Rheumatoid arthritis (RA) is a chronic inflammatory disease mediated by immune mechanisms and affects multiple organs & tissues in the body although generally manifests with joint involvement as its major presentation.

It is considered to be an autoimmune disease where the body’s immune structures due to certain faulty system attack some organs & tissues instead of defending them.

Frequency & distribution

This disease occurs all over the world and affects all races & both sexes although women are affected more than men. The disease characteristically presents during middle age and most of the cases present between 35 and 50.

What cases RA?

RA is an immune mediated inflammatory disease and it appears that a combination of genetic & environmental factors is responsible for the development of this disease.

Genetic factors are thought to explain abut 60% of the disease susceptibility to RA. Some of the frequent genetic makers include;

* HLA-DRB1
* HLA-DR4
* HLA-DR1 etc.

Since the genetic susceptibility alone cannot account for the incidence of RA environmental factors are incriminated too and few such factors include;

* Urbanization & climatic changes
* Smoking (HLA-?1 susceptibility)
* ? Infectious causes etc.

The earliest miscoscopical lesions seen in RA include micro vascular injury & increase in the number of synovial lining cells. As this process continues the synovial tissue becomes edematous and protrudes into the joint cavity as villous projections.

The RA lesions are with activated macrophages, lymphocytes & fibroblasts and they secrete chemical substances called as cytokines & chemokines. These agents are thoughtd to induce the synovial, cartilage & bone damage also the systemic manifestations of RA.

Clinical manifestations

RA symptoms and signs can be grouped under two categories including;

* Joint manifestations & related
* Systemic manifestations (non-joint)

The joint manifestations include;

Multi-joint involvement usually symmetrical is characteristic feature of RA. Both small and/or large joints may be involved although the involvement small hand joint is very characteristic. Affected joist are swollen, painful and stiff. This stiffness is characteristically seen in the morning. Joint involvement is associated with generalized weakness, low grade fever, sick feeling (malaise), loss of appetite & weight etc.

The Systemic manifestations of RA include;

* Rheumatoid nodules
* Vasculitis
* Lung & pleural involvement
* Heart & pericardial involvement
* Peripheral neuropathy/ mononeuritis multiplex
* Cervical spine (atlanto-axial joint damage)
* Eye involvement
* Felty’s syndrome
* Osteoporosis (bone thinning)
* Tumor development (lymphoma) etc.

Rheumatoid nodules occur in about 20 to 30% of RA patients and geerally occur near joints and extensor surfaces. Rheumatic vasculitis affects the blood vessels and can affect virtually any organ and patient’s manifestation would depend upon the type of organ involved (e.g. heart involvement can induce heart attack). Lung & heart involvement may be secondary to vascilitis ir due to nodular development. The nerve damage is either bilaterally symmetrical peripheral neuropathy or in the form mononeuritis multiplex.

Felty’s syndrome comprises;

* Chronic RA
* Enlarged spleen
* Decreased White & red blood cells and platelets.

Osteoporosis occurrence is common to RA and this can be aggravated by glucocorticoid usage. RA patients rarely may develop B cell lymphomas.

Diagnosis

The following investigations are performed including;

* Blood tests
* Radiological studies

X-ray studies
CT or MRI
Bone scanning etc.

* Synovial fluid analysis
* Synovial biopsy etc.

The following blood tests are usually considered to detect and/or assess the prognosis of RA;

* RA factor
* Anti-CCP
* ESR or CRP
* Complete blood count (CBC)

RA (rheumatoid) factor is one of the most commonly employed blood test (serological test) in this regard although there are some indication that anti-CCP may be a better test for this purpose. This antibody is detected in more than 60% of RA patients. But it is not specific for RA as about 5% of general population may harbor this antibody in their blood and also may be seen in patients having their disorders like lupus (SLE), Tuberculosis, syphilis etc.

Anti-CCP, antibodies to CCP, has sensitivity similar to TA factor and more specific for RA so now-a-days there is some recommendation to use this test instead of RA factor. But again anti-CCP is not totally diagnostic for RA and its sensitivity is only comparable with RA factor that means many patients who indeed have RA may not be detected by these two blood tests. Also they are not specific means these tests come abnormal even if somebody do not have RA.

ESR (sed rate) and CRP (reactive protein) are examples for acute-phase reactants and they are elevated in varieties of acute inflammatory conditions and are not specific for RA. However these agents are frequently ordered as hey serve as a supporting evidence for underlying the inflammation and also give some clue as the activity of the disease, in the sense a high blood value of sed rate or CRP generally correlate with an on going active inflammation rather than controlled chronic disease.

A CBC may reveal normo-chromic, normocytic type anemia and increased platelets and these two findings generally correlate with disease activity.

Radiological tests are frequently used for RA diagnosis and management. Simple plain x-rays are generally more than sufficient. None of the radiological findings are diagnostic of RA. They reveal findings including

* Fluid in the joints
* Synovial thickening
* Loss of joint cartilage
* Bone erosions etc.

The symmetric involvement especially the smaller joints of the hands are highly characteristic for RA although yet not diagnostic.

Other imaging studies like MRI, CT, bone scan etc may be able to detect minor pathologies missed by x-rays especially in the early stages of the disease although most often they are not necessary as the combination of clinical features, blood abnormalities and plain x-ray findings are more than sufficient for arriving at the diagnosis.

Synovial fluid analysis may be performed to confirm the inflammatory nature of the joint swelling and fluid accumulation. The typical findings include turbid fluid with reduced viscosity, elevated protein count, normal or slightly decreased glucose, increased WBCs (white blood cells) especially the neutrophills. C3, C4, total hemolytic components are characteristically decreased in RA.

There are certain criteria put forward for the diagnosis of RA and this system uses both clinical features & investigational findings as below

1) Morning stiffness in and around the joints
2) Arthritis of three or more joint areas
3) Arthritis of hand joints
4) Symmetric arthritis
5) Subcutaneous nodules (rheumatoid nodules)
6) Serum rheumatoid factor
7) Typical radiographic changes

Out of these seven at least four criteria should be positive to consider a patient is having RA. This system of identifying RA has a sensitivity of abut 91 to 94% and specificity of around 89%.

Management

RA has no curative treatment so far and the purpose of the treatment is to provide symptomatic relief, reduce joint inflammation, and slow down or suppress any chronic joint destruction a

In general the therapeutic approaches to RA may discussed under seven headings

1) NSAIDs (non steroidal anti-inflammatory drugs)
2) Steroids (glucocorticoids)
3)  DMARDs (disease modifying anti rheumatic drugs)
4)  Biologic agents
5)  Immunosuppressive therapies
6)  Surgical therapies
7) General measures

NSAIDs are useful when patients present with acute severe pain & inflammation of joints. Although they help symptomatically they do not have any impact on the course of the illness.

Examples for traditional or non specific NSAIDs include;

* Ibuprofen
* Indomethacin
* Piroxicam
* Paracetamol etc.

Examples for the newer COX -2 inhibitors include;

* Celecoxib

The selective COX-2 inhibitors are considered to be safer for the stomach compared to the on selective COX inhibitors however the cardiovascular complications like heart attack, stroke are a concern with these agents.

A low dose oral steroid like prednisolone usage is generally recommended. In addition to alleviate pain & inflammatory manifestations it may slow down the onset of bone erosion as well. Although small doses of steroids are not as notorious as the large dose steroids to produce serious side effects but still the following side effects are possible including;

* Gastro intestinal ulcers
* Diabetes mellitus
* High blood pressure
* Osteoporosis (thinning of bones)
* Infections etc.

DMARDs like methotrexate are routinely used on long term basis to slow down or control the course of RA. Studies have revealed that DMARDs do not induce remission but rather suppress the symptoms.  The side effects of chronic usage of methotrexate include;

* Oral ulcers
* Gastrointestinal upset
* Liver damage
* Lung damage etc.

Biologic agents are a recent addition to the therapeutic intervention for RA and few of these available agents include;

* Infliximab
* Rituximab
* Abatacept
* Etanercept
* Adalimumab
* Anakinra etc.

These are TNF (tumor necrosis factor) neutralizing agents or IL-1 receptor antagonists and help in controlling the clinical manifestations of RA. They may be used with agents like methotrexate or alone. In addition to ameliorating the symptoms they also slow down the disease process and joint damage. However some of these gents are associated with serious complications on long term usage including;

* TB (tuberculosis) reactivation
* Lymphoma tumor development
* Lupus like disease development etc.

