A Miserable Human Malady

                       PKGhatak,MD

Migraine.


One of these days, someone will invent a misery detector to record the misery index of human diseases and I bet sixty four thousand dollars that Migraine will top that list. Misery from chemotherapy, though bad, does not come close; after all, it lasts only a few weeks. But migraine attacks happen once or twice a week, every week for the entire span of patients' lives. Also, migraine attacks come at the most inconvenient time - final examination, job interview, wedding, childrens' birthday parties, vacation, etc. and an attack lasts as long as 3 days and patients experience absolute misery, and the entire family also suffers from its consequences. And in those weeks the patients are free of migraine, their mental peace is replaced by anxiety in anticipation of a migraine attack

Archaeological digs from very ancient burial sites uncovered human skulls with holes; they speculated that surgery was performed to relieve intracranial pressure or release bad spirits, as they believed was the cause of migraine. Egyptians recorded illnesses that were no doubt Migraine attacks. Greek physicians, in ancient times, noted two distinct types of migraines- one that was preceded by an aura and the other without an aura.
Migraine attacks proceed in four stages – prodrome, aura, headache and postdrome. It is now recognized that people who suffer from migraine are born with a certain inherited vulnerability to have an exaggerated brain response to common sensory stimuli.

Inherited vulnerability:
It has a complex genetic basis. The familial hemiplegic migraine with aura is an autosomal dominant inheritance. Mutation of genes controlling voltage gated calcium channels on chromosome 19 is implicated in this disorder, in type II familial hemiplegic migraine sodium/potassium pump controlling gene on chromosome I and mutation of dopamine D2 receptor gene increase susceptibility. Calcium channels mediated the release of serotonin in the mid-brain and the imbalance of calcium/ magnesium is implicated in the genesis of aura. Migraine with intermittent ataxia, the calcium channel related gene mutation, is noted.

Prodrome and Aura: These two are distinct. Prodrome symptoms are vague but very familiar to an individual sufferer and generally precede an attack by a day, whereas, an aura is a focal neurological symptom, usually visual, auditory, other sensations and motor functions, usually proceeds up to one hour before the headache begins. Postdrome: feels like a hangover and my last 24hrs.  Aura is present in about 20 to 25 % of migraine patients. It is a nerve cell derived depression of the subcortex, that starts at the back in the visual cortex then slowly marches forward to the frontal lobe. It is a result of abnormal ion movement across the cells. Like prodrome aura is hereditary, it is an exaggerated response to ordinary stimuli.

Headache: may last 3 days, it is intense, usually localized to one side of the head, throbbing in nature or sense of drilling inside the head, associated with nausea, vomiting, watery nasal discharge and increased tearing and other symptoms related to the activation of parasympathetic nerves.

For centuries physicians believed the pain of migraine was due to intense vasodilatation. Throbbing headaches, a high prevalence of heart disease, hypertension and stroke in migraine patients point to the vascular origin. This was supported by the fact that a good response was achieved by the use of vasoconstrictor ergotamine.

A headache in migraine is currently believed to be due to a neurovascular event, even though the precise cause is unknown. The meningeal blood vessels of the frontal and middle fossa of the brain and venous sinuses in between Dural folds are densely innervated by unmyelinated C fibers and thinly myelinated delta fibers of the trigeminal nerve. Similar structures in the posterior fossa are supplied by the upper cervical nerves. Nerve cells synthesize Calcitonin Gene Related Protein (CGRP). CGRP granules migrate down to the nerve terminals and are stored as vesicles at terminals. After an appropriate stimulus, the nerve terminals release CGRP. CGRP binds with CGRP Receptors (CGRPR) and physiological actions begin with marked vascular dilatation. The extravasation of plasma and release of Substance P(SP) initiate headaches. It is a sterile inflammation and often lasts for 3 days.

In humans, Calcitonin Gene Related Protein (CGRP) was discovered in a patient with medullary thyroid cancer arising from parafollicular cells otherwise known as C-cells of the thyroid gland. A gene known as the CALC gene is responsible for the production of a large molecule of pre-pro-polypeptide. This molecule is cleaved into Calcitonin, CGRP, Pre-adrenomedullin, and Islet amyloid precursor protein. Besides nerve cells of the CNS and peripheral nervous system, other cells also produce CGRP; these are endothelial cells, immune cells and cells of intestinal vasculature.

CGRP is present in two distinct forms of isomers namely Alpha and Beta. CGPR Alpha is mostly seen in the nervous system and CGRP Beta in the GI tract. Initially, two separate CGRP receptors were identified, one for Alpha CGRP and the other for Beta. Now it is known that one CGRP receptor binds both Alpha and Beta isomers.
These two isomers are present in both the nervous system and in the GI tract but Alpha CGRP is dominant in the CNS and peripheral nervous system. Whereas Beta CGRP is mostly present in the GI system.

Blocking Antibody:
Antibodies are designed to bind with CGRP Receptors (CGRPR) thereby blocking CGRP to attach with its receptors, as a result, the vasodilatation and release of chemicals are prevented and headache is averted. Like CGRP receptors, antibodies are also chemically polypeptides. Antibodies are denatured by gastric acid and digestive enzymes of the gut when administered orally. The antibodies are given as an injection which limits their use at the moment when the drug is needed most. A search for small molecule antibodies against the CGRP molecule itself resulted in the production of several drugs

Preventive therapy for migraine:
Erenumab: This is a humanized anti CGRP Receptor antagonist. It is administered by subcutaneous injections. This antibody binds CGRP Receptors and blocks them from combing with CGRP. As a rest dilatation of vessels and release of chemicals are prevented so also prevents the start of inflammation and pain.

Frenanezumab. It is an antibody to Alpha and Beta CGRP. It does not cross blood brain barrier and is not degraded by the liver or eliminated by the kidney. It is given by injection. It binds with CGRP and the blood level of CGRP falls. And thereby prevents migraine from happening.

Galcanezumab: It is an antibody to CGRP Alpha and Beta. Its mechanism of action is similar to Frenanezumab.

All these three drugs are effective in reducing attacks of migraine at least by 50%. They have a good safety profile.

To avert an attack of migraine the following devices are in various stages of development and approval-

Transcranial Magnetic Stimulator (TMS). It is a patient operated, handheld battery power device, that delivers a quick, sharp, single magnetic pulse to the back of the head over the occipital cortex. It is used in cases of migraine with aura. It reduces migraine attacks.

Vegas nerve stimulator. It is a handheld battery power electric stimulator. When activated it delivers two 90-second electric pulses to the side of the neck over the vagus nerve. It lessens migraine attacks. It probably works by releasing the neurotransmitter glutamine.

Supraorbital transcutaneous stimulator. Mini electrical pulses are delivered to the forehead from a battery powered instrument by the patient at the very onset of an attack with good effect in averting a full blown migraine.

