; and release them into circulation when required.

You will not find spleen creating much fuss; it keeps on doing its good work very efficiently, unseen, and without a murmur.   In traffic accidents, people may sustain crush injuries to the rib cage and the spleen may be lacerated. And spleen may be buried in a football game. In diseases like  Leukemia, Thalassemia, and Sickle cell anemia and in acute infections like mononucleosis, septicemia and in chronic malaria you may find significant enlargement of the spleen. An enlarged spleen may produce dull aches under the rib cage.

Spleen is like brain tissue, when damaged it can not be properly stitched together; it may bleed continuously. A lacerated spleen has to be removed surgically. Once it is gone its function, to a certain extent, is taken over by the Liver. But the disease fighting quality remains inadequate. Certain bacterial and parasitic infections are common in an asplenic individual. More frequent vaccinations for certain diseases are required.

I believe, now, you may be ready to pay a tribute to one of the unsung heroes of our amazing body.

Saturday, July 9, 2011

Abnormal Genes and Cancer

                                          
                                 
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 the average, contains 17,000 Base Pairs and may contain as many as several million. Human chromosomes carry 3.2 billions of base pairs and only 25,000 genes are known to code proteins.We have 23 pairs of chromosomes and we inherit one strand of 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, time to achieve maturity, time to die and be replaced by a new cell. Different cell lines have different lifespan 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 a tumor growth and ultimately ends up in a cancer formation.
In an individual, the cells are dividing regularly throughout the 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). 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 increased cancer rate in old age. Increasing concentration of cancer causing chemicals in the environment, food additives, hormones, pesticides, cigarettes, ultraviolet rays of 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 the defective genes, other genes are endowed with surveillance function and are called Tumor- Suppressor Genes. However, there is no guarantee that mutation will not happen to this 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 rate of mutation in all genes. Another class of genes, called Gatekeeper Gene, restrains the growth of individual cell 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 his neighbors but it must escape from the surveillance cells before it can divide again. When mutant cells have gone through 5 to 10 generation 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 chicken. Similar genes (homologous genes) are also present in human cells. But they are very tightly controlled by tumor-suppressor 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 chromosome 9 is grafted to chromosome 22. This abnormality is better known as 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. Mutation of one copy of the tumor-suppressor genes does not adversely affect the individual; to have an increased risk of cancer both copies of tumor-suppressor genes must be defective.  This mode of inheritance is called Autosomal recessive inheritance. 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 finding of a new gene for particular cancer.It does not mean that 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 on 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 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 over activity.
4. Hereditary Breast/ Ovarian Cancer 1: Due to oncogene mutation of BRCA1gene, located on   17q21; dominant mode of inheritance. Carrier of BRCA1gene has 80% risk of breast cancer and 60% risk of ovarian cancer; and has some increased risk of colon, pancreatic, uterine cancers.
5. Hereditary Breast/Ovarian Cancer 2:  Due to oncogene mutation of 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 colon, stomach, gall bladder, 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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Saturday, July 2, 2011

Fat Cells (Adipocytes)

 Fat is getting a bad press recently. It began with convincing epidemiological studies linking increased rate of heart attacks with elevated blood levels of fat and cholesterol. The present generation of people is repeatedly warned that their bulging waist lines will make them susceptible to many diseases from diabetes to cancers as they grow older.

If fat is that bad: why we have fat cells in the first place?

 You must have seen the painting of the smiling face of 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 which 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 such packing kidneys, liver, spleen, and other abdominal organs will have a hard time in staying in respective places and work.