Immunosuppressive therapy with drugs like

* Azathioprine
* Cyclosporine
* Leflunomide
* Cyclophosphamide etc.

Their effectiveness and side effects are in general comparable with DMARDs although methotrexate in general is favored by physicians than other agents.

Surgery I required if major joint damage has taken place and some commonly performed procedures include joint replacement, synoviectomy etc.

The general management includes;

* Exercise and activities as tolerated
* Some rest during severe symptoms
* Splinting the severely inflamed joints
* Assistive & orthotic devices etc.

SLE (systemic lupus erythematosus) also simply called as lupus is an autoimmune disorder in which auto antibodies & immune complexes may attack various tissues and organs in the body and cause their malfunctioning.

The role of immune system is to protect the body however there are certain instances where instead of helping it actually troubles the body and may produce myriad number of disease conditions and this situation is called as autoimmune disorder.

Frequency & distribution

A whopping 90% of SLE sufferers are women and belonging to the reproductive age however no race, age, sex is exempt from this disease.

What causes SLE?

SLE as mentioned above is an autoimmune disorder and appears to result from a complex interaction between;

* Genetic &
* Environmental factors.

The environmental factors thought to contribute for the development of SLE include;

* Gender (Female sex – hormonal factors)
* Ultraviolet light
* Infections
* Other factors.

The staggering high incidence of SLE in women is imputed to the female hormonal factors. Estrogen hormone in certain ways appears to activate or sustain the activity of the abnormal immune pathway and effectuate the cell damage. Women who are on estrogen containing birth control pills or HRT (hormonal replacement therapy) are found to have increased susceptibility to SLE further supports the hormonal role.

When SLE patients are exposed to UV light about 70% of patients develop flare up of this condition and it indicates that this environmental factor has some role too.

EBV (Epstein-Barr virus) is one of the viral environmental factors that are ascribed to trigger the SLE in susceptible patients. Studies have shown that SLE patients have a higher incidence of this viral infection as compared to non SLE people. The virus survives in side the B lymphocytes for decades and also certain amino acid sequences of this virus resemble the sequences contained in human body cells so the antibodies generated against EBV may act as auto antibodies and damage the patient’s tissues and organs.

It appears that it all begins initially in the form of an introduction of certain antigens to the susceptible individual. Patient’s body tries to tackle these antigens through its immune system by activating its various immune components as T cells, B cells, complement actors, macrophages etc. Due to certain handicap in the immune system the antigen are not contained efficiently and this results in the formation of abnormal immune complexes, auto antibodies etc.

The activation of immune & complement system promotes the release of myriad chemical substances including cytokines, chemotaxins, vaso-active peptides, destructive enzymes etc and all these above developments result in the cell damage.

Body involvement in SLE

SLE is one of those diseases that can affect majority of the tissues and organs in the body. Some of common organs involved and the resulting disease or clinical manifestations are highlighted below.

* Neurological involvement

Diffuse lupus cerebritis
Seizures (fits)
Strokes
Bleedings
Psychosis
Depression etc.

Lung related;

Inflammation of pleura (lung covering)
Pleural effusion
Lung infiltrates
Interstitial inflammation an fibrosis
Bleeding into lung tissue etc.

Heart related;

Inflammation of pericardium (heart covering)
Myocarditis
Libman-Sacks fibrinous endocarditis
Heart attacks etc.

Blood vessel (vascular) manifestations;

Vasculitis (inflammation of blood vessels)
Strokes
Heart attacks etc.

Skin manifestations

Lupus dermatitis etc.

Kidney manifestations

Lupus nephritis
Nephrotic syndrome
ESRD (end stage renal disease) etc.

Hematological & vascular manifestation

Anemia
Hemolysis
Lymphocytopenia
Thrombocytopenia
Venous & arterial clots etc.

GI (gastrointestinal) manifestations

Nausea, vomiting & diarrhea
Autoimmune peritonitis
Intestinal vasculitis etc.

Eye manifestations

Sicca syndrome etc.

Diagnosis

The diagnosis of SLE requires both clinical and investigational inputs.

The Investigations arranged during the diagnosis & evaluations of SLE include:

* Blood tests
* Urine analysis
* Imaging studies (e.g. Ultrasound, Echo, x-rays, CT, and MRI) etc.

The blood tests are done mainly to look for abnormal antibodies. ANA (antinuclear antibodies) are highly sensitive (about 98%) but not specific. Antibodies to double strand DNA (Anti-dsDNA) and to smooth muscle antigen (anti-sm) are highly specific for SLE although not as sensitive as ANA.

The other antibodies some times tested during the diagnosis of SLE (less sensitive & specific than the three antibodies mentioned above) include;

* Antiphospholipid
* Anti-RNP
* Antihistone
* Anti-Ro (SS-A)
* Anti-La (SS-B)
* Anti-platelet
* Anti-erythrocyte
* Anti-ribosomal P
* Anti-neuronal antibodies etc.

Other blood tests include ESR (sed rate) or CRP (c reactive protein) and these tests come frequently abnormal especially during active flare ups although they are not specific for this condition.

Diagnostic criteria for SLE

There are 11 points listed as below that are included for helping with the diagnosis of SLE. If ?4 are present then the diagnosis of SLE is highly likely with specificity approximately 95% and sensitivity approximately 75%.

1. Malar rash
2. Discoid rash
3. Light sensitivity (photosensitivity)
4. Ulcers in the mouth & naso-pharynx
5. Arthritis
6. Serositis
7. Kidney diseases
8. Neurological diseases
9. Hematological disorders
10. Immunological disorders
11. Antinuclear antibodies

Management

The management of SLE generally includes;

* Stabilization of the patient
* Hospitalization if necessary
* Symptomatic management (pills for pain etc)
* Specific treatment;

Steroids
Hydroxychloroquinone
Methotrexate
Cyclophophamide
Azathioprine
Mycophenolate etc.

There is no curative treatment as of now so the treatment is focused on controlling the acute attacks, prevention of future attacks, and symptomatic treatments.

Generally when a patient presents with a SLE flare especially a severe one the patient needs to be admitted to the hospital an treated wit a course of intravenous methyl prednisolone (a steroid) and this is generally followed by a course of tapering dose of oral steroids like prednisolone and a small dose ma be continued as maintenance dose.

If the attacks are serious, life threatening or involving vital organs like kidney etc then generally a combination of steroid and one of the immunosuppressive agents (cyclophosphamide, mycophenolate etc) are used.

The chronic usage of steroids and immunosuppressive agents unfortunately produce a host of complications including;

* Infections
* Gastrointestinal ulcers
* Hypertension
* Diabetes mellitus
* Osteoporosis (thinning of bone)
* Develop of tumors like lymphomas, leukemia etc.

For the management of skin conditions including the facial rash topical steroids, sunscreen agents etc are of help.

Shock; when this term is used by physicians it indicates of a medical disorder, in fact a serious one that is the consequence of widespread & imperfect perfusion of the body cells.

The body cells are dependent upon a constant supply of blood to meet their need for oxygen, fuels & other nutrients. If for any reason this blood supply becomes critically inadequate and also happens diffusely in the body then the out come is a state of shock.

Please note that this term is not equivalent with the general non-medical term shock which usually connotes of a traumatic emotional experience.

Types/ Classification of shock

The following are the types of shock;

* Hypovolemic (decreased blood volume)
* Traumatic
* Heart related (cardiogenic)

Intrinsic
Compressive

* Neurogenic
* Septic

Hyperdynamic
Hypodynamic

* Hypoadrenal (adrenal gland related)

Hypovolemic shock: This is the most common form of shock and results from severe blood loss or fluid loss in the form of vomiting, diarrhea, excessive urine out put etc. Patient’s lips, mouth are dry, skin loses its turgor and veins are collapsed.

Cardiogenic shock: This results due to conditions like major heart attack. Here actually the total body fluid content is not subnormal rather blood pools in the venous bed due to heart’s inability to pump it into the arteriolar circulation. Patient’s do not appear dry and also their veins are not collapsed rather may look more prominent.

Traumatic shock is mostly due to blood loss and hypovolemia but there is usually more that that. Due to the injury certain inflammatory substances promote the loss of plasma from the vessels in to the interstitium. The clinical manifestations in generally resemble the hypovolemic shock.