Implantable occipital nerve stimulator. An electrode is implanted along the occipital nerve at the back of the head and connected to a programmable battery pack is placed in a surgically created pocket in the chest wall. Like a heart pacemaker, this device delivers electrical pulses, as programmed, to abate a migraine attack.

Sphenopalatine ganglion stimulator. A small device is implanted in the gum just above the 2^nd molar tooth. Electrical stimuli are delivered by the patient by pushing a button of a battery powered remote controller.

Other medications are still in use but not as effective as CGRP receptor antibodies and antibodies to CGRP.
Triptan: Triptan has been in use for a long time and for a while it was the only drug that had a somewhat predictable effect on migraine. Triptan binds serotonin 5HT1B and 1D receptors at the neurovascular junction. It is effective in limiting the duration of migraine but is not preventive. It is a potent vasoconstrictor and not safe in patients with coronary artery disease and hypertension.
Recently a new generation of triptan 5HT1F agonists has been investigated. It has a selective preference for receptors in blood vessels supplied by the trigeminal nerve.

Nasal Oxytocin: It is a vasoconstrictor and reduces sterile inflammation in an attack of migraine.

Botox injection. Initially, the use of Botulinum toxin used in controlling headaches of migraine was thought to be a novel idea and initial results were encouraging. But recent experiences are not so glorifying; overuse and side effects are significant. It is still in use but in more selected cases.

Recent advances in brain imaging techniques and studies on experimental animals improved our understanding of the cause and progression of migraine. These advances are directly linked to the development of new drugs and devices. The CGRP receptor antibody drug has proved to be the game changer, now orally administrable CGRP antibody going to extend the success further, and one day migraine headaches can be effectively treated and even migraine attacks will be prevented.

 

 

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Multiple Sclerosis

Multiple Sclerosis

Multiple Sclerosis.

Multiple sclerosis is a devastating illness, it affects the majority of women in their prime soon after the birth of a child, robbing their happiness, finance, and family lives, and produce lifelong disabilities, often patients are bedridden or wheelchair bound. It is an autoimmune disease but what triggers the misdirected immune response is still unknown. Recent advances, in new blood and cerebrospinal fluid tests and refinements in neuroimaging, made early detection of the disease possible and newer drug therapies have increased the odds of reversing or preventing the progression of the disease.

For centuries physicians were treating patients with symptoms which we know today as Multiple Sclerosis (MS) but they had no idea about the nature of the illness was, until in 1868 a French physician Dr. Jean Martin Charcot demonstrated scar tissue, which he called plaques, in the brain and spinal cord at the postmortem examination of one of his patients and correlated sites of lesions with patient's symptoms. In 1828 Dr. Louis Ranvier discovered that Oligodendrocytes produced Myelin, the insulating layer around the axon (nerve fiber), which was destroyed in MS and caused patients' symptoms. Dr. Thomas River identified immune cells that actually destroyed the myelin and subsequently, the immune cells were known as B cells and T cells. This led the way to huge excitement in MS research and the discovery of new drugs was possible. It was subsequently proved that T cells not only damaged the myelin but also the axon and the nerve cells as well, explaining the development of permanent disabilities in MS patients.

Most recent research indicates that MS autoimmune disease is related, if not the actual cause, to the two different metabolic paths the tissue resident T-cells can take. In normal people, the tissue resident T-cells use fatty acid- Oleic acid as the energy source in the suppression of excessive inflammatory activities. In MS patients the Oleic acid content of fatty tissue is deficient. Published reports show EB virus infection triggers immune reactions which are misdirected to myelin and destroy it.

One of the three ways patients may present with Multiple Sclerosis (MS).

Relapsing and Remitting: This is the usual presentation. Sudden onset of some or all of the following symptoms - difficulty in focusing, double vision, difficulty in maintaining balance, weakness of legs or clumsiness of movements of hands, various sensory disturbances of the limbs and trunk. Then a period of steady improvement for months or years, then a return of the same symptoms and more new symptoms appear. And the pattern then repeats at intervals. Difficulty in voiding and retention of urine usually accompany.

Secondary Progressive: in some of the above groups of patients years later a change in the behavior of the illness results in a steady deterioration of the condition without any remission in between attacks. 

Primary Progressive: This type of presentation is less frequent. From the onset, symptoms are progressive and relentless. Severe disability followed by early death is common.

Another type of MS is known as Devic's disease, patients present with sudden blindness or no vision in the center of the visual field and are associated with loss of movement of both lower extremities with sensory loss of both lower limbs (transverse myelitis).

Laboratory Tests:

The cerebrospinal fluid (CSF) shows an increase in immunoglobulin concentration, an increase in cell count of mixed cell types (pleocytosis) and a narrow spike of gamma globulin on electrophoresis (oligoclonal band). CSF cytokines CXCL13, TNF and IFNy are elevated in relapsing recurrent MS patients. Recently, various degradation products of myelin have been found in blood tests. These are, however, also seen in a few other diseases of CNS.

Neuroimaging:

MRI is the most sensitive modality to detect damaged myelin sheath of the brain and the spinal cord in MS. Multiple areas of lesions of varying sizes and ages should be present. Lesions are located in the white matter above the caudate nucleus, around the ventricles, cerebellum and the long tracts, both motor and sensory tracts of the spinal cord and optic nerves. MRI images are several types -T1, T2 weighted images, gadolinium enhanced images are many others. These special images are taken to increase the sensitivity and specificity of the test.

Evoke Potential Tests:

Delays in response to visual, auditory, somatic sensory stimulation are observed in this test by attaching recording electrodes to appropriate points on the skull. In MS visual evoked potential test is usually positive even when patients may not have eye symptoms.

Diagnosis:

Relapse and remitting features of the disease, spastic paralysis, urinary retention, gait and balance disturbances, pleocytosis and oligoclonal band in the CSF with MRI of the brain and spinal cord showing evidence of multiple lesions of varies stages of development should make the diagnosis of MS with confidence. Certain infections of CNS like Lyme disease, HIV, syphilis, should be excluded. Lupus, Sjogren syndrome, lymphoma and subacute combined degeneration of the spinal cord from vitamin B12 deficiency should not be confused when making MS diagnosis.

Treatment:

There are increasing numbers of new drugs available for targeted therapy – to induce remission of an acute attack, prevent the progression of the disease and reduce the frequency of attacks.

For remission of acute attacks:

Intravenous Methylprednisolone is given for 1 to 3 days followed by oral prednisone in high doses until symptoms abate then the dose is slowly reduced.

Plasma Exchange:

The blood of the patient is withdrawn and the plasma is separated from the cells, the plasma is discarded, the cells are transfused back into an albumin solution. It is done in cases where IV steroid therapy is ineffective.

Disease Modifying Therapy (DMD): These are very briefly discussed under the heading - by injection and by oral route.

Drugs are given by subcutaneous injections or IV.
Glatiramer Acetate. It is a synthetic protein containing 4 basic antigenic amino acids of myelin. When injected in patients it attracts immunocytes CD4, CD8 and T cells and thus spares the myelin sheath from inflammatory effects; it also increases Thymic 2 T cells in the CNS which act as a suppressor of inflammation. Side effects are local reactions at the injection sites, flashing, chest pain and GI disturbances.

