CME

CME TOPICS

Chronic Diarrhea

Definition.
Loose stools with or without increased stool frequency persisting for more than 4 weeks.

Etiology: Infection. Giardiasis, amebiasis, Clostridium difficile, Cryptosporidium

Whipples disease, caused by Tropheryma whippleii, is a unique cause of diarrhea. Begins as a nondeforming arthritis in middle age, which may be manifest for years before GI symptoms begin. The illness progresses to include abdominal pain, diarrhea, weight loss, fever, lymphadenopathy, and occasionally CNS symptoms. Diagnosis is by biopsy of the small intestine yielding the offending organism.

Inflammation. Ulcerative colitis, Crohns disease, ischemic colitis, diverticulitis, AIDS-related chronic diarrhea, collagenous colitis (very common in middle-aged and elderly women), microscopic (lymphocytic) colitis.

Drugs. Laxatives, antibiotics, NSAIDs, magnesium-containing antacids, alcohol.

Malabsorption. Short bowel syndrome, celiac sprue (gluten sensitive enteropathy), carbohydrate malabsorption, pancreatic insufficiency, bacterial overgrowth.

Endocrine. Hypothyroidism or hyperthyroidism, diabetes, adrenal insufficiency, hypoparathyroidism, Zollinger-Ellison syndrome.

Motility disorders. Irritable bowel syndrome, dumping syndrome.

Infiltrative disorders. Amyloidosis, diffuse intestinal lymphoma, scleroderma.

Hormone-producing tumors. VIPoma, carcinoid tumor, pheochromocytoma, ganglioneuroma, villous adenoma, medullary thyroid carcinoma or systemic mastocytosis.

Others. Fecal incontinence, food allergy, radiation enteritis or colitis.

Most patients with chronic watery diarrhea and abdominal pain have no identifiable cause for diarrhea except for irritable bowel syndrome.

Evaluation

History. Inquire about diurnal variation, relationship to meals, weight loss, and character of stools (such as foul-smelling or greasy stools characteristic of malabsorption or chronic bloody stools and abdominal pain or tenesmus suggestive of inflammatory bowel disease or tumor). Absence of stools at night suggests (but does not prove) a non-organic etiology.

Physical examination. Look for abdominal tenderness, distension, organomegaly, anal fistulas, rectal mass, and hyperactive bowel sounds.

Laboratory analyses.

1. CBC with differential. Anemia is suggestive of chronic blood loss, infection, malabsorption, or neoplasm. Eosinophilia may be secondary to parasitic disease or allergic reaction. Megaloblastic anemia may result from vitamin B12 or folate malabsorption.
2. ESR, C-reactive protein. If elevated, may indicate chronic inflammation.
3. Serum electrolytes, magnesium, iron, renal function, albumin, cholesterol. Calcium, phosphate, and alkaline phosphatase levels to evaluate for parathyroid disease. A fasting or random glucose can be used to screen for diabetes. Carotene levels may be low because of fat malabsorption. PT/PTT may be abnormal because of decreased vitamin K absorption. Thyroid function abnormalities should be ruled out. Hypocalcemia may be due to vitamin D malabsorption.
4. Stool exam for occult blood, leukocytes, and ova and parasites. A stool specimen should be sent for culture and sensitivity; one culture is sufficient. Stool antigen test (sensitivity 92%, specificity 98%) is available for Giardia organisms and is more sensitive than an "O & P." The same type of test is available for Cryptosporidium. Generally 3 stools are sent of ova and parasites.
5. Special tests.
1. A 72-hour fecal fat quantitation or Sudan staining of stool if steatorrhea (fat malabsorption) is suspected.
2. d-Xylose absorption (decreased in disorders of proximal small intestine).
3. A stool pH <5.3>
4. Small intestinal biopsy (useful for Whipples disease, celiac sprue, regional enteritis, some parasitic infestations).
5. Smooth muscle endomysial antibody titers may be positive in celiac sprue/gluten insensitivity. Tissue transglutaminase is starting to be utilized as an alternative test (see Sprue below).
6. Small bowel culture for bacterial overgrowth.
7. Stool test with phenolphthalein (test for factitious laxative abuse). Bring stool pH to 8.0. If the specimen turns maroon in color, this indicates the presence of phenolphthalein, an ingredient in over-the-counter laxative products. Urine tests are available to detect aloes, senna alkaloids, and bisacodyl.
8. Sigmoidoscopy should be done to detect inflammation of the colon or rectum, neoplasms, and parasites.
9. Radiographic studies. Plain abdominal radiography and barium studies of the upper GI tract, small intestine, and colon.