In starved conditions Fat cells ( adipocytes)  release a breakdown product of fat called Fatty Acids which provide needed energy. When excess energy is taken in (food) over and above body’s immediate needs the excess energy is turned into triglyceride (fat) and stored in adipocytes.  As fat accumulates the adipocytes bulge with fat. When a person gains weight fat cells increase four times the original size before dividing and thereby increasing the absolute number of fat cells. On the other hand, when he loses weight the fat cells shrink in size but do not decrease in number. Adipocytes, when stretched with loaded fat, release a hormone called Leptin. Leptin acts on the appetite center directly and via the vagus nerve. It decreases appetite and increases energy expenditure. Besides leptin, adipocytes produce blood pressure regulating Angiotensinogen, a vascular protective protein called Adiponectin, a blood clotting inhibitor known as Plasminogen activator inhibitor I, complement called Adiposin or factor D, and cytokines - Interleukin IL6 and Tumor necrosis factor alpha.  These chemicals help to regulate BP, blood sugar, blood lipids, blood vessels’ health,  healthy body weight and competent immune system.
When body weight increases the leptin production also increases but for one reason or other leptin fails to shut down hunger sensation in the appetite center located in the hypothalamus. Either the secretary products of adipocytes have a rate-limiting production or 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, macrophages and has a rich supply of blood vessels and nerve fibers.
Fat cells (Adipocytes) belong to Fibroblast Family of Cells of connective tissue origin. Other members of this prominent family are myofibroblasts, smooth muscles 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 of adipocytes in the body with a weight of about 30 lbs. Adipocytes are two different kinds: 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. (When one molecule of Glycerol combines with 3 molecules of fatty acids the compound is called triglyceride). The nucleus of the cells is pushed to one side and the cytoplasm of the cell just barely covers the fat globule like a rim. Once loaded with the excessive amount of fat the white fat cells can divide and increase the total number.  An adult person turns over 10% of fat cells every year. Preadipocytes in the fat connective tissue generate new adipocytes. Connective tissue fibroblasts transform into adipocytes when required. And this is not a one-way phenomenon, under appropriate circumstances, adipocytes can transform into fibroblasts/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 new born babies are brown fat cells. Brown fat cell population decreases with age. In adults, brown fat cells are found in lower neck and chest- around main blood vessels. Hibernating mammals have relatively more brown fat cells. The fat in brown adipocyte is dispersed 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 without shivering by a process known as uncoupled respiration and thermogenesis because they contain a unique mitochondrial protein. The simple meaning of this high sounding process is that when exposed to cold the norepinephrine stimulates fat breakdown in both white and brown fat cells. But brown fat cells burn fatty acids and glycerol and generate body heat.The white fat cells, on the other hand, release fatty acids into circulation. Brown fat cells are closer, in origin, to skeletal muscle cells than to white fat cells. In experimental animals, white fat cells can be switched into brown fat cells. Many studies are underway currently to turn human white fat cells into brown fat cells.

The fatty tissue used to be considered as storage and packing material but now is considered as an endocrine organ. When the method of turning white fat cells into brown fat cells in the human will be developed and 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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Monday, June 13, 2011

Carcinoid and other Neuroendocrine tumors

                                           
                                              

Carcinoid means tumor having some but not all the features of cancer when examined under a microscope. Neuroendocrine implies 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 kept 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; tumor located in one organ secretes two or more hormones. Carcinoid or neuroendocrine tumors have the same pathological features whether they are benign or malignant, only their biologic behavioral differences make them one or the other. Diagnosis is delayed because of their 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 distributions 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 brain and spinal chord develop and the inner tube is known as 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 neural crest. These cells have potential to form many varied functions. Some of the cells of neural crest attach to the developing primitive gut and find their ways to different locations in 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 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 secretary 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 of 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 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 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 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, chromogrnin and elnolase 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 a million population per year in the USA. Small intestinal carcinoid tumors produce carcinoid syndrome most frequently and tumors are usually small and multiple. Other sites of origin of this tumor are stomach, pancreas, bronchial tree, Meckel’s diverticulum, colon, rectum, appendix, ovary, and testis.  Carcinoid tumors of 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 rectum and appendix. Once the tumor metastasizes to the liver it may produce carcinoid syndrome due to direct access of serotonin into the bloodstream. This is also the case in ovarian carcinoid and retroperitoneal carcinoids though the incidence 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 tumor accounts 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. The peripheral carcinoids are aggressive tumors metastasize early in the regional lymph nodes and bone. Patients present with a cough, pneumonia and other sign of bronchial obstruction.CT scan of 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. Flushed upper part of the body appears red in color and 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 Receptor on the cell surface. There are 5 subtypes of somatostatin receptor  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 % 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 scan 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 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 long term use of a potent gastric acid suppressing drug known as Proton-Pump-Inhibitor called Pantoprazole. Pantoprazole suppresses gastric acid but increases Gastin (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 increased incidence carcinoids. It is suspected that pantoprazole may be just one of several factors involved in the transformation of normal neuroendocrine cells into to carcinoid tumor of the stomach. In MEN1 (multiple endocrine neoplasia 1) and Zollinger-Ellison syndrome, the gastrin levels are high and carcinoids 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 to the submucosal layer of the stomach, and 25% 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% cases metastasize to the liver.
Some gastric carcinoids lack DOPA- decarboxylase enzyme. Under normal condition, 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/hormone 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 small intestine, stomach, biliary tract, liver, ovary, and omentum. As in carcinoids these tumors may or may not secrete hormone but are capable of producing several hormones/chemicals in small quantities.
Those tumors that secrete hormone cause severe symptoms in patients but often are too small for a quick localization and treatment; whereas those do not secrete hormone 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 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. 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 beside severe low blood sugar in fasting state.