Interferon Beta: it is a polypeptide. It is normally produced by fibroblasts; for medical use, it is manufactured by engineered E. coli. When injected, it binds with the receptors on the surface of cells then directs the production of cytokines which results in a reduction of Thymic 17, a subset of T lymphocytes. It decreases the entry of immune cells into the brain and facilitates healing. Side effects are fever and chills like flu, and local reactions at the injection site, anxiety, and irritability.

Humanized monoclonal antibody:

Four drugs of this group are approved for use in recurrent relapsing MS and primary progressive MS.

1. Natalizumab. It is an alpha 4 integrins blocker on the lymphocyte surface, preventing it from binding with the endothelium of CNS blood vessels, preventing them from crossing the blood-brain barrier. Patients receiving it must be negative for the JCV antibody test, otherwise, progressive multifocal leukoencephalopathy (PML) may follow. An increased incidence of melanoma transformation of cutaneous nevus is seen.

2. Rituximab. It is an anti CD20 antibody. It causes apoptosis of beta cells of the circulation; decreases complement and cellar cytotoxicity. Side effects are patients become susceptible to infections and thrombotic events.

3. Ocrelizumab. It is also an anti CD20 antibody.

4. Alemtuzumab. It binds with CD52, expressed on the surface of T and B lymphocytes, macrophages and eosinophils. Its use is associated with the reactivation of CMV, listeria meningitis, ITP (Idiopathic Thrombocytopenic Purpura), nephropathy and low TSH.

Oral agents:

Fingolimod. It is a sphingosine 1 phosphate analog (S1P). It binds with receptors expressed on the surface of B and T lymphocytes. The fingolimod then degrades the receptors and prevents the release of lymphocytes from the lymph nodes. As a result, T and B  lymphocyte cell numbers decrease in blood and CNS. It also decreases Thymic 17 cells. Fingolimod crosses blood brain barrier and protects neurons and helps repair damaged tissues.

Side effects: Headache, rise in liver enzymes, macular edema, increased chance of infections.

Teriflunomide. It interrupts the pyrimidine synthesis of T and B lymphocytes. It blocks inflammatory response. Side effects are headaches, raised liver enzymes, alopecia, and nausea. It is teratogenic and should not be used in pregnancy.

Dimethyl fumarate. It decreases memory T cells and lowers Thymic 1 and Thymic 17 memory cells thereby proinflammatory activities are decreased and also activates Th2 anti-inflammatory cell population. Side effects are flushing, abdominal pain, skin rashes and itching, lymphopenia and an increased chance of PML.

Cladribine. An orally administered purine nucleotide analog. It is cytotoxic to lymphocytes. Side effects are Hairy cell leukemia, reactivation of tuberculosis, and teratogenic to developing fetus.

Many other S1P agents are in various stages of development and approval from FDA.

Besides the specific treatment of the primary cause of MS, several associated disabilities and complications have to be managed properly and adequately. These are not discussed here.
Recent animal experiments have shown that damaged axion of nerves can be repaired by Metalloprotease 4, an analog of human Metalloprotease 17, by stabilizing Fusogen EFF-1 at the damaged site and then beginning repairs. 

High-efficacy therapies included rituximab, ocrelizumab, alemtuzumab, mitoxantrone, and natalizumab.

The window of therapeutic opportunity refers to the first 5 years of the disease when inflammation is highest.
The benefits of early high-efficacy treatment seemed to continue past the time when all patients were on high-efficacy treatment.

 

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The Soft Bones and Porous Bones

Soft Bones and Porous bones

             PKGhatak,MD

The soft bone develops due to a failure of normal mineralization of bones, when it happens in childhood known as Rickets and in adults called Osteomalacia. Porous bone develops due to excess removal of the protein matrix of bone in relation to new bone formation. In medicine, this is called Osteoporosis, commonly referred to as brittle bones.

New bone tissue continuously forms and the dead bone is removed and this process is called remodeling and the process continues all through the lifetime. The rate of new bone tissue formation is faster till about midlife, then after midlife and menopause in women, the new bone formation lags behind the removal process. Whereas, Osteopenia is another term when both minerals and matrix are lost resulting in smaller bone mass.

The growth process of the bones of arms and legs is different from the growth of the skull, scapula and pelvis. In the case of limb bones, cartilage structures grow initially, followed by the deposition of calcium and phosphate. A plate of cartilage at each end of the bone remains sandwiched between the shaft and the two ends, this is called the growth plate. The growth plate continues to divide and grow in length till the mid to late 20s when the growth period ends. The width of long bones increases due to new bone formation underneath the bone covering called the periosteum. The flat bones of the skull, wing bones and pelvis are laid down as connective tissue plates followed by calcium-phosphate mineralization. The enlargement of the size of flat bones is due to the growth of membrane around the margins and when fully ossified called suture lines.

Soft bones: - Rickets and Osteomalacia.

Children with short statures, bowed legs, deformed head, pigeon breast, rachitic rosary chest, knobby knees and wrists, hunched back, lordosis and crooked pelvis, etc. are well documented in old Chinese and Greek literature. We know these children today as rickets. The word rickets was taken from an old English word Wrickken, meaning twisted. In 1645 Dr. David Whistler described English children with similar deformities, and he called it the Malady of English Children. In 1919 Dr. Edward Mellanby discovered vitamin D and its role in bone formation. The deficiency of vitamin D and calcium in diet in childhood was very common due to poverty when children were raised on mothers' milk alone and in an environment where sun rays were obscured by a thick layer of coal burning smoke. It is still prevalent in poor countries. Besides diet and sunshine, growth hormone, parathyroid hormone, calcitonin, thyroxine, and adrenocorticoids are also involved in bone development and growth. Deficiency of any of these hormones, malabsorption, and liver and kidney failure are some of the other causes of rickets.

Osteomalacia:

Deficiency of vitamin D and calcium, phosphorus and magnesium from any cause in adults will lead to a negative balance of calcium and phosphorus; this results in the mobilization of minerals from bones and bones become weak and soft. Symptoms of osteomalacia are few or absent at the beginning, a bone fracture without an injury may be the first symptom. Diffuse bone pain, weakness of muscles of thigh and arms, difficulty in climbing stairs, and waddling gait may be present.

Osteomalacia is more common in women and in pregnancy, nursing home patients, prolonged bed rest from debilitating diseases, long term use of anti seizure drugs, renal diseases, and vegans are more prone to osteoporosis. Malabsorption syndrome including celiac disease, certain malignancies and gastrointestinal disorders, resection of small bowel and post gastric surgery may result in Osteomalacia. Hereditary vitamin D and phosphate deficiency is a rare cause of osteoporosis.