Treatment

Should be directed toward underlying cause of the chronic diarrhea.

Occasionally, when a definitive diagnosis cannot be made, one might empirically try:

Dietary restriction. Restricting lactose, gluten, or long-chain fatty acids in the diet. Restrictions should be done systematically so that if symptoms improve, the restricted factor can be identified and removed permanently from the diet. Lactase replacements (such as Lactaid caplets) are available OTC for patients intolerant to lactose.

Pancreatic enzyme supplementation (Creon [pancrelipase] capsules) for suspected pancreatic exocrine deficiency (such as cystic fibrosis, chronic pancreatitis).

Increase dietary or supplemental fiber.

Cholestyramine, which tends to have a constipating effect.

Antimicrobials (such as metronidazole).

Judicious use of antidiarrheal medication may be appropriate for symptomatic relief in some patients. Avoid opiates in the treatment of chronic diarrhea. See acute diarrhea section for dosages and cautions

Sarcoidosis

A multisystem granulomatous disorder of unknown etiology, characterized histologically by noncaseating epithelioid granulomas involving various organs or tissues, with symptoms dependent on the site and degree of involvement.

Sarcoidosis occurs mainly in persons aged 20 to 40 yr and is most common in Northern Europeans and American blacks. The lifetime risk of developing sarcoidosis is particularly high among Swedish men (1.15%), Swedish women (1.6%), and American blacks (2.4%).

A single provoking agent or disordered defense reactions triggered by various insults may be responsible, and genetic factors may be important. The characteristic histopathologic findings are multiple noncaseating epithelioid granulomas, with little or no necrosis, occurring commonly in mediastinal and peripheral lymph nodes, lungs, liver, eyes, and skin and less often in the spleen, bones, joints, skeletal muscle, heart, and CNS. These granulomas may resolve completely or proceed to fibrosis. Although similar granulomas can occur in various infections, hypersensitivity reactions, pneumonia, and foreign body reactions, characteristic patterns of involvement indicate sarcoidosis.

SYMPTOMS AND SIGNS

Symptoms depend on the site of involvement and may be absent, slight, or severe. Fever, weight loss, and arthralgias may occur initially. Persistent fever is common with liver involvement. Peripheral lymphadenopathy is common and usually asymptomatic; even insignificant nodes may contain granulomas. Organ function may be impaired by the active granulomatous disease or by secondary fibrosis. Cough and dyspnea may be minimal or absent.

Skin lesions (plaques, papules, subcutaneous nodules) are frequently present in patients with chronic sarcoidosis, and nasal and conjunctival mucosal granulomas may occur. Erythema nodosum, often with fever and arthralgias, is commonly the presenting symptom in Europeans but less commonly in Americans.

Hepatic granulomas are found on percutaneous biopsy in 70% of patients, who may be asymptomatic with normal liver function tests. Hepatomegaly is noted in <>

Granulomatous uveitis occurs in 15% of patients; it is usually bilateral and, if untreated, may cause severe vision loss due to retinal involvement, severe vitreitis, or secondary glaucoma. Lacrimal gland enlargement, conjunctival and eyelid infiltrations, and keratitis sicca occasionally are present.