Neurogenic shock: This generally occurs during a high level (neck level) spinal cod injury and resulting hypo-functioning of adrenergic response. These patents do not appear dry and their veins are generally not collapsed.

Hypo adrenergic shock: When body is encountered with stress the adrenal gland hyper secrete cortisol (glucocoticoid) to withstand the stress as much as possible. However due to any adrenal hypo-functioning during stressful situations cortisol secretion is not adequate and this will result in shock.

What causes shock?

When acute & severe circulatory failure happens the body cells are deprived of their oxygen and other nutrition and result in cellular dysfunction. This cellular injury induces the production of what are called as inflammatory mediators and these substances further compromise the circulation of blood through what is called as microvasculature. The outcome of this is a vicious cycle during which the diminished blood flow results in cellular injury and the response of injured cells results in decreased perfusion and this can continue on and on until severe and irreversible damage to multiple body organs may take place and eventual death.

How do the different tissues & organs respond to shock?

Neuroendocrine response:

The decreased blood volume, blood pressure and oxygen concentration in the blood activate systems called as baroreceptos & chemoreceptors which in turn increase adrenergic activity and suppresses parasympathetic & vagal activities. The stress and pain induces the secretion of steroids (glucocorticoids)  and the out come of these various activities is to increase the blood sugar, cut down on blood flow to non vital organs like skin, gastrointestinal tract etc and optimize blood low to vital organs like brain, heart etc.

Cardiovascular response:

Unless the heart is injured and itself caused the shock (cardiogenic shock) the response of heart to shock is by beating faster & stronger mainly due to increased sympathetic (adrenergic type) activity so that the blood volume can be restored. The increased adrenergic activity also causes narrowing of the venous blood vessels and augments the return of blood to the heart and facilitates its pumping from the heart.

Kidney response:

Kidneys try to reduce urine out put so as to restore the blood volume. Kidneys also release an enzyme called as renin that cleaves a substance by name angiotensin I from a protein substrate. Angiotensin I in turn is converted to angiotensin II in the lungs. Angiotensin II is a powerful constrictor of blood vessels and also it stimulates the release of a hormone by name aldosterone from the adrenal glands. Both angiotensin II and aldosterone try to elevate the blood pressure.

Metabolic response:

The severe decreased perfusion and resultant diminished fuel supply forces the body cells to look for alternate source. As mentioned above the adrenergic, steroid hormones make more glucose available although to use it efficiently the cells need oxygen which is limiting. So cells resort for alternate but less efficient means of utilization of glucose called anaerobic pathways and a substance called as lactate is produced in the process. If too much of lactate accumulates it can increase the acidity of the blood and contribute for additional cell damage.

Lung response:

The lungs try to compensate for diminished oxygen in the blood by increasing the breathing rate. A condition called as respiratory alkalosis can result due to rapid breathing. Shock can also result in a severe form of lung injury called as ARDS (acute respiratory distress syndrome).

Diagnosis

The diagnosis of shock is mostly a clinical one although several investigations are required to identify the cause of shock.

The following are certain characteristic clinical manifestation that would help in identifying the shock;

* Severe low blood pressure (generally <60 mmHg mean arterial pressure)
* Patient either comatose or with decreased level of consciousness
* Decreased urine out put of varying grades

The following investigations or procedures are generally necessary in the diagnosis & management of shock including;

* Blood tests
* Urine analysis
* Imaging studies
* Any special tests (e.g. biopsy) etc.

A complete blood count may show anemia indicating blood loss, increased white blood cells indicating infection etc. Electrolyte analysis may reveal abnormalities that might hint blood concentration, kidney dys-functioning etc.

Imaging studies including U/S, Echocardiogram, CT or MRI may be necessary to detect liver, heart or kidney pathologies. U/S uses ultrasound signals where as CT uses x-ray and MRI uses the magnetic impulses to image an organ. Echocardiogram looks at the heart by using U/S technique. A study like U/S, CT or MRI may reveal an occult pus collection somewhere in the body that may have precipitated septic shock. Echocardiogram may identify a heart attack that was the culprit for shock.

Under special circumstances a biopsy study of an organ or tissue (for example kidney biopsy) may be necessary.

Management

The general managements of this life threatening condition include;

* Hospitalization of the patient
* Oxygen supplementation (mechanical ventilation if necessary)
* Swan-Ganz catheter may be necessary to assess hemo-dynamics

The specific management would depend upon the type of shock and it is usually approached along the lines as shown below.

Hypovolemic shock:

Rapid large volume intravenous fluid infusion with 14 to 16 gauze needle and about 2 liters of fluid is given in about ½ hour. 0.9% Normal saline or Ringer’s lactate are preferred.

Cardiogenic Shock:

Treatment of acute pulmonary edema if present (with diuretics, morphine, head propped up position, oxygen etc.

Hypotension is treated with drugs like nor-epinephrine, dopamine, dobutamine depending upon the degree of it & kidney status.

If acute heart attack is the cause then consider reperfusion therapy (primary coronary intervention or CABG or clot buster agents)

If compressive cardiogenic shock like cardiac temponade is present then immediate pericardiocentesis.
If tension pneumothorax is present immediate chest tube insertion and chest decompression.

Septic shock:

Rapid intravenous fluids about 2 liters in 1st ½ hour.
Antibiotics
Steroids
If disseminated intravascular coagulation with bleeding is present then fresh frozen plasma and platelet infusion.

Neurogenic shock:

Rapid intravenous fluids
Injection norepinephrine
Injection pheylephrine

Anaphylaxis/ Anaphylactic shock:

Injection epinephrine
Injection diphenhydramine or pheniramine maleate
Injection hydrocortisone

In addition to the above measures any precipitating or exacerbating causes for shock are identified and treated accordingly.

Pain is one of the most common manifestations of an underlying illness and its significance ranges from being only a discomfort to a signal of life threatening health conditions.

Pain is one of the features of a process called as inflammation which is the body reaction when it is injured or infected. In conditions like migraine headache pain serves no purpose to the body at all and just out-and-out annoying however sometimes it serves as the only clue to certain underlying pathologies like a cancer etc.

Peripheral mechanisms involved in pain mediation

The perception of pain occurs in the brain and it all starts when body encounters a pain producing stimulus like an injury such a stimulus will activate nerve fibers called as;

A delta &
C fibers.

The terminals of these nerve fibers are considered as receptors for the pain sensation, means the stimulation of these nerve endings will generate electrical signals and they are conducted across these nerve fibers and enter the spinal cord and eventually the brain where pain is perceived. These pain receptors are also called as primary afferent nociceptors or simply nociceptors.

The nociceptors also have a role in tissue protection and they do so by release of certain neuro-effector substances like substance P. This chemical released from the nociceptors facilitates several biological activities that primarily serve as a protective mechanism although as pointed above at time it is simply a nuisance and nothing else.

These pain receptors respond to several types of pain stimuli including;

* Heat
* Cold
* Irritating chemicals like bradykinin, serotonin, ATP, histamine
* Strong mechanical stimuli like pinching etc.

Central mechanisms involved in pain mediation

The following structures are involved;

* Spinal cord
* Spinothalamic tract (ascending pathway of pain)
* Thalamus
* Cerebral cortex

The nerve fibers from the peripheral pain receptors enter the posterior aspect of the spinal cord through peripheral nerves (e.g. sural nerve) and link themselves with the nerve cells called as neurons. They excite these neurons through certain chemical mediators like glutamate, substance P etc and the signals generated in the spinal cord neurons will travel upwards through the spinal cord then brainstem through the ascending pathway of pain named as spinothalamic tract.

The primary perception of pain for human beings occurs in the thalamus area of brain. But the exact localization, intensity & quality discrimination occurs in the parietal cortex of the cerebral hemispheres and thalao-cortical fibers connect thalamus with these areas of the cortex. From the thalamus fibers also project to other areas of cerebral cortex and they are related with the control of the emotional & behavioral aspects of the pain.

Certain special pain conditions

Referred pain:

This phenomenon is associated with pain originating from the visceral structures like heart, gall bladder, appendix etc. When there is some inflammation going on in these deeper structures the pain not necessarily will be experienced exactly in the skin overlying that particular structure rather it might be experienced else where, few examples include;

* Right shoulder pain with gall bladder injury
* Left shoulder pain with heart injuries
* Umbilical pain with appendix pain etc.