Treatment of Rickets and Osteomalacia is straightforward. An adequate supply of vitamin D and calcium, phosphorus, and magnesium should be the first order of business, and then adequate supply must be maintained for the rest of life. Treatment of the underlying case where possible must accompany.

Osteoporosis:

Unlike osteomalacia, osteoporosis is very common. It is estimated that people over 70 years have some degree of osteoporosis detected by the Bone Mineral Density (BMD) test and reported as T-Score. T- 1 is normal, and T- 2.5 or over is destined for fractures.

To comprehend osteoporosis, a step back is necessary. Bone is a dense but living tissue, bone cells are Osteoclasts and Osteoblasts. The outer layer of bone is very dense and called the Cortex, inside the bone is a cavity filled with Cancellous bones and bone marrow cells. The cortex and cancellous matrix are linked together to provide strength and stability of bones. Osteoblast, when activated, lays down new bone and osteoclast dissolves minerals by secreting hydrochloric acid locally and digests collagen of the matrix by an enzyme collagenase. The cell surface is loaded with receptors for hormones, vitamins, prostaglandins and other chemicals. When the receptors bind with appropriate chemicals, it either stimulates a specific cell function or suppresses it. Osteoblast and osteoclast communicate with each other by chemical signals. After midlife, the activities of osteoclasts are not matched by the slower speed of the activities of osteoblasts. This results in a weaker bone which is prone to compression fractures of the spine and neck of the femur with minor trauma.

Conditions leading to Osteoporosis:

The white race, female sex, small stature, sedentary life, alcohol, cigarette smoking, prolonged bed rest, space flights, prolonged use of corticosteroids, falling blood levels of sex hormones, food fetishists, thyrotoxicosis, hyperactive parathyroid, heparin, certain oral diabetic pills, certain antidepressant drugs, rheumatoid arthritis. Diabetes, liver disease, vitamin C deficiency, genetic disorders involving collage formation, etc. are some of the causes of osteomalacia. Osteoporosis may coexist with osteomalacia.

Symptoms:

In the early stage, the patients are symptom free, pain from compression fracture of the spine may be the first symptom. Subsequent symptoms are all related to deformities of bones from fractures and pain in muscles and connective tissues.

Treatment and prevention:

Until recently vitamin D and calcium supplements were the mainstays of treatment. Now, it is well demonstrated that this has failed to reverse osteoporosis, moreover, renal stones and high serum calcium may lead to heart disease and other complications.

At present vitamin D 800 iu to 1000 iu along with 1000 mg of calcium daily is recommended.

Other commonly prescribed medications:

1. Bisphosphonates, a synthetic analog of pyrophosphate, are given orally but IV formulation is also available. It inhibits osteoclast mediated bone resorption. GI side effects of bisphosphonates are significant and many patients are unable to continue this drug. The long term use is associated with subtrochanteric fracture of the femur and necrosis of the jaw bone.

2. Raloxifene, an estrogen receptor modulator, is useful in post-menopause patients. It stimulates osteoblasts in new bone formation. Side effects are edema, hot flashes, and deep vein thrombosis.

3. Strontium ranelate. Available as tablets, it increases bone density and strength. Its use is associated with an increase in heart attacks and deep vein thrombosis.

4. Denosumab, an antibody to RANKL. The RANKL is a signal pathway to osteoclasts by osteoblasts which is the first signal in the process of bone resorption. The drug is given by subcutaneous injections every 6-month interval. Pain and cellulitis at the injection sites are reported.

5. Teriparatide, a recombinant human parathormone peptide. Given subcutaneous injection daily. It increases new bone formation and bone density. It may cause high serum and urine calcium, nausea, headache and dizziness are common.

6. Calcitonin, derived from salmon fish, is given as an injection or by nasal spray. Calcitonin is a good pain reliever in compression fractures. Prolonged use is associated with liver cancer.

7. Anti-sclerostin antibody, is osteocyte secreted protein, given by IV, that increases bone density in post-menopausal women.

8. Several other Androgen and estrogen modulators are in the process of evaluation.

 

 

edited 2020.

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Blood Thinners

Blood Thinners.

    PKGhatak,MD

If you watch an artist painting a portrait you will notice that the paint comes out of a paint tube like toothpaste and the artist takes a portion of paint and a few drops of paint thinner and mixes to the thinness the painter likes, and then proceeds. We are not talking about blood thinners like that here, it refers to drugs that delay the clotting of blood within the living body and in medicine, it is known as prolongation of clotting time.

Why and how blood clots.
Blood is a viscous fluid and contains blood cells, water, various proteins, nutrients and oxygen and other substances. Various proteins are present in the liquid part of the blood called plasma, some of these proteins are involved in clot formation and another group in dissolving blood clots. All of these proteins remain in the blood in an inactive state and an initiator is required to start the process like cars have accelerators and brakes but the driver decides which one to push to speed or stop the car.

In response to injuries, the first responder to the scene is Platelet. The platelets enlarge in size, the surfaces become knobby and sticky, adhere to each other and release several chemicals. The aggregated platelet globs plug gaps in blood vessels and the released chemicals that start a chain of events, handing down the product to the next step, like passing the baton in a relay race leading to the formation of clots. This leg of clot formation is called Platelet derived clot pathway.
At the same time, the injured tissue also releases a tissue clotting factor; another series of clotting chain reactions begin. This path is called Tissue derived pathway. These two paths meet down the chain, leading to the formation of a solid clot. These clot promoters are known as clotting factors and are designated by Roman numerical I to XIII. Factors II, VII, IX, X are synthesized in the liver and depend on vitamin K. In addition, Calcium and other substances are also required in clot formation are called co-factors.


Clot dissolving process:
The inner wall of blood vessels is lined with endothelial cells. In response to clot formation, these cells release a clot dissolving factor- tissue Plasminogen Activator (tPA). It acts on a protein, Plasminogen, present in blood clots. Plasminogen is converted to Plasmin. Plasmin is a powerful enzyme and it breaks down fibrin fibers and thereby dissolves clots. This group of drugs is commonly called clot busters.

Currently, available thrombolytic agents (clot busters) are Streptokinase, Recombinant tissue plasminogen activator, Reteplase, and Tenecteplase. These drugs are given by IV and patients are monitored continuously.

Natural Anticoagulants:
Antithrombin, heparin, protein C, and protein S slow down clot formation and prevent clot propagation. Clot promoters and regulators are kept in dynamic equilibrium to ensure the normal circulation of blood.

Anticoagulants:
Heparin:
It is a naturally occurring anticoagulant, present in the Basophils of blood and Mast cells of tissues. Heparin was first detected in the liver cells of dogs (hence the name heparin - hepar=liver), Intestine of pigs and cows is the primary source of heparin. It is available in three forms- Unfractionated UFH, Fractionated or Low molecular LMWH, and synthetic heparin – Fondaparinux. Heparin delays clot formation and prevents the extension of clots.