Glocagonoma:
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It is also a pancreatic tumor. It produces glucagon in excessive amount.  In normal circumstance, glucagon prevents hypoglycemia by raising blood sugar.  Patients with glucagonoma often develop a distinct skin rash around mouth or groin or buttocks, other presenting symptoms of glucagonoma are diarrhea, weight loss, diabetes and recurrent thromboembolisms.
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 amount. 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 duodenum; next common sites are 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 high basal gastric acid secretion rate. Gastric pH remains below 2. In borderline cases, Secretin Stimulation Test showing an increase in gastrin level 200ng/L over the basal gastrin level is consider diagnostic. This tumor is often malignant and metastases to liver, bone and lymph nodes. Gastrinoma associated with MEN1 is located in duodenum and multiple in number. 

Somatostatinoma Syndrome.
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Somatostatin is a neurotransmitter for the central nervous system and 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, gall bladder 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 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.
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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Monday, May 30, 2011

Parathyroid Glands and Parathyroid Hormone.



In 1880 Ivar Viktor Sandstrom, a Swedish medical student identified parathyroid glands in human. That was the last major discovery in human anatomy. His discovery remained unknown till 1891 when Eugene Gley of France established 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 circumstance, 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 6cm x 3cm, weighing about 50mg 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 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 3rd pharyngeal pouch; the thymus gland develops from the ventral wing of this pouch. By the 7th week of fetal development these glands loose 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 4th pharyngeal pouch and descend only a short distance to occupy their positions behind the upper part of the thyroid lobes.

In about 10 % cases supernumerary parathyroid is found due to fragmentation of glands during descend; 3 % cases less than 4 glands are present. In about 20 % cases the ectopic location of Parathyroid glands is seen. Thymus and inferior parathyroid glands descend together, any abnormalities of this process may lead to positioning of inferior parathyroid glands in the lower part of the neck or further down in chest- in front of the heart, behind 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 an endoplasmic reticulum of 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.  Gogi apparatus truncate it further to a linear protein containing 84 amino acids. In this form, it is stored in the secretory granules. If not required to be released immediately it is degraded to fragments containing amino terminal PTH (1-34) and PTH   (7-84) containing carboxyl terminal and midregion.The Intact PTH or I-PTH (1-84) or PTH (1-84) and PTH (1-34) - fragments containing amino terminal 1 through 34 amino acids are the biological active parathyroid hormone.  The PTH (1-34) crystallizes as a lightly bent long helical diamer.    Fragments containing carboxyl terminal and midregion PTH (7-34) are biologically inactive; so thought previously. Now, their properties are better known – they have opposite effects on serum calcium and on the bone compared with PTH (1-34). Fragments PTH (7-34) may constitute 50% of serum PTH determined by immunoassays. To circumvent these difficulties 2nd and 3rd generations of immunoassays have come into practice.  The Immuno-chemi-lumimiso-metric assay is a third generation assay technique, it is known as chemiluminescence PTH assay, better known as BI-PTH Assay (Biologically active PTH assay).This assay is based on sequential binding of amino acids 1-4 of the PTH thereby eliminating C-terminal PTH (7-84) binding. 
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 (1-11) has the same biological properties as native PTH (1-34).