This phenomenon occurs due to what we call dermatomal distribution of sensory spinal roots. For example right sided c5 spinal root receives pain impulses from both gall bladder and right shoulder area. When gall bladder is inflamed because of same dermatomal distribution it might be referred in the shoulder area.

Sympathetically mediated pain syndrome:

There are mainly two types including;

* Causalgia &
* Reflex sympathetic dystrophy (RSD)

The above two conditions produce somewhat similar manifestations, causalgia occurs due to peripheral nerve injuries where as RSD occurs due to soft tissue injuries, fractures, stroke heart attack etc.

In the causalgia the injured peripheral nerve fibers acquire adrenergic sensitivity (autonomic sympathetic type) and mediate usually very uncomfortable & long duration pain even when the primary injury appears to have subsided. Swelling & discoloration of the limbs, thinning of bone (osteoporosis) and arthritic changes are frequently seen too. It is an example of sympathetic (adrenergic) over activity after an injury.

Neuropathic pain:

Although generally a damage to the peripheral or central pain pathways produce decreased or loss of pain sensation however paradoxically they may produce pain itself and this condition is called as neuropathic pain.

This type of pain may occur due to injuries to;

* Peripheral nerves
* Spinal nerve roots (pinched nerve root)
* Spinotalamic tract
* Thalamus etc.

Certain typical examples for above mentioned injuries include;

* Peripheral neuropathy
* Herpes zoster (shingles)
* Pinched nerve roots
* Thalamic stroke etc.

Neuropathic pain at times may be induced by even light touch and has very unusual tingling, burning or electrical-shock like quality. Patients generally have an area of loss sensation over the skin corresponding to the injured nervous pathway. They exhibit hyperpathia (minor painful stimulation is perceived as quite serve pain) & allodynia (non painful stimulation is perceived as pain).
Neuropathic pain is attributed to sensitization of the damaged area of the pain pathway to the stimuli. Normally such stimuli will not generate pain however due to the injury now these damaged site act as pain receptor that too in an exaggerated fashion.

Diagnosis

Pain is a subjective symptom and the presence of it should alert the physician of an underlying cause and accordingly a meticulous search must be done in this regard.

The investigations chosen depend upon what we are suspecting and examples include;

* Peripheral neuropathy;

Electromyography & nerve conduction studies
Blood tests
Nerve biopsy etc.

* Belly pain;

X-ray, ultrasound, CT or MRI of the belly
Blood tests (like liver function tests) etc.

* Headache;

CT or MRI of brain
CSF (cerebrospinal fluid) analysis
Angiogram of brain etc.

Chest pain;

Heart related (blood tests, ECG, Echocardiogram etc)
Lung related (e.g. chest x-ray, CT chest) etc.

Back pain;

CT or MRI of spine
Electromyography of the leg & back muscles etc.

Management

The management of pain will include the treatment for the pain itself as well as what caused it.

The treatment of the pain itself (symptomatic therapy) is accomplished by choosing drugs from the following groups;

NSAIDs (non steroidal anti-inflammatory drugs);

Paracetamol
Tramadol (also a narcotic drug)
Diclofenac
Piroxicam etc.

Opioids (narcotic);

Tramadol
Morphine
Pentazocin
Pethidine
Fentanyl skin patches etc.

Muscle Relaxants;

Tizanidine
Baclofen
Methocarbamol
Carisoprodol etc

Steroids;

Prednisolone
Dexamethasone
Methylprednisolone etc.

Anticonvlsants;

Gabapentin
Pregabalin
Sodium valproate
Carbamazepine etc.

Antidepressats;

Duloxetine
Amitriptyline etc.

Additional agents;

Ergotamine
Triptan medications
Drotaverine
Hyoscine etc.

The same medication or group of medications may not help with each & every condition. Below is a list of some of the commonly encountered pain conditions and in the bracket the commonly used medications for these conditions.

* Musculoskeletal pain (NSAIDs, muscle relaxants)
* Colicky (visceral) pain e.g. kidney stone pain (opioids, drotaverine, hyoscine etc)
* Cancer pain (long acting opioids like fentanyl skin patches)
* Acute migraine headache (ergotamine, triptan medications etc)
* Chronic migraine headache (amitriptyline, sodium valproate etc)
* Trigeminal neuralgia (carbamazepine, muscle relaxants etc)
* Back pain/pinched nerve root (e.g. gabapentin, muscle relaxants, NSAIDs, opioids) etc.

Edema is defined as an abnormal accumulation fluid in the interstitial tissue of the body and caused by varieties of disease conditions.

Tissue means a collection of similar cells that carry out certain functions in the body. Interstitial tissue lies between the cells of a structure and is predominantly made of fibrous tissue and abnormal amount o fluid may accumulate in it to produce edema.

Edema is a disease manifestation and its presence indicates the presence of an underlying disorder. A severe edema state is called as anasarca. The term edema is generally used for fluid collection in the interstitial area under the skin, and special forms of edema include ascitis (fluid accumulation in the belly cavity) & hydrothorax (fluid accumulation in the cavity around lungs produced by pleura).

What causes edema?

Around 60 to 70% of total body water is confined to the extra cellular space and about 70 to 75% of this water is present in the interstitial space and the remainder is in the plasma (the liquid part of blood devoid of blood cells).

The fluid in the interstitial & vascular compartments (inside the blood vessels) normally enjoys a balance in such a way that there is no excessive fluid accumulation in either of these compartments. The physiological forces that maintain this balance is governed by what is called as starling forces.

Thee forces are related with hydrostatic & colloid oncotic pressure of the vascular compartment with the oncotic pressure of the interstitial compartment and edema may generally result if one or more of factors are abnormal as below;

* Increased hydrostatic pressure inside the blood vessels
* Decreased oncotic pressure inside the blood vessels
* Increased oncotic pressure of the interstitial compartment

In addition to these three factors there are few more that contribute to the development of edema and include;

* Elevated permeability of blood vessel walls (occurs with inflammation)
* Impediment to the fluid clearance by the lymphatic system etc.
The following physiological systems assume a contributory role for the development of edema in diseased conditions.

* Renin angiotensin aldosterone (RAA) system
* AVP (arginine vasopressin)
* Endothelin etc.

Renin is a substance released in the kidneys and converts a protein substrate to angiotensin I. In the lungs angiotensin is converted in to angiotesin II and this substance in addition to its vasoconstrictor activity promotes secretion of a hormone from the adrenal glad by name aldosterone. This hormone acts on the kidney and facilitates the re-absorption of sodium. If rennin-angiotensin activity is excessive then it can cause abnormal sodium retention and can promote edema.

AVP (arginine vasopressin): This is a hormone secreted from the posterior pituitary gland and promotes re-absorption of free water from the renal tubules and collecting duct. The excessive action of this hormone can cause water retention and edema formation.

Endothelin: This substance is released from the endothelial cells and its level is elevated in heart failure patients and it causes narrowing of arteries to the kidneys, sodium retention and promotes edema.

Important causes of edema

* Congestive heart failure (CHF)
* Nephrotic syndrome
* Cirrhosis of the liver
* Severe malnutrition
* Hypo-albuminemia (due to any cause)
* Any condition favoring sodium & water retention
* Medication induced etc.

Let us find out now how some of these above listed conditions will promote the development of edema.

CHF: In CHF the pumping ability of the heart is compromised and this results in more blood pooling in the venous compartment. This will increase the pressure inside the venous side of capillaries and forces the fluid escape the vascular compartment into the interstitial compartment. The reduction in effective arterial blood volume will activate RAA system favoring sodium & water retention and further contributing to the edema generation.

Cirrhosis of liver: Cirrhosis promotes sodium retention by the kidneys; this and the decreased albumin levels will facilitate retention of fluid in the interstitial tissue. As with CHF the RAA system is activated and the end result is the same.

Hypo-albuminemic states: This condition causes decreased colloidal oncotic pressure and facilitates the development of edema. The clinical conditions associated with

* Nephrotic syndrome
* Severe malnutrition
* Severe chronic liver disease like cirrhosis
* Protein losing enteropathy etc.

Hypoalbuminemia, similar to above two conditions mentioned activates the RAA system with similar outcome.

Edema related with medication usage: There are different kinds of medications that can precipitate edema and they may do so by different mechanisms too.