UFH binds with Antithrombin III(ATIII). This complex acts mainly on clotting factor Xa (activated factor X) and to a lesser degree on other factors and inactivates them at various stages of clot formation.
LMWH like UFH combines with ATIII and acts on clotting factor Xa; and unlike heparin, it has minimal action on other clotting factors.
Fondaparinux acts directly and only on clotting factor Xa, antithrombin is not required.

Heparin, in any form, must be given by injection. Because heparin has a short half-life, continuous intravenous infusion is preferred. A laboratory test-activated Partial Prothrombin Time (aPPT) is used to monitor the heparin dose.


Vitamin K Antagonist (Blood thinner):
  1. Drugs that interfere with vitamin K in the liver in the synthesis of clotting factors are known as vitamin K antagonists. Warfarin (coumadin) has been in use for a long time. To use it, in an effective and safe way, a Prothrombin Time test is necessary. The results are reported as a ratio of the patient's test result in relation to a standard number called INR (International Normalized Ratio). The therapeutic range of INR varies according to the patient's clinical diagnosis. An INR in excess of the recommended range may lead to bleeding in the brain or other vital organs.

Certain vegetables, containing significant amounts of vitamin K, and nutritional supplements containing vitamin K should not be taken when on coumadin. Several drugs interfere with the action of coumadin - some drugs prolong INR, and others depress INR. Before taking over-the-counter pills or prescribed medicine, one must check with doctors or pharmacists when on coumadin.

   2. Direct Acting Anticoagulant (DOA):
Two groups of DOAs are currently available and can be administered orally. One group acts directly on factor Xa, the other on Thrombin (factor IIa). DOA has the advantage over coumadin because no food and only a few drugs interfere with DOA. A fixed dose is generally given to patients. It acts quickly and no blood test is required to monitor this drug. Most of them are cleared by kidneys and use in renal failure is risky. DOA also causes excessive bleeding but less frequently than coumadin. And the anticoagulant effect is not reversible except for dabigatran

Rivaroxaban and Apixaban are examples of direct acting Xa inhibitors.
Dabigatran is an example of a factor IIa inhibitor.
The very high price of DOAs limits their wider use.

The use of DOA in patients with artificial heart valves is not possible because factor XII becomes activated when blood comes in contact with mechanical valves. DOA has no effect on factor XII, whereas Coumadin is effective. And the incidence of cerebral bleeding in DOA use is significant and prohibits its wider use.

3. Naturally occurring anticoagulants:


a). Antithrombin III: It is produced in the liver but not dependent on vitamin K. It inactivates thrombin and clotting factors IXa and Xa. Heparin greatly enhances its actions. Antithrombin deficiency may be inherited and also seen in renal failure and cirrhosis of the liver.

b).   Protein C and S: are synthesized in the liver and are vitamin K dependent. Protein C inactivates clotting factors Va and VIIIa. Protein S acts as a cofactor for Protein C.
The gene for protein C is located on chromosome 2.  The deficiency of Protein C is associated with spontaneous clot formation. FDA has approved a recombinant human protein C for use in severe sepsis cases.

4. Antiplatelet Drugs:
This group of drugs is specially important because they prevent blood clots in the Arterial side of the circulation. Antiplatelet drugs are used extensively in post-op coronary bypass graft surgery, coronary stent placement, myocardial infarction, cerebrovascular diseases, and peripheral vascular diseases. It is not used as a clot inhibitor on the venous side of the circulation.
Antiplatelet drugs are classified according to the enzymes they inhibit. Its use results in the prevention of platelet aggregation and release of platelet clotting factors, thereby preventing soft clot formation and the chain reactions leading to firm clot formation.

Blockers of P2Y12 receptors on ADP: Examples of these groups are clopidogrel (Plavix), prasugrel, ticagrelor.
Irreversible Cyclooxygenase inhibitors: example- aspirin.
Reversible Cyclooxygenase inhibitors: example - NSAIDs
Phosphodiesterase inhibitors: for example- cilostazol.
Adenosine uptake inhibitors: for example- Dipyridamole (Persantin)
Thromboxane inhibitors: example- aspirin.

When and why Anticoagulants are necessary:
Stagnant blood promotes spontaneous clotting. Very obese people are at risk of blood clots in the leg veins. Prolonged bed rest from disease or disability causes venous blood to clot in pelvic or leg veins. Recent leg or pelvic bone fractures or surgery on joints and bones have increased of risk of clotting. Pregnancy and recent childbirth are risky times for a woman. Cancers of solid organs and malignancy of bone-marrow cells promote blood clots. When blood has too many cells, as in polycythemia or leukemia blood clots are likely complications. When circulation is slow in the legs as in congestive heart failure or patients with varicose veins blood may clot. Prolonged forced sitting, as it happens in long airplane rides or cars, is a known risk factor.
Certain illnesses promote micro level blood clots in all tissues and organs. This situation leads to deaths in most cases. This entity is called Disseminated Intravascular Clotting (DIC). Sepsis produces a similar picture. ITTP (Idiopathic Thrombotic Thrombocytopenia) produces a similar situation. Thrombocytosis, a condition where platelet count is very high, also predisposes to clot formation.

Inherited clotting disorders:
A deficiency of protein C, protein S, and antithrombin leads to spontaneous venous thrombosis.
Other causes of increased risk of thrombosis are - oral contraceptives, sex hormones, and high homocysteine levels in the blood.

Besides these conditions, an anticoagulant is used to prevent blood clots inside the chambers of the heart. Blood clots in the left sided heart chambers get pushed out into circulation and may block the blood supply to the brain and other vital organs. Patients having episodes of atrial fibrillation and recent myocardial infarction are specially prone to clotting. A clot from the right ventricle or clots from leg or pelvic veins carried to the right ventricle are pushed into the Pulmonary artery and produce pulmonary embolism. When heart valves are infected with bacteria or fungi, vegetation grows on heart valves and dissemination of infected vegetation to other organs frequently occurs. Aortic and mitral valves are more prone to infected vegetation.
Prevention of stroke and pulmonary embolism are common reasons for anticoagulants are used. Anticoagulants may produce serious gastrointestinal or major cerebral bleeding. Patients taking multiple drugs are at higher risk of bleeding because of the interaction between drugs. It is a serious problem and requires careful planning.

When clot lysis drugs are used:
When the arterial circulation of an organ is blocked by clots, immediately removable clots are essential. This is particularly important in strokes, myocardial infections, pulmonary embolisms, and arterial blockage of limbs. Thrombolytic agents are administered intravenously and patients are monitored carefully because the risks of bleeding are high. Many institutions have strict guidelines for its use. In situations where the thrombolytic agent is contraindicated, IV heparin is the initial choice followed by oral anticoagulant- long or short terms, based on the underlying conditions. 

 

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Enlarged Prostate Gland

Prostate Gland Enlargement

PKGhatak,MD

Prostate gland enlargement is due to excessive growth of normal prostate tissue. It is a common problem in elderly men. About 90% of elderly over 80 years of age will have some degree of prostatic enlargement. In the same population cancer of the prostate gland is also common.