Several factors can interfere with PTH blood level determination. Patients must be fasting 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 anticonvulsants 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 (1-84) is broken down at a faster rate and   PTH secretion rate is slower but PTH fragments- PTH (7-84) levels do not decrease.
PTH (1-84) and PTH (1-34) 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 hormone PTHrP. Structurally the PTHrP is distinct from PTH and may contain 134 to 173 amino acids. PTHrP also breaks down to smaller fragments like normal PTH. In an experimental animal, PTHrP behaves almost as if  PTH derived from parathyroid glands. It is, however, not shown to be present in 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 Calcium sensor CaSR. CaSRs are located on cells of parathyroid glands, calcitonin producing 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.   Calcium sensors belong to G-protein- couple receptor GPCR. When stimulated, by calcium binding on the surface of the sensor, it suppresses PTH secretion. As soon as serum calcium falls the inhibitory influence is lifted and parathyroid glands release preformed PTH into circulation and within minutes serum calcium level returns to normal. And the system resets again. When low ionizes calcium persists in blood the intracellular part of the sensor induces PTH messenger RNA expression and within hours and more PTH is produced. Prolonged low serum calcium induces cellular replication of parathyroid and the gland size increases. Receptor of vitamin 1,25(OH)2D (VDR) strongly suppresses PTH gene transcription.  In prolonged hypocalcemia VDR action is lifted from parathyroid glands. Low serum magnesium increases PTH secretion, severe intracellular magnesium deficiency depresses PTH production.
CaRS present in the cortical thick ascending limb of Henle cTAL acts independent of PTH.CaSR and vitamin 1,25(OH)2D influences in regulating 20% of filtered calcium in the urine. Both high serum calcium and magnesium inhibit this action and the action is accelerated in low blood levels of serum calcium or magnesium. In distal renal tubule 10% of filtered calcium in urine is controlled by Na+ / Ca2+ exchange mechanism and the process is tightly controlled by PTH. 

PTH and PTHrP Receptors
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Biologically active Parathyroid hormone and Parathyroid related proteins both bind to Parathyroid hormone receptor PTHR.  The C-terminal midregeon PTH binds to a different receptor called c-PHR receptor.
There are two distinct classes of PTH receptors known as PTH-R1 and PTH-R2. Both receptors belong to G-protein coupled receptors GPCR group. Receptors have external hormone binding site with an intracellular extension that binds with G-protein. The intracellular component of the PTH-R2 receptor is distinct from PTH- R1 receptor in having a 39 amino acid hypothalamic peptide also called Tubulo-infundibular 39 peptide TIP39.
The biologically active PTH binds with both PTH-R1 and PTH-R2 receptors The PTHrP binds with an only PTH-R1 receptor. The PTH-R2 receptors are abundant on Parathyroid glands, thyroid C-cells, liver, pancreas, kidney, brain, smooth muscle, endothelial cells of blood vessels and many other tissues. Bio-active PTH can bind with more than one G-protein and second-messenger- kinase pathway. Once the receptors are stimulated by binding with PTH the intracellular part of the receptors induces second messenger activation which in turn switches on various metabolic processes.    
PTH has multiple actions on bone. 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. And
2.Activates  Na +/ Ca2+ transport.
3. In distal tubules, it stimulates  Ca2 + transport.And
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 in the maintenance a steady calcium environment and a 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, the 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 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 parathyroid gland by producing excessive amounts of PTH at the expense of the bone calcium. The stimulation of PTH secretion remains high as long the renal failure continues. Ultimately, parathyroid glands undergo hypertrophy and occasionally turn into adenoma.

In about 20% 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.

The 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 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 a rare autoimmune disease, antibodies are directed against CaSR. Stimulation of CaSR by antibodies leads to suppression of PTH secretion and a low serum calcium. In 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 up regulated and excessive PTH-R1 actions are seen in bone and kidney. Calcium is mobilized from bone and blood calcium level rises. In children, this condition leads to short-limb- dwarfism and in adults bone changes resembles hyperparathyroidism.
In DiGeorge syndrome, there is a defective development of 3rd pharyngeal pouch. In this condition both thymus and parathyroid glands are rudimentary. Abnormal development of bones and arteries derived from 3rd pharyngeal pouch takes place. This condition is transmitted by autosomal dominant inheritance and due mutation on chromosome 10; sporadic cases of DiGeorge syndrome is due to micro-deletion of genes on chromosome 21q42-43. A translocation defect of GATA13 on chromosome 10   is associated with low PTH, deafness and renal dysfunction; known as HDR syndrome. There are many other hereditary causes of Hypoparathyroidism like Kenny- Caffey syndrome, Sanjad -Sakate syndrome