Steroid preparations like prednisolone promote sodium re-absorption from the kidneys and causes sodium & water retention. Medications causing dilatation of arteries like hydralazine cause decreased effective arterial blood volume and activate RAA system. NSAIDs (non steroidal anti-inflammatory drugs) like indomethacin cause constriction of arteries of kidneys and activate RAA system. Drugs like interleukins cause edema by damaging the capillaries.

Clinical manifestations

Generally patients complain to the doctor about the swelling of legs or around the eyes or puffiness of face. Because of gravity effect the fluid in the day time may collect around the ankles in ambulatory patients and in bed ridden patients around the sacral area (lower back). If edema is not severe or in the early stages patients may not have noticed it so certain leading questions may be asked by the doctor to find out if patient has edema. For example if the patient has any difficulty in putting on or removing a ring from the finger, the shoes from the feet etc.

Diagnosis

Edema is a clinical diagnosis so the investigations that are ordered are mostly for identifying the cause of edema.

The investigations ordered in the setting of edema generally include;

* Blood tests
* Urine tests
* Imaging studies;

U/S (ultrasound)
Echocardiogram
X-rays
CT
MRI etc

* Special tests (ascitis, pleural fluid analysis etc)

Initial basic blood tests:

* Electrolytes like sodium, BUN, creatinine etc
* Serum albumin
* Liver function tests (LFT)
* Urine analysis (looking for albumin, creatinine etc)

The above routine blood tests will provide generally lot of initial clues as to the cause of edema. For example a low albumin level will lead towards causes like cirrhosis of liver. LFT may show findings suggestive liver dysfunction including cirrhosis. Urine analysis may show severe loss of albumin through the urine that may be suggestive of nephrotic syndrome.

Imaging studies including U/S, Echocardiogram, CT or MRI may be necessary to detect liver, heart or kidney pathologies. U/S uses ultrasound signals where as CT uses x-ray and MRI uses the magnetic impulses to image an organ. Echocardiogram looks at the heart by using U/S technique.

Management

The general measures of edema management include (on a case-to-case basis);

* Stabilizing the patient
* Hospitalization if necessary
* Fluid restriction
* Salt restriction
* High protein & nutritious diet
* Diuretics
* Taping of ascitis or hydrothorax if they are large (for symptomatic relief) etc.

Specific measures include the management of;

CHF – medications to augment the pumping action of the heart, ACE inhibitors, Beta blockers, CRT (cardiac resynchronization therapy) etc.

Nephrotic syndrome – steroids, immunosuppressive agents etc.

Malnutritional states – Protein rich nutritious diet etc.

Drug induced – If possible to switch over to other agents or reduce the dose etc.

Fever is an abnormally elevated body temperature and not a disease by itself rather it is a manifestation of certain underlying diseases.

The normal oral body temperature  for otherwise healthy individuals is around 98.2±0.7°F (36.8°±0.4°C) with generally the lowest temperature of the day is in the early morning (round 6 am) and the highest body temperature is around evening (around 4 pm). And these values represent most of the healthy individuals (about 98th percentile) and based on these facts;

“Fever can be defied as body temperature as measured by oral methods is >98.9°F (37.2°C) in the morning time or >99.9°F (37.7°C) in the evening time.

The core body temperature as measured by the rectal methods is supposed to be about 0.7°F (0.4°C) higher than oral method.

Distinction between fever & hyperthermia

It is difficult to touch the topic of fever without any reference to hyperthermia as there are certain similarities between them although there are differences too as noted below.

Elevated body temperature is either fever or hyperthermia. Before going to the finer details first let us familiarize with how fever & hyperthermia are produced?

A region in the brain called as hypothalamus regulates the body temperature. This region receives the inputs from two sources including;

* Temperature of the blood that bathes this region
* The peripheral nerves that conduct signals from the warmth/cold receptors in the skin

The above two types of signals are integrated in the temperature controlling areas of the hypothalamus so that optimum body temperature is maintained. Out of range body temperature either high (fever & hyperthermia) or low (hypothermia) all will have deleterious influence on the body functions and if severe can even result in death.

Coming back to the distinction between fever & hyperthermia; it is fever if it exceeds the normal daily variation and occurs together with an increase in the hypothalamic set point (e.g. 37°C to 39°C). On the other hand hyperthermia is characterized by an uncontrolled increase in body temperature that exceeds body’s ability to lose heat on the back ground of unchanged settings of hypothalamic thermoregulatory center. Also a fever may be mediated by pyrogens but hyperthermia does not involve such substances and it results from results from excessive;

* Heat production in the body or
* Heat exposure from the environment.

Types of hyperthermia include;

* Drug induced (cocaine, amphetamine etc)
* Heat stroke
* Serotonin syndrome (fluoxetine)
* NMS (neuroleptic malignant syndrome) – anti-psychotics like haloperidol
* Malignant hyperthermia (succinyl choline, inhalational anesthetics etc)
* Endocrine disorders (thyrotoxicosis etc)
* Central nervous system injuries – hypothalamic damage, stroke etc.

Diagnosis

The clinical diagnosis of fever & hyperthermia are accomplished by using a thermometer and checking the oral or core body temperature. Whenever possible a core body temperature should be measured as it is more reliable and less susceptible to external factors.

Once the diagnosis of fever is confirmed then a search will be done to look for its cause and if such cause is crystal clear then exhaustive investigations may not be always necessary. On the other hand if the cause is not clear then varieties of investigations are necessary. In general once a thorough history taking & examination is don majority of the time the physician will have some clue as to what may be the source of fever or hyperthermia

In general in the beginning one or few of these tests are all sufficient including;

* Blood tests (routine)
* Urine tests (routine)
* X-rays (chest, abdomen, bones etc)
* Blood cultures
* Urine cultures etc.

If the above tests either do not give any hints or give only partial hints then the following special tests may be necessary including;

* CSF (cerebrospinal fluid) analysis
* Aspirations of body fluids like pleural fluid
* Bone marrow biopsy
* Other tissue or organ biopsies etc.

In the blood tests routine CBC (complete blood count) may show increased WBC count. With bacterial infections generally neutrophils increase and with non bacterial infections like viral ones usually the lymphocytes increase although it is not a golden rule.

Urine analysis will be abnormal if UTI is present and shows findings like WBCs, increased protein, RBCs. Gram stain may show bacteria. Urine culture may grow the bacteria.

Chest x-ray is of immense value if lung pathology like pneumonia is suspected. I may also osteomyelitis (bone infection) etc. U/S, CT or MRI is not routinely necessary but if the preliminary tests do not help then they will be employed especially to look for occult pus collection etc. An echocardiogram may reveal endocarditis as a cause for fever.

If meningitis, encephalitis etc are suspected CSF analysis is mandatory.

Management

The management of fever & hyperthermia are dealt mainly at the following levels including the management of;

* The fever itself
* Its cause.

Fever specific treatments include;

* Stabilization of the patient
* Hospitalization if necessary
* Medications to reduce the temperature (paracetamol etc)
* Tepid sponging
* Adequate fluids (if required intravenous)
* Adequate nutrition etc.

The specific management

* Antibiotics for meningitis, UTI, pneumonia etc
* Aspiration or drainage of abscess (pus collections)
* Aspiration/drainage of pleural, peritoneal fluids
* Treat inflammatory conditions like lupus (steroids, immunosuppressive agents etc)
* Discontinue;

Drugs like haloperidol with NMS
Drug like SSRI in serotonin syndrome
Anesthetics, succniyl choline etc with malignant hyperpyrexia

Anemia is a manifestation of underlying deficiency of hemoglobin, an iron containing pigment present inside the RBCs (red blood cells) and it is a laboratory diagnosis and can have myriad health consequences.

The normal hemoglobin for adult men is 13 to 17 g/dl, and for adult women is 12 to 15 g/dl. As per the WHO (World Health Organization) criteria anemia is defined as a hemoglobin level < 13g/dl for men and <12 mg/dl for women.

Hemoglobin is a complex of heme (an iron containing pigment) & globin (a protein substance) and has a vital role in the transport of oxygen in the blood from the lungs to the body cells. It also helps in bringing some of the carbon dioxide from the cellular level back to the lungs for expelling it out.