Some doctors are gentle with patients when examining the prostate. Your gentle doctor will ask you to lie on your side on the examination table, ask you to pull your knees to your chest. Then he will put on a pair of gloves, gently insert a finger in your anal canal and feel the prostate gland. You may be embarrassed but will not feel any pain. Others are rough, ask you to drop your pants and bend over the examination table and then insert a gloved finger and do the examination. It is not only a crude way to examine but very much unnecessary. Ask for a gentle prostate examination when you go for an examination next time.

Why prostate enlarges:

It grows in proportion to the general growth since birth. At puberty, it grows rapidly and then returns to the usual growth pattern until men reach age 45. Then it starts to grow again. The reason for the second growth is not precisely known. It is postulated that when the blood levels of testosterone begin to fall at age 45, the gland begins to grow again. Others have suggested that the blood levels of testosterone might be below but in the prostate tissue the concentration of Dihydrotestosterone (DHT), derived from testosterone, a more potent agent for prostate growth, remains high and that causes prostate enlargement.

Cancer of the prostate is another cause of prostate enlargement.

Symptoms of Prostate enlargement or Benign Prostatic Hyperplasia (BPH):

Going to the toilet frequently, getting up at night multiple times to go to the toilet, cannot wait when has to go and then wetting underpants, feeling that the bladder did not empty fully, having difficulty in initiating urination, standing too long for starting urination, urine comes in drips and drops, blood in urine and painful urination from infection are symptoms of BPH

Cancer of the prostate usually produces the same symptoms and the two conditions may present at the same time.

How doctors know an enlargement is cancer:

There are no symptoms that are specific to cancer, but fresh blood in the urine and pain and discomfort in the genital area are more common in cancer.

Going to the doctor:

After an examination, the doctor may say the gland is not only large but hard and has lumps. But that is not diagnostic of cancer. A blood test – PSA level may be elevated but that is not enough. An ultrasound test through the rectum may show the irregular pattern of growth and nodules in the gland. But ultrasound test is not diagnostic either. An MRI of the prostate provides better information. A needle biopsy of the prostate is necessary for the diagnosis of cancer.

PSA test:

A protein secreted by the prostate cells known as Prostate Specific Antigen (PSA), is present in blood in free and bound forms.

The PSA test was introduced as a surveillance tool for detecting the recurrence of cancer in patients treated successfully. PSA levels fall to zero and remain zero following cancer treatment; the reappearance of PSA in the blood is an indication of cancer recurrence. Subsequently, it was used as a screening tool for prostate cancer. Later studies showed many patients were unnecessarily subjected to prostate biopsies and treatment on the basis of elevated levels of PSA. PSA is present in blood in free and bound forms. When total PSA is over the normal limits - 25 % or more of free PSA in relation to total PSA is associated with a low probability of cancer; whereas, a 10% or lower ratio of free PSA/ bound PSA is considered as positive for cancer. A rising level of PSA over time, a high ratio of PSA in relation to the prostate volume, and a sharp rise in the level over the previous year were considered as the presence of cancer. But none of these tests are not full proof, both false positive and false negative results are common.

A normal level of PSA is age specific. Blood levels of  2 to 4 ng/ml are generally accepted as normal for people between 45 and 79 years of age. For people 80 or over, a level up to 5.5 ng/ml is taken as normal.

At present, a routine PSA test for people over 80 years of age is not recommended.

Besides BPH and cancer, other causes of elevated PSA levels are - prostate infection, injury to the prostate, prostate examination, recent sexual activities, and urinary tract infection.

Prostate Biopsy:

The prostate gland is accessed through the wall of the rectum. Local or general anesthesia is used. It is still a painful procedure. 6 to 12 pieces of tissue are obtained during the biopsy. Prostate cancer grows at different rates at different sites and varies in the degree of abnormality from one side to the other, that is why multiple tissue samples are taken from different sites.

Based on the degree of abnormality of cells and the distortion of architecture of the glands, when examined under a microscope, a biopsy report is given a score from 2 to 10 on the Gleason score. A score of 10, being the most aggressive, and a core of 2 is atypical growth but not cancer.

 All 12 biopsy samples are individually assessed and graded on a 1 to 5 scale based on the degree of cancerous changes and architectural distortions. Only two samples with the highest grade are selected and reported and this is the basis of reporting on Gleason's score.

Like the interpretation of PSA tests, the prostate biopsy reports and interpretations are confusing. Quite often, Pathologists disagree among themselves when examining the same tissue sample.

If digital examination of the prostate gland, PSA, and ultrasound are indicative of a low chance of cancer, the doctor may recommend regular follow up with PSA tests before suggesting a biopsy or on the other hand, if the possibility of cancer is high then a biopsy will be recommended.

For treatment of BPH, the doctor may prescribe one of the two types of medications: 

One that decreases the frequency of urination and urgency:

They are called alpha-blockers. Urinary bladder contracts in response to alpha stimulation of the sympathetic nervous system. The neck of the bladder is rich in alpha receptors and alpha blockers block receptors and thereby interfere with bladder contraction and help relaxation of the bladder.

The other group of drugs is called 5- alpha reductase inhibitors.
These drugs block the action of 5-alpha reductase on testosterone and prevent the formation of Dihydrotestosterone (DHT), thus preventing prostate cell proliferation and gland growth. And when used on a long term it actually reduces cell volume and prostate size.

A combination of these two groups of drugs is available as tablets and is often prescribed.

Complications and surgery:

Common complications are- infection of urine and the prostate, acute urinary retention and backpressure in the bladder leading to a decrease in renal function.

Infections of the prostate and urinary bladder are treated with antibiotics and are followed by preventive therapy that includes surgery of the prostate.
Acute retention is relieved by inserting a catheter into the urinary bladder and may require to drain the bladder for a prolonged period by Foley catheters.

To relieve obstruction at the bladder neck by the enlarged prostate, the extra gland tissue is shaved off by instruments inserted through the urinary passage. The procedure is called Transurethral Resection of the Prostate (TURP), a modified version is called Transurethral Incision of the Prostate (TUIP), and by Open Prostatectomy

Other modalities like Laser, Radiofrequency Ablation, Microwave, Hyperthermia are also used. Still, other methods are in the developmental stages.

Health food stores sell herbal products claiming these promote “prostate health” and prevent BPH. It may be true for some of these products but the potency of these pills varies according to country of origin, seasonal variation of plant growth producing a different concentration of active ingredients and may be contaminated with pesticides. There are no federal regulations certifying the safety of these products.

Other tests and procedures at the time of evaluating BPH are:

Cystoscopy of the urinary bladder, MRI. IVP, urinalysis, urine culture, cystometrogram, and urodynamic profile, etc. are not required to make a diagnosis of BPH but to detect associated complications.

It is important to note: BPH does not cause cancer, but cancer may coexist with an enlarged gland.