In hereditary mitochondrial disorder 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 hypoparathyroidism varies depending on whether the condition is of acute onset or chronic.   In an acute situation, hypocalcemia produces muscle cramps, tetany, carpopedal spasm, abnormal sensation around mouth, hand, and feet. Serious cardiac arrhythmias may develop. In a chronic situation, Parkinson disease like rigidity and extrapyramidal movements like athetosis and chorea are present associated with calcification of 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 guanyl-nucleotide binding protein complex, as a result, the intracellular cyclic AMP fails to increase. Hypocalcemia and increase phosphate loss through the kidney continue even when PTH levels in the blood are high.
 There are several variations of pseudoparathyoidism and will not be discussed here.

Tumors and Malignancy of Parathyroid glands.
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Multiple endocrine neoplasias (MEN) is associated with tumors of the parathyroid gland. In general, all inherited malignant diseases are due to overexpression of proto-oncogenes and / loss of function tumor suppressor genes.
In MEN1 hyperparathyroidism is associated with tumors of 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 adrenal glands. Multiple genetic mutations are implicated. Biallelic loss of function HRPT2 gene on chromosome 1q25 is the primary abnormality. In MEN2B in addition to features of MEN2A, multiple neuromas are present and hyperparathyroidism is absent in some cases. Mutation of RET proto-oncogene is seen in all MEN2 cases. Tumor suppression gene Rb located on chromosome 13q14 is often found to be deleted in some parathyroid cancers. There are 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 progress to carcinoma.
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Tuesday, March 29, 2011

Emphysema


  Emphysema in Greek means inflation or blown with puffed cheeks. In medicine, emphysema is classified under chronic obstructive lung disease. The underlying structural problem in emphysema is 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 air was released the elastic recoil could not bring the balloon back to the original size and appear 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 lungs by pulmonary artery, it branches repeatedly and the arterial branches follow 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 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 lungs and 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 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 nose and air reaches the alveoli. The exhalation (expiration) is a passive process: muscle contraction, that was holding chest wall in an expanded condition, is terminated and 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 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. Now a days 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, the elastin is laid down and removed continuously in lungs. For removal, the elastin is digested by an enzyme called elastase produced locally by white blood cell- 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 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 its 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 individual with MM allele has a normal blood level of a-1AT, whereas 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 combination 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 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 are 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. Others 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 lungs, even though the coal is inert. The coal dusts are picked up by macrophages when dust particles reach lungs and carried to the walls of alveoli. Here macrophages release enzyme elastase and collagenase and the destruction of 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 cigarette smokers.
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 a known cause of emphysema and bronchitis.
7. Allergy and hypersensitivity.
Airway hypersensitivity in 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 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 lung because of emphysematous changes of the top of lung or just underneath the pleura. An enzyme Lysyl oxidase responsible for cross linkage of elastin. In individual 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 lungs uniformly; in some cases, upper lobes are damaged; in other cases, 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, 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 PA and lateral views of chest radiographs are all that is required to make a diagnosis. Subsequently, all emphysema patients should have complete pulmonary function tests, oximetry, and serum alpha-1antitrypsin levels determined. Then they may be categorized as early, moderately-advanced and far-advanced stages of the disease.

Treatment.
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It is never too late in giving up smoking. All available facilities should be explored in helping patients in 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 oxygen saturation 87% or below at rest, should use oxygen on 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 progression of pulmonary hypertension and heart failure, improves the quality of patients’ lives and extends abilities to stay engaged in the work place.

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]steroid.

[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 hand held nebulizer. It counteracts effects of acetylcholine. Acetylcholine produces bronchial smooth muscle constriction when released at the neuromuscular junction by stimulation of vagus nerve in the lung. People having prostrate 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 now a days because of gastrointestinal and cardiac side effects. It inhibits enzyme phosphodiesterase 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 onset of fatigue and improves functional capacity of muscles.