Normal RBC & hemoglobin physiology

The normal adult men contain about 5 – 6 million of RBCs per cubic millimeter & for women this number is about 4 – 5 millions similar units. The mature RBC is about 8 micrometer in diameter, biconvex and is synthesized in the bone marrow. The production RBCs require a hormone called as erythropoietin (EPO) that is secreted in the kidneys.

RBCs are produced from stem cells contained in the bone marrow. It begins with division of pluripotent hematopoietic cells that are capable of producing RBCs, WBCs (white blood cells), and platelets. From these stem cells erythroid line of cells are produced and these erythroid cells repeatedly divide and generate RBCs.  Hemoglobin is incorporated into the RBCs during their formation.

Types of anemia/ classification

Anemia can be diagnosed functionally (physiologically) into three major categories including;

* Hemorrhage/ hemolysis related
* Hypo-proliferative related (problem with bone marrow proliferation of RBCs)
* Maturational disorder related

Hemorrhage/ hemolysis related;

* Blood loss due to bleeding
* Intravascular hemolysis (destruction of RBCs in the blood vessels)
* RBC membrane abnormalities
* Metabolic defects
* Immune destruction of RBCs
* Hemoglobinopathies
* Fragmentation hemolysis etc

The hypo-proliferative

* Iron deficiency
* Bone marrow damage (e.g. infiltrative lesions)
* Decreased stimulation (e.g. Kidney diseases, inflammations)

Maturational disorders;

* Iron deficiency
* Thalassemia
* Sideroblastic anemia
* Vitamin B12 deficiency
* Folic acid deficiency
* Drug toxicities etc.

Clinical manifestations

Examination findings usually include;

* Pale skin and/or mucus membranes (nail beds, wrinkles of the palm etc)

Anemia makes the heart to pump more blood to compensate for reduced oxygen concentration in the blood and this will produce findings including;

* Strong arterial pulses (e.g. Radial pulse)
* Forceful heart beat
* A heart murmur (systolic type)

Diagnosis

A mild anemia may be missed clinically but moderate & severe grades of anemia are rarely missed clinically.  Irrespective of this certain investigations are necessary and they assist with;

* Laboratory confirmation of anemia &
* Help in detecting the cause of the anemia.

Investigations to confirm anemia include;

* Blood tests;

CBC (complete blood count)
Peripheral smear

The following CBC values are obtained including:

* Hemoglobin (normal: 13 g/dl for men & 12 g/dl for women)
* Hematocrit (normal: 45 to 52% for men & 37 to 48% for women)
* MCV (mean cell volume) – normal: 80 to 100 femtoliters
* MCH (mean cell hemoglobin) – normal: 27 to 32 picograms?* MCHC (mean cell hemoglobin concentration) – normal: 32 to 36%

MCV test gives an idea of the morphology of RBCs. For example small RBCs may be seen with conditions like iron deficiency & lead toxicity anemia, large RBCs (megaloblasts) are seen with conditions like Vitamin B12 or folate deficiency

Investigations to helping detecting the cause of anemia include;

* Peripheral smear
* Reticulocyte count
* Serum iron studies (total iron, ferritin, iron binding capacity etc)
* Vitamin B12, folate levels
* Thyroid tests (T4, T3, and TSH etc)
* Bone marrow studies etc.

A peripheral smear helps in identifying the morphological features of blood cells and also to look for specific anemic disorders like sickle cell anemia etc.

Reticulocytes are fresh batch of RBCs just released from the bone marrow. The normal range of these cells is around 1 to 2% of the circulating RBCs. A reticulocyte count is a key tool in the initial diagnosis of anemia. An increased reticulocyte count along with anemia indicates the bone marrow and the steps associated with RBC production are ok and that means the cause of anemia is hemolysis or blood loss.

A bone marrow examination is done when the reticulocute count is decreased, anemia is of normal size/shape and coloration (normocytic, normochromic) and iron storage of body is normal. These findings suggest strongly a bone marrow pathology like any infiltrative diseases, myelofibrosis etc.

Management

General measures of anemia management include;

* Stabilization of the patient
* Hospitalization if necessary
* Oxygen supplementation (if patient breathless)
* Avoiding strenuous activities
* Nutritious diet etc.

Specific measurements include;

* Iron deficiency anemia:

Oral iron supplementation (mild)
Parenteral iron supplementation (moderate to severe)

* Megaloblastic anemias:

Vitamin B12
Folic acid

* Chronic kidney diseases:

Recombinant EPO (erythropoietin)

* Many other conditions like myelofibrosis are appropriately treated

Blood transfusion/ packed RBCs may be required for severe anemia cases (especially related with blood loss type).

Obesity is now convincingly proved as a major health disorder and it is the state of having abnormally excessive fat in the body in its storage areas called as adipose tissue.

The most commonly used tool to measure obesity is called as BMI (body mass index). This index is obtained by this formula; weight divided by height² (as kg/m²). A BMI ?25 is considered abnormal; between 25 & 30 is generally regarded as overweight status and >30 as obesity.

The epidemiological studies have conclusively shown that both overweight & obesity lead into multiple untoward health conditions.

What causes obesity?

The obesity appears to develop when there is a long term excessive energy rich food intake relative to the intensity of energy expenditure. Whenever there is a net energy in the body it is stored as fat. This fat accumulates in the adipose tissues that are especially concentrated around the belly, thighs, buttocks etc although it can be stored anywhere under the skin, internal organs, and various body tissues including the blood vessels etc.

It is true the prime cause of abnormal deposition of fat does revolve around a relative excess energy for the level of body needs but if that is all then just curbing on some food intake and optimizing physical activities might have solved the epidemic of obesity. Of course the point here is not to underestimate the significance of these factors but it is much more complicated than that.

There are multiple genetic & environmental factors that contribute or influence these and not all the mechanism are completely understood now. Obesity frequently runs in the families and supports the genetic theory but how exactly it influences fat deposition is not entirely clear. The genetic factors & environmental factors may act through endocrine system and influence food intake its expenditure etc. Other factors like sleep deprivation, altered gut flora, viral infection all have been implicated in the development or maintenance of obesity.

Anatomy of adipose tissue

Adipose tissue or the body’s fat-storage site is not confined to one particular location rather it is seen under the skin, around the internal organs (visceral fat), breast tissue and in the yellow bone marrow.

The source of fat in the adipose tissue originates from the diet and any excess fat in the diet is generally stored in the adipose tissue. Even excess carbohydrates and to some extent proteins can also be converted into fat in the body. If the fat deposition continues on a long term basis then it will result in overweight or obesity.

In addition to serve as a storage depot for fat in the body the adipose tissue subserves with several endocrine functions. It secretes several hormonal chemicals that are involved in energy expenditure, insulin sensitivity blood pressure control etc. Few examples of such substances include adiponecin, leptin, interleukin etc.

Regulation of energy balance

Energy input (food intake):

The appetite center is located in the hypothalamus area of the brain. There are myriad number of factors that either increase or decrease the appetite through hypothalamus and some prime examples include vagal input from gastrointestinal tract, gut peptides like ghrelin, hormonal factors like insulin, leptin etc.

The energy expenditure is distributed generally as follows;

* BMR (basal metabolic rate) energy spending at rest
* Energy expenditure for metabolism & storage of food
* Exercise related expenditure
* Adaptive themogenesis

Abut 70% of total daily energy spent is used for BMR. Active physical activities require about 5 to 10%.

Complications of obesity

* Type 2 DM (diabetes mellitus)
* Cardiovascular disorders (heart attack, stroke etc)
* Disorders of reproductive system & sexual function (impotence etc)
* Lung diseases (obstructive sleep apnea)
* Gallstones
* Bone, joint diseases (arthritis)
* Skin diseases (acanthosis nigricans, fungal infection of skin etc)
* Cancer (higher mortality from cancer e.g. colon cancer)

Certain obesity related medical conditions

Examples of hereditary obesity conditions include;

* Laurence-Moon- Biedel syndrome
* Prader-Willi syndrome
* Cohen syndrome
* Carpenter syndrome etc.

Examples of certain other syndromes associated with obesity;

* Insulinoma
* Cushing’s syndrome
* Hypothyroidism etc.
* Hypothalamic tumors, craniopharyngioma etc.

Diagnosis

The diagnosis of overweight & obesity is accomplished by generally using the BMI criteria as described above. The investigations are performed generally to ascertain the causes of obesity & to look for any complications of obesity.