 

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Chronic Myeloid Leukemia

Chronic Myeloid Leukemia

      PKGhatak,MD

Chronic Myeloid Leukemia (CML), also called chronic myelogenous leukemia, develops due to an acquired abnormality of a chromosome and has become an important milestone in medicine in more than one way.

In 1959 Dr. Peter Nowell, a pathologist at the University of Pennsylvania, PA, while microscopically examining the blood of a Leukemic patient, detected an abnormal chromosome. Dr. David Hungerford, a Zoologist working on his Ph.D. at the Fox Chase hospital in Philadelphia, corroborated with Dr. Nowell. They established that the abnormality was on chromosome 22. They named this abnormal chromosome as Philadelphia Chromosome (Ph Chromosome). The Ph chromosome is present in all CML cases. It is also present in 20% of acute lymphatic leukemia and 2% of mixed types of leukemia.

The long arm of chromosome 9 breaks away at ABL (Abelson Leukemia virus) and the broken piece gets attached to the breakpoint BRC (Breakpoint Cluster Region) of chromosome 22. This results in a fusion gene called the BCC-ABL gene. The broken piece from chromosome 22 attaches to chromosome 9. The process of swapping genetic materials between two chromosomes is called Reciprocal Translocation.
This discovery was the first of a Chromosomal abnormality as the cause of human leukemia, and the abnormal chromosome was visible on blood smears. This discovery generated a lot of interest in research in finding genetic mutations in the development of malignancy.
In 1973 Dr. Janet Rowling at the University of Chicago identified the mechanism behind reciprocal translocation.
The scientific notation for this translocation is t (9;22) (q34.1; q11.2)

t stands for translocation; 9 and 22 within the parentheses are chromosomes no. 9 and no. 22. In the next parentheses, q stands for the long arm of chromosomes and the two digits are for the band location on Chromosomes.

The normal ABL gene carries instructions for the synthesis of a protein called Tyrosine Kinase (TK). TK speeds up the rate of cell division and also repairs corrupt DNA. The rate of synthesis of TK is auto-regulated. When ABL is fused with the BCR gene, this fusion gene loses its auto-regularity property and begins producing an excess quantity of TK. Some myelocytes contain this fusion gene.  An excessive number of white cells appear in the blood, and only a small fraction of granulocytes carries this Ph gene in their nucleus. The protein produced by BCR-ABL is named according to the molecular weight and location (p120 to p180). The protein p230 is associated with CML.

The normal BCR gene regulates cell movement and cell functions. It may work as an on and off molecular switch within the cell.

Clinical Features of CML:

CML patients present in three distinct phases of the illness-

Chronic phase CML, Accelerated phase CML and Acute Blast phase or Acute leukemic phase.

Chronic CML:

The patients are generally symptom free. The disease is detected in a routine blood test done for other reasons. The white cell counts (WBC) over 50,000/mcL are usual. Further, tests detect the Ph chromosome. A bone marrow biopsy is required to establish a CML diagnosis.

When patients develop symptoms, they are likely to complain of night sweats, lack of energy, low grade fever, left sided abdominal pain, joint pain and increased WBC counts of 100,000/mcL or more. Enlargement of the spleen is usually detected. And a ratio of BCR-ABL / ABL (abnormal over normal gene ratio), detected by PCR test (polymerase chain ratio), of the white cells and bone marrow shows a ratio over 0.01(the range of 0.02 to 0.25). This ratio helps to determine when to start treatment. It is also an important indicator of the effect of therapy and adjustment of medications.

When mature white cell numbers fall, viral or bacterial infections result. When the WBC count reaches 150,000/mcL or higher, the blood becomes thick and blocks capillaries of the retina and blurred vision results. A segmental visual field loss is the rule. Similarly, obstruction of brain vessels may occur and produce strokes.

About 18 years ago Imatinib, an oral medication, was introduced to treat CML. It blocks the uncontrolled production of Tyrosine Kinase by the fusion BCR-ABL gene. Since then, the outlook of patients with CML has changed dramatically. About 98% of CML patients respond to this drug and patients remain in stable condition for 10-15 years or more. Some patients may even be taken off the medication and are observed with blood tests only.

However, a minority of patients either do not respond to Imatinib or develop resistance to medication. The BCR- ABL/ABL ratio increases, so also the WBC count. In these cases, other TK inhibitors - Nilotinib, Dasatinib and Bosutinib are effective.

The accelerated phase of CML:

Those patients who do not respond to Tyrosine Kinase Inhibitors (TKI) or develop further mutation of BCR-ABL gene, develop worsening of fatigue, weight loss, weakness, fever, gum bleeding, and pain in the abdomen and joints. Anemia and an enlarged liver may be present on examination. An increase in WBC count over 200,000/mcL, 10 to 19% basophils in blood, an increase in BCR-ABL/ABL ratio and an increase in blast cells in blood and bone marrow are present. A new mutation in the BCR-ABL gene may be detected. T315I mutation is resistant to several TKI drugs.

Patients generally respond to increasing dose of TKI or switching to different TKI and at the time a combination of two TKI drugs are used. Those patients who still do not respond are treated with a new TKI drug, Ponatinib, with a good response. Some young patients may be considered for allogenic Stem Cell Transplantation but transplant results are mixed.

Acute Blast Phase or Blast Crisis:

Patients are sick with increased intensity of all existing symptoms. Increasing weight loss, high fever diarrhea, sepsis, high blood sugar, and pain over bones and joints, nose bleeding, cerebral bleeding, and abdominal pain usually develop.

Anemia and a very high WBC count and decreased platelet count, blast cells over 20% in the peripheral blood, and 20% or more blast cells in bone marrow are usual. Internal organs show blast cell infiltration. Testing for mutation of BCR-ABL gene is mandatory before treatment is initiated because the selection of medications depends on the detection of the correct mutation. Acute Lymphoblastic Leukemia develops in 20% of cases. Acute myeloblastic leukemia in 2% and mixed Acute Leukemia are also seen.

Treatment of Myeloid blast crisis consists of administrating one or two TKI drugs and multiple chemotherapeutic agents to induce remission. Afterward, suitable TKI drug or drugs are continued. Omacetaxine, a non-TKI drug is approved for use in the blast and accelerated stages of CML. It may produce severe bone marrow depression, cerebral hemorrhage, elevated liver enzymes, and diarrhea.

Early allogenic stem cell (stem cells obtained from a donor) transplantation is recommended in blast crisis. But the results are not that impressive.

The introduction of tyrosine kinase inhibitors has changed the outlook of over 90% of CML patients. The majority of them can expect to live their lives normally. Peripheral blood PCR test helps an accurate evaluation of the disease progression and early detection of the emergence of resistance and modification of treatment are possible before more serious complications could develop.