[B] Steroid.  Corticosteroid like many synthetic steroid hormones are extensively used in medicine.    It has direct anti-inflammatory effect when delivered locally or in the entire body when given orally or intravenously. 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, just too many to list here.
In emphysema, it is used mostly as an inhaler. Since it encourages fungal growth in mouth and tongue known as thrush or oral candidiasis, the patient should rinse 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 patient 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 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, 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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Wednesday, March 23, 2011

Phosphorus

Phosphorus and calcium are like twin brothers- always together; but also have sibling rivalry. When the product of phosphorus and calcium (phosphorus in mg/dL X calcium in mg/dL) in blood goes over 50, the one having a lower concentration in blood is prevented from getting in from the gut, and or, eliminated through the kidney by the other; like a stronger eagle chick pushes out the weaker one from the nest. Otherwise, calcium phosphate will be deposited in tissues.On other occasions when calcium levels are low, more phosphates are lost in urine and phosphates levels in blood come to par with calcium, like a true twin.
Phosphorus is present in all cells. All DNA and RNA and various enzymes and coenzymes are organic phosphates, also the intermediate products of glucose and fat metabolism, high energy phosphates like ATP, ADP, cyclic ADP, NADP and many other essentials.

Think this way: If phosphorus is rendered inactive; we will not be able to extract energy from food, deliver oxygen to tissues, unable to manufacture steroid hormones, unable to unlock instructions from the genetic code from DNA, and vital energy will be wasted as heat.

Various enzymes, coenzymes, water soluble vitamins, intermediate products of carbohydrate and lipid metabolism, and structural proteins are also organophosphates. The important respiratory coenzyme NADP belongs to phosphate family.
It is useful, perhaps, to mention here a few of them.

If one opens a book of biochemistry and looks up “The common metabolic pathway” also known as the tricarboxylic acid cycle or Krebs cycle, one will find fatty acids, glucose, amino acids are converging at different points into this cycle and many reacting intermediate metabolites are phosphate compounds. Enzymes and coenzymes are essential for this process, also the high-energy bound phosphate packets in ATP, ADP, and AMP. This process not only unlocks energy present in food but also generates Acetyl CoA, a vital step in the synthesis of sterols, amino acids, and fatty acids synthesis and generates more ATPs. Vitamin Pyridoxine (vitamin B6 or pyridoxal phosphate) is the prosthetic part of a group of enzymes called cocarboxylase. It acts as amino transfer vehicle to and from amino acids; Vitamin Niacin is present in nicotinamide adenine dinucleicleotide (NAD) and in NAD phosphates. It acts as hydrogen and electron transfer agent, a vital process of cell respiration.
Thiamin and pantothenic acid are a part of oxidative dehydrogenases enzyme, an essential part involved in the formation of Acetyl- CoA, the initial step of the Krebs cycle. Functions of others are too numerous to mention here.


Phosphorus is also present in the inorganic form. Inorganic phosphates are H2PO4, NaHPO4, and HPO4. Inorganic phosphates are present in all cells and in serum. The concentrations of phosphate within the cell and in the plasma are almost equal, and phosphates can move in and out of the cells easily. The levels of inorganic phosphates in blood are expressed in term of Phosphorus and the normal levels are 2.5 to 4.5 mg/dl or, 0.75 to1.45 nM/L. Blood levels of phosphates vary widely, lowest concentration is in the morning in a fasting state. About 10% of serum phosphate is bound to proteins and the rest in a free ionized from.
The primary regulator of blood phosphate level is the kidney; acts by adjusting the rate of renal tubular phosphate reabsorption.


Phosphate in Bone
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85% of 1.2 lbs of phosphate in the body is present in bones and teeth. Phosphate is bound with calcium as a poorly crystalline dihydroapatite form. One may look up the article on calcium for more information.

Phosphate in Blood
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Phosphates act as a buffer, minimizing pH change of blood. Whenever [H+] accumulates in blood the [H+] anions move in the cells and reacts with [HPO4-] and form H2PO4 thereby pH of the blood remains unchanged. A reverse process happens when there are excess [HPO4-] ions. Red blood cell (RBC) picks up carbon dioxide (CO2) from tissues and carries it to the lungs for exchange with oxygen. The rate of CO2 uptake by RBC is speeded up by carbonic anhydrase to form carbonic acid (H2CO3), which dissociates into [H+] and [HCO3-]. HPO4 combines with [H+] to form H2PO4 and keeps the pH from changing. A reverse reaction takes place in the lung as RBCs take up O2 and release CO2.
The total cellular volume of the body is twice that of blood volume, thereby, the cells contain a larger proportion of phosphates and a single blood level determination may not give a true picture of total body content of phosphates.
RBCs need phosphate for respiration. Deficiency of phosphate limits RBCs’ ability to deliver oxygen to tissues, and also damage the structural integrity of RBC.