Some of the tests ordered to detect the cause of obesity include;

* Thyroid tests (T4, T3, and TSH etc)
* Insulinoma tests (blood sugar, insulin & c-peptide levels)
* Cushing’s disease (blood mineralocorticoid sodium, potassium levels etc)
* MRI (or CT) of brain to look for hypothalamic lesions etc.

Management

The management aspects of obesity may be approached along the following three lines including;

1) Obesity specific
2) What caused obesity
3) Obesity complications.

1) Obesity specific measures include;

* Diet therapy:

Low calorie diet (500  to 1000 Kcal/day)
Low fat diet
Choosing smaller portion sizes
Consuming more vegetables & fruits
Consuming more whole grain cereals
Choosing lean meat
Reducing fried foods
Substitution water for energy rich beverages like coke

* Exercise/ physical activity therapy
(About 60 to 90 minutes of moderate intensity exercise on daily basis)

* Behavioral therapy

Self-monitoring techniques (weighing, measuring food & activities)
Management of stress
Control of stimulus (not eating in front of TV etc)
Social support
Cognitive restructuring etc.

* Medication therapy (if above measures fail)

Medications inducing loss of appetite (E.g. sibutramine)
Acting on the intestine (e.g. orlistat)
Endocannabinoid systems (e.g. rimonabant)

* Surgical options

Restrictive ( laparoscopic adjustable silicone gastric banding)
Gastric bypass
Biliopancreatic diversion
Biliopancreatic diversion with duodenal switch etc.

2) Measures dealing with what caused obesity may include;

Decreasing or stopping  steroid therapy (cushing’s syndrome)
Surgical tumor removal, chemotherapy (insulinoma)
Thyroid hormone supplementation (hypothyroidism)
Treatment of hypothalamic lesions (e.g. surgery radiation therapy) etc.

3) Measures dealing with obesity complications include;

Obstructive sleep apneas (sleep studies, CPAP etc)
Diabetes (plasma sugar tests, insulin, oral hypoglycemic agents etc)
Hyperlipidemia (Lipid profile, statin therapy etc)
Hypertension (salt control, medications etc)
Arthritis (e.g. anti-inflammatory agents, surgery) etc.

Hyperlipidemia is the term used for abnormally elevated fats (lipids) in the blood and such elevation is long standing (chronic) in nature can produce deleterious effects on various organs & tissues in the body with many serious consequences.

Lipids are type of food stuffs so they have nutritive value. They are a source of fuel (energy) and they are essential for various physiological activities taking place in the body so a deficiency of them can have major consequences including even death on the other hand abnormally elevated levels too are not good for health.

More details about lipids in the body

The lipids in the body are generally of two forms including;

* Lipoproteins &
* Non lipoprotein form (the free form).

The non lipoprotein form is seen for example in the adipose tissue where fat is stored. However in majority of other situations lipids are present as lipoproteins.

Lipoproteins are complex of lipids & proteins (apolipoproteins) and they are vital for the absorption & transportation of lipid as well as fat soluble vitamins (Vitamin A, D, E & K). The major lipids that are absorbed from the food include;

* Triglycerides
* Cholesterol
* Fatty acids etc.

There are various types of lipoproteins and they may be arranged from above downwards depending upon their density as below;

* HDL
* LDL
* IDL
* VLDL
* Chylomicrons etc.

The different apoliporoteins include ApoA, B, C, D, E, H, J, L, M, (a) etc.

Lipoprotein metabolism

Exogenous pathway:

The dietary lipids including triglycerides, cholesterol, fatty acids are absorbed into the blood in the form chylomicrons. These lipoproteins are secreted into the lymphatic system and enter the systemic circulation directly through thoracic duct and skip the liver. These lipoproteins are processed by peripheral tissues like adipose tissue & skeletal muscle and after this the cholesterol, phospholipids etc are transferred to HDL and the residual chylomicron remnants reach liver and are taken up by it.

Endogenous pathway:

During this process VLDL is secreted by the liver and first the adipose and muscle tissues take the fatty acids. The remnants are called as IDL and part of this is taken up by the liver and remaining though additional processing becomes LDL. LDL contains more than 50% of blood cholesterol. lDL is either taken up by the liver or by peripheral issues.

HDL metabolism & reverse cholesterol transport:

Through this pathway the cholesterol from the periphery is transported back to the liver for the purpose of its excretion from the body.

And the immediately above paragraph explains why HDL is considered as the good cholesterol. LDL is considered as bad cholesterol as it contains most of the blood cholesterol and also it takes them towards the tissues & organs of the body facilitating their deposition there and favors development of atherosclerosis, a condition with serious health ramifications.

Classification of lipoprotein disorders (hyperlipidemia type)

The primary disorders of lipopoprotein metabolism are classified by Frederickson & Levy and are as follows;

* Type I
* Type II

IIa
IIb

* Type III
* Type IV
* Type V

Type I;

* Lipoproteins elevated are chylomicrons
* Triglycerides-severely elevated
* Cholesterol – mild to moderately elevated
* LDL levels decreased
* HDL levels increased
* Eruptive xanthomas are seen
* Pancrearitis is a complication
* Atherosclerosis is not a major risk with this disease
* Molecular defects include LPL & apoC-II

Type IIa;

* Lipoprotins elevated are LDL
* Triglycerides-not elevated
* Cholesterol – moderately elevated
* LDL levels increased
* HDL levels slightly elevated
* Tendon & tuberous xanthomas are seen
* Pancrearitis is not a complication
* Atherosclerosis is a major risk with this disease especially the coronary arteries
* Molecular defects include LDL receptor, ApoB-100, PCSK9

Type IIb;

* Lipoproteins elevated LDL & VLDL
* Triglycerides- elevated mild to moderately
* Cholesterol – moderately elevated
* LDL levels increased
* HDL levels increased
* No xanthomas are seen
* Pancrearitis is not a complication
* Atherosclerosis is a major risk especially of coronary arteries
* Molecular defects are unknown

Type III;

* Lipoprotins elevated are chylomicrons & VLDL remnants
* Triglycerides-moderately elevated
* Cholesterol – moderately elevated
* LDL levels decreased
* HDL levels increased
* Palmar & tubero-eruptive xanthomas are seen
* Pancrearitis is not a complication
* Atherosclerosis is a major risk especially of coronary arteries
* Molecular defects include ApoE

Type IV;

* Lipoprotins elevated include VLDL & chylomicrons
* Triglycerides-moderately elevated
* Cholesterol – not elevated or mildly elevated
* LDL levels decreased
* HDL levels increased
* No eruptive xanthomas are seen
* Pancrearitis is not a complication
* Atherosclerosis risk may or may not increase with this disease
* Molecular defects include ApoA-V & unknown

Type V;

* Lipoprotins elevated are chylomicrons & VLDL
* Triglycerides-severely elevated
* Cholesterol – elevated moderate to severely
* LDL levels decreased
* HDL levels increased
* Eruptive xanthomas are seen
* Pancrearitis is a complication
* Atherosclerosis risk may or may not increase with this disease
* Molecular defects include ApoA-V & unknown

Secondary causes for hyperlipidemia include;

* Type 2 DM (diabetes mellitus)
* Obesity
* Hypothyroidism
* Kidney diseases;

Nephrotic syndrome
End stage renal disease (ESRD)
Post kidney transplantation patients

* Liver diseases
* Excessive alcohol consumption
* Drugs induced (cyclosporin, thiazide diuretics etc)
* Cushing’s syndrome
* Estrogen
* Lysosomal storage disorder etc.

Diagnosis

The purpose of the investigations accomplished include to;

* Confirm hyperlipidemia
* Find out what is causing them
* Detect the complications related with hyperlipidemia.

The test ordered to confirm hyperlipidemia is;

* Blood lipid profile.

This test is done on serum (a component of blood) and preferably a fasting sample (about 6 to 8 hours after last food) is obtained. Generally a routine or basic lipid profile is first obtained then additional or detailed lipid profile maybe ordered if required. The routine lipid profile includes

* Total cholesterol
* VLDL
* LDL
* HDL
* Triglycerides

Chylomicrons, IDL etc are not obtained routinely.

Investigations to find out what is causing hyperlipidemia include;

* Diabetes mellitus tests (blood sugar, HbA1c etc)
* Thyroid tests (T4, T4, and TSH etc)
* Kidney tests (electrolytes, kidney function tests, albumin levels, urine out put etc)
* Serum levels of corticosteroids
* Lysosomal storage disorders (genetic tests) etc.