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The Otherside of Transplant

                                             The Other Side of Transplant

                                                     PKGhatak,MD

                                           

                                       
Many diseases fail to respond to the best possible treatment and usually end in organ failure. Research and advances in medicine have made it possible to extend life by the use of Mechanical Ventilators, Renal Dialysis Machines, Artificial Heart Pacemakers, and Mechanical Heart Pumps. These devices are life-extenders but far from a cure. Implanting a functioning organ from a recently deceased person came next, and kidneys from living donors and a portion of the liver are also accepted. Transplants are now standard practice for end-stage organ failure. But a shortage of available organs and rejection of the transplanted organs by the recipient's body, lead to further refinements of patient selection, organ harvest, post-transplant immunosuppression medications, and prevention of infections.

After the patient's specialist recommends transplantation, the patient is interviewed and thoroughly examined by a transplant team. The team is made up of surgeons, physicians, immunologists, nurses, pharmacists, psychologists, social workers and others. The patient is well advised about risks, future complications, and the requirement of strict compliance with the treatment regimen. Once selected for transplant, then the patient waits and waits - till the day an organ is available. For most patients, this period is long but is full of hope and sweet dreams - a promise to return to a normal life.

Shortly after successful transplantation, the initial elation is replaced by anxiety. Fear of catching an infection, and concerns about rejection become unconscious preoccupations. Some of those are discussed here:

Rejection:
Lung transplant patients have the most frequent rejection incidents, and the kidney the least, liver, pancreas, and heart are in between. The rejections are of two types- Acute and Chronic. About 50 to 80 % of transplant patients will have at least one episode of rejection in the post-transplant period.

Acute Rejection: This usually happens within a year of transplantation. In a kidney transplant, the incidence is 10 % in patients who have undergone the pre- transplant immunosuppressant therapy, in non- treatment group the incidence is 20 -30 %. In Lung transplants the rejection incidence is over 50% for one episode, often multiple incidences occur and lead to bronchiolitis obliterate – a fatal disease. In cases of heart, the incidence is over 50% and 2 to 3 incidences occur in the same patient. In liver transplant cases, the first incidence of rejection often occurs within 2 weeks.
To reverse the acute rejection the patient needs to be hospitalized. Laboratory blood, urine tests, X-rays, scans, ultrasound tests, etc. may not be enough to make a diagnosis. A biopsy of the transplant organ is usually required for each episode of rejection. The procedure is painful and has associated risks.
The treatment of acute rejection includes biological agents. These are:
  
Polyclonal Antibodies:    Administered via a central vein. Chills, high fever, joint pain are common and symptoms of acute serum sickness may develop, occasionally anaphylaxis is seen.
Monoclonal Antibodies: Can be given via a peripheral vein. The side effects are milder than polyclonal antibodies.
Alemtuzumab, Belatacept, Rituximab and other agents are in the process of development.

Chronic Rejection: This may occur at any time for the life of the transplant organ. The incidents vary according to the organ transplanted. The symptoms of chronic rejection are mild and deterioration of the function of the transplant organ is the usual sign. A biopsy of the organ may be required. Chronic rejection is a progressive insidious process and is due to atrophy of the transplant organ and fibrosis.
To prevent chronic rejection patients are placed on immunosuppressant therapy which consists of several drugs -

Drugs used:
Usually, more than one drug is used, often requiring a change of medications and a close follow up for the rest of patients' lives. The following drugs are commonly used. -
Glucocorticoids: Initially given in large dosages by intravenously then switched orally. The dosage is tapered slowly over time and the maintenance dose is around 10 mg a day. This drug has significant side effects – Osteoporosis, compression fractures of the spine and hip fractures, cataracts, and fungal infections.
Cyclosporine: administered orally. It is toxic to kidneys, decreases renal function over time, gum hyperplasia, increases blood potassium and elevates blood sugar are commonly seen. Increase hair growth often occurs. Dose adjustments are made based on the blood levels of the drug.
Tacrolimus: It is also toxic to kidneys. It increases blood sugar. It is given orally. Dosage adjustments are made on blood levels.
Sirolimus: It is given orally and has no renal toxicity. It increases blood lipids, causes oral ulcers and anemia. Blood levels are obtained for dosage adjustment.
Azathioprine (Imuran): It may produce bone marrow suppression. It is administered orally.
Mycophenolic Acid: It causes GI disturbances, nausea, abdominal pain and low white cell and platelet counts. It is available as pills.
Drug Interactions:
Cyclosporin and Tacrolimus are metabolized faster by Anti TB drugs and blood levels fall below the therapeutic range, whereas, blood levels reach toxic levels when used with calcium channel blockers, antifungal drugs, erythromycin and clarithromycin. Cyclosporin and Tacrolimus are nephrotoxic and should not be combined. Cyclosporin and sirolimus should be given at least 6 hrs. apart to prevent excessive blood levels of sirolimus. Mycophenolic acid blood levels are higher when used with tacrolimus or sirolimus concurrently.


Infection:
Cytomegalovirus (CMV): The infection is often due to the reactivation of an old infection. If the transplant organ is seropositive for CMV, implanted in a seronegative recipient then it becomes a serious problem and multi system failure may occur.
Hepatitis B virus (HBV): Patients receiving a liver transplant as a consequence of previous HBV infection are properly monitored and treated to prevent reactivation of infection, otherwise, fulminate hepatitis and liver failure would follow. If a patient is seropositive for HBV, then he becomes ineligible for transplant of organ other than liver.
Hepatitis C Virus (MCV): Risks are similar to HBV infection but the symptoms are milder and the disease progresses slowly.
Ebstein-Barr Virus (EBV): Infections may lead to the development of Lymphoma.
Human Herpes Viruses: (HHV): Infections may lead to renal graft loss and kidney failure.
Fungal Infections: Mucormycosis, Aspergella, Candida infections are common due to immunosuppression.
Cryptococcus: Infection to the brain and meninges lead to a serious situation.

Infection Prophylaxis:
Appropriate medications are given, short or long term, to prevent infections against CMV, HHV, Pneumocystis, Nocardia, and in endemic countries against Tuberculosis.

Malignancy:
The incidence of carcinoma of the skin and lips is high and accounts for 50% of all malignancies in transplant recipients. The incidence of lung cancer, Kaposi sarcoma, renal cell carcinoma, urogenital carcinoma is higher than the general population.
Non-Hodgkin lymphoma accounts for about 25% of all malignancies and is about 40-fold higher than the general population.

Immunization:
Pneumococcal vaccines, Hepatitis B vaccines, yearly Influenza vaccine and Varicella-Zoster vaccine are recommended. Recipients of transplants should never receive any live vaccine.

Organ transplantation should be done only in transplant centers. A transplant team is essential and only dedicated centers can attract and retain the highly qualified and technically super-gifted people. All tests must be done in house and results must be available instantly. A good outcome of implantation depends on patients' full compliance with the medical advice, and such centers have people and follow up protocols for tracking each patient for a very long time.

Transplant of bone marrow, stem cells, cord blood cells, skin, face, fecal, beta cells of the pancreas, and small intestine, etc. are also done but these are not discussed here.

 

 

 

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