Phosphate in Gut
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Phosphates, for the most part, are absorbed in the small intestine directly and can still be increased further by another 25% by vitamin D. Phosphate absorption is regulated in the gut by a transport system called NaPi2. Low blood phosphate level accelerates this system. About 500 to 1,000 mg of phosphate is absorbed from the gut in a day. Large doses of calcium, aluminum hydroxide (antacid) lower dietary absorption of phosphates.

Phosphate in Kidney
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Kidney filters about 5 gram of phosphate in the glomerular filtrate in a day. The amount of phosphate appears in urine in a day depends on the amount and time of gastrointestinal phosphate absorption. On the average 85% of filtered phosphate is reabsorbed in the proximal convoluted tubules (PCT). The higher the intestinal phosphate load is the more phosphate appears in the urine. The [Na+/PO4-] co-transporter (NaPi2) regulates Sodium [Na+] and Phosphate [PO4] reabsorption in the proximal convoluted tubules of the kidney. Parathyroid hormone (PTH) depresses this NaPi2 and resulting in increased phosphate excretion in urine. A new hormone recently identified called Fibroblast Growth Factor (FGF 23) produced by the osteoblasts of bone. It decreases phosphate reabsorption in the PCT and also inhibits activation of vitamin D in distal convoluted tubules and thereby decreases phosphate absorption in the gut. A low phosphate diet increases FGF23 activities and high phosphate depresses FGF23.
Phosphate reabsorption in the kidney is depressed in conditions of low calcium and low magnesium levels in the blood.

Hypophosphatemia.
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What are the causes of low blood levels of phosphates( hypophosphatemia).
The renal loss of phosphates is the dominant cause. The other important causes are clinical conditions where phosphate moves out of blood into the cells - as seen in cases when insulin is used in the treatment of diabetic coma, also when rapid correction of metabolic acidosis has taken place, respiratory alkalosis, septicemia, blast crisis in leukemia, toxic shock syndrome etc.. Dietary deficiency is a rare cause of low phosphate level but diseases of small intestine interfering with fat absorptions may be significant, alcoholics have low phosphates. Prolonged starvation then fed with starch. In conditions where bone formation are accelerated as in Paget’s disease of bones, correction of vitamin D deficiency, and osteoblastic bone metastases.
Some of the important conditions leading to phosphate loss by the kidneys are:-
1.Hyperactive parathyroid glands 2.Deficient conversion of active vitamin D [1, 25(OH) 2D] by the kidney. 3. Congenital genetic abnormalities of the kidney in phosphate reabsorption- known as congenital renal rickets and many other genetic abnormalities. 4.Acquired rickets and osteomalacia. 5.Tumors producing parathyroid hormone like molecules.

Symptoms of hypophosphatemia: in an acute situation are- dysfunction of lung, heart, liver and other organs. Cardiac arrhythmias, skeletal muscle breakdown (rhabdomyolysis), hemolytic anemia, severe oxygen deficiency of vital organs, renal failure (renal tubular acidosis), GI bleeding. In chronic situation: the symptoms are- bone pain, various neuromuscular symptoms, including -weakness, paralysis, seizures, sensory deficit, coma, and many other non-specific symptoms.

Hyperphosphatemia.
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A level over 5.5mg/dL or 1.8mM/L is considered as hyperphosphatemia.
Renal failure is the dominant cause due to decreased filtration of phosphates. Other causes are decreased parathyroid activities from any reason, vitamin D, and vitamin A toxicity, respiratory and metabolic acidosis, prolonged immobilization, extensive cellular damage e.g.- crush injuries, chemotherapy, severe hepatitis, hyperthermia. Excessive dose of phosphate containing laxatives, prolonged heparin therapy, and many other clinical conditions.

Symptoms of hyperphosphatemia are related to wide spread deposition of calcium phosphates in tissues and a low calcium level as a result of it. Acute heart block may be life threatening. Metabolic acidosis, renal failure, and dysfunction of vital organs are presenting symptoms, tetany is often a predominant symptom.
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