With regard to the complication related investigations it essentially depends upon what organ is involved and what exactly is the damage produced etc. Some examples include; pancreatitis tests may include amylase, lipase, calcium etc; heart attack investigations may include cardiac markers, ECG, Echocardiogram, coronary angiogram etc; stroke investigations may include CT or MRI of brain, carotid or vertebral artery angiogram etc.

Management

The managements of hyperlipidemia include;

* General &
* Specific aspects.

The general management includes;

* Dietary modifications (restriction on saturated fat & cholesterol)
* Dietary additives (consuming plant stanol & sterols)
* Weight loss
* Exercise
* Cessation of smoking
* No excessive alcohol intake etc.

Specific management approaches include;

HMG COA inhibitors:

Atorvastatin
Pravastatin
Simvastatin
Rosuvastatin
Lovastatin etc.

Cholesterol absorption inhibitors:

Ezetimibe

Combination of above two groups (e.g. Atorvastatin + Ezetimibe)

Fibrates;

Fenofibrate
Bezafibrate
Gemfibrozil
Gugulipid etc.

Other drugs:

Niacin
Fibers (isphagula or psyllium)
Garlee (garlic preparation)
Omega 3 fatty acids
Anti oxidants etc.

Diabetes mellitus (DM) is a group of common metabolic disorders that all share the characteristic feature of chronic hyperglycemia (increased blood glucose levels).

Anatomy & physiology relevant to DM

The hormone that keeps the blood glucose concentration under check is insulin and it is secreted by pancreas an organ situated inside the belly cavity (abdominal cavity).

This hormone secretion is stimulated whenever the glucose concentration in the blood rises or example after food intake and the process digestion is underway. Insulin by various mechanisms helps in pushing the glucose in the blood to inside the body cells and this glucose is used either for energy production or storage as glycogen or fat. Insulin assists in the cell entry of fatty acids and amino acids as well.

So if insulin is absent or deficient then the blood concentration of glucose, fatty acids, amino acids are abnormally elevated and this itself can cause injury to cells & tissues. Also the chronic deprivation of nutrients inside the cells adds up to this insult. There may be other additional mechanism of injuries as not all pathological changes associated with DM can be explained just based on these two above mechanisms.

Classification of DM

DM is generally classifies based on what causes it (etiological factors) ad broadly there are four categories including;

* Type 1 DM (there is beta cell destruction)

Immune mediated
Idiopathic (cause is known)

* Type 2 DM (insulin deficiency and/or insulin resistance)
* Other specific types of DM

A- genetic defects in beta cell function (e.g. maturity onset DM)
B- genetic defect in insulin action (e.g. Type A insulin resistance)
C- Diseases of exocrine pancreas (e.g. pancreatitis)
D- endocrine disorders (e.g. acromegaly)E- chemical or drug induced (e.g. steroid drug induced)
G- infections (e.g. congenital rubella)
G- uncommon forms of immune mediated DM (e.g. stiff-person syndrome)
H- Other genetic syndromes (e.g. myotonic dystrophy)

* Gestational DM (GDM)

What causes DM?

DM is caused by a complex interaction between genetics & environmental factors. The various mechanism involved in resulting hyperglycemia include;

* Absent or reduced insulin secretion
* Insulin resistance & decreased glucose utilization in the cells
* Increased glucose production.

Type 1 DM: There is an interaction among genetic environmental & immunological factors give rise to this DM. These factors ultimately result in the destruction the beta cells of the pancreas.  Type 1 DM is the result of an autoimmune disease in majority of the patients.

Type 2 DM: Although what exactly induces type 2 DM is not precisely known now but it is also thought to be the result of a complex interaction between genetic & environmental factors. There is no evidence for autoimmune injury for type 2 DM. The genetic influence appears to be somewhat more with type 2 as compares to type 1 DM. It starts as insulin resistance and follows with insulin secretory defect.

Risk factors for Type 2 DM;

* History of DM in the family
* Obesity
* Long term physical inactivity
* Race & ethnicity (e.g. Asian American)
* History of GDM or delivery of a baby >4kg
* Hypertension
* Triglycerides >250 mg/dl
* HDL cholesterol < 35 mg/dl)
* Polycystic ovarian syndrome etc.

Complications of DM

Acute complications (short term) include;

* Diabetic ketoacidosis
* HHS (hyperglycemic hyperosmolar state)

Chronic (long term) complications include;

* Micro vascular (small vessel) disease;

Retinal damage (retinopathy)
Nerve damage (neuropathy)
Kidney damage (nephropathy) etc.

* Large vessel disease;

Coronary artery disease (angina, heart attack)
Cerebro vascular disease (stroke)
Peripheral arterial disease etc.

* Other complications;

Infections
Sexual dysfunctions
Cataracts etc.

Clinical manifestations

The symptom of DM can be grouped as either;

* DM related or
* Related with DM complications.

DM related symptoms include;

* Poly-uria (excess passage of urine)
* Poly-dipsia (excess thirst)
* Weight loss
* Fatigue
* Generalized weakness etc.

Related with complications of DM include;

* Retinal damage – blurring of vision, loss of vision etc
* Nerve damage (neuropathy) – numbness, pins & needles, foot drop etc
* Atherosclerosis – strokes, heart attack, angina etc
* Infections – fever etc

Examination findings generally include;

* Retinal changes (diabetic retinopathy)
* Weak peripheral pulses (if atherosclerosis has taken place)
* Diabetic foot-ulcer, gangrene etc.

Diagnosis

The frequent blood investigations ordered to diagnose & mange DM include;

* Random plasma glucose (can be done any time of the day)
* Fasting plasma glucose (no energy intake for at least 8 hours before blood test)
* GTT (glucose tolerance test)
* HBA1c (to check long term blood glucose control) etc.

A diagnosis of DM can be made if one or more criteria are met including;

1) Random plasma glucose ?200 mg/dl with typical DM symptoms like excess thirst, excess passage of urine & weight loss.

2) Fasting plasma glucose ?126 mg/dl.

3) Two-hour plasma glucose ?200 mg/dl during an oral GTT (using 75 g glucose load).

Management

The general managements of diabetic patients include;

* Stabilization of the patient
* Hospitalization if necessary
* Symptomatic treatment (e.g. gabapentin for numbness)
* Treatment of complications like infections, stroke, heart attack etc
* Dietary adjustment (low calorie but nutritious)
* Adequate exercise
* Weight loss for Type 2 DM
* Sugar substitutes like aspartame etc.

Specific treatment for the DM would include

* Oral hypoglycemic agents
* Insulin

Type 2 DM are generally started with oral hypoglycemic agents and some of them may require insulin as well. Type 1 DM is treated with insulin.

The following are some of the most commonly used oral hypoglycemia agents;

* Biguanides:
* Alpha glucosidase inhibitors
* Sulfonylureas
* Meglitinides
* Glitazones etc.

The commonly used drugs under each category are mentioned below.

* Biguanides;

Metformin

* Alpha glucosidase inhibitors;

Miglitol
Acarbose

Sulfonylureas;

Gliclazide
Glimepiride
Glipizide etc.

Sulfonylurea and biguanide combinations;

Gliclazide + Metformin
Glimeperide + metformin
Glipizide + Metformin etc.

Meglitiides;

Tab Repaglinide
Tab Nateglinide

Glitazones;

Rosiglitazone
Pioglitazone

Similar to biguanide and sulfonylurea combination there are combinations available with other drug groups as well.

The insulin preparations are available from various sources including human, animal (bovine & porcine). In addition to the source they are also categorized based on their time for onset of action (OA), duration of action (DA) etc and some important such preparations include;

* Ultra rapid acting (OA 15 minutes, DA 3- 5 hours);

Insulin Lispro
Insulin Aspart etc.

* Rapid acting (OA 30 minutes, DA 6- 8 hours)

Regular human  insulin

* Intermediate acting (OA 2-4 hours, DA 18 – 26 hours)

NPH insulin ( isophane insulin )
Lente Insulin

Long acting (OA 4-8 hours, DA > 36 hours)

Ultra Lente insulin

Some insulin mixtures include;

Huminslin 30/70
Huminsulin 50/50 etc.