Myocardial involvement, noted in 5 to 10% of patients, may cause angina, heart failure, or fatal conduction abnormalities.

Acute polyarthritis may be prominent; chronic periarticular swelling and tenderness may be due to osseous changes in the phalanges. Acute periarticular ankle inflammation often occurs without cutaneous lesions and is often not recognized as a presentation of sarcoidosis.

CNS involvement is of almost any type, but cranial nerve palsies (especially facial paralysis) are most common, affecting 5% of patients.

Diabetes insipidus may occur. Hypercalcemia and hypercalciuria (the result of increased 1,25-dihydroxyvitamin D production by alveolar macrophages and sarcoid granulomas) may cause renal calculi or nephrocalcinosis with consequent renal failure, but prednisone has reduced the frequency of disordered Ca metabolism. Hyperparathyroidism appears to be unusually frequent and should be considered when hypercalcemia does not promptly respond to corticosteroids.

LAB FINDINGS AND DIAGNOSIS

Chest x-ray abnormalities occur in 90% of patients. Mediastinal adenopathy often is discovered on routine chest x-ray. X-ray findings of bilateral hilar and right paratracheal adenopathy are virtually universal (90% of patients), although adenopathy occasionally is unilateral. Pulmonary infiltration may have a diffuse, fine, ground-glass appearance on x-ray. It may accompany or follow adenopathy; occur without visible adenopathy; occur as reticular or miliary lesions; or be present as confluent infiltrations or large nodules resembling metastases. Cough and dyspnea may be minimal or absent. Pulmonary fibrosis, cystic changes, and cor pulmonale are late results of progressive disease.

Leukopenia is frequently present, and serum uric acid elevation is common, but gout is rare. Serum alkaline phosphatase and gamma-glutamyl transpeptidase levels may be elevated as a result of liver involvement. Depression of delayed hypersensitivity is characteristic, but a negative second-strength tuberculin reaction reliably excludes complicating TB. Hypergammaglobulinemia is common in blacks.

Pulmonary function tests show restriction, decreased compliance, and impaired diffusing capacity. CO2 retention is uncommon, although airway obstruction is common in patients with endobronchial disease or in late stages with pulmonary fibrosis or bullae. Serial pulmonary function tests are important for assessing disease progression and guiding treatment.

Sarcoidosis may be diagnosed in asymptomatic patients with typical chest x-ray findings but should also be considered with normal findings when the symptoms and signs described above occur. Because the differential diagnosis includes lymphoma and fungal infections (eg, histoplasmosis, coccidioidomycosis), tissue biopsy with microbiologic and histologic examination is essential if symptoms are present and if corticosteroid therapy is indicated. When superficial or palpable lesions (eg, in skin, lymph nodes, or conjunctiva) are present, biopsy is positive for sarcoidosis in > 85% of such specimens.

When peripheral sites are not available for biopsy, transbronchial biopsy by fiberoptic bronchoscopy is the best initial procedure for securing histologic evidence of sarcoidosis; granulomas can be seen in 50 to 80% of patients regardless of whether the chest x-ray reveals pulmonary infiltration or hilar adenopathy alone. Lung tissue can also be sampled via thoracoscopy.

Other possible biopsy sites include normal-appearing conjunctiva or the mediastinum, which can be approached by mediastinotomy or mediastinoscopy. Liver biopsy shows granulomas in 70% of cases. Local sarcoid reactions in a single organ (eg, liver) and pulmonary granulomas due to infection, hypersensitivity reaction, or foreign body reaction must be excluded. In questionable cases, more than one site should be biopsied to thoroughly search for an infection or foreign body reaction.

The Kveim reaction, a granulomatous reaction appearing 4 wk after intradermal injection of sarcoid spleen or lymph node extracts, is positive in 50 to 60% of patients, but reliable antigens are not available in the USA because of FDA restrictions on the use of human material for diagnostic testing.

Serum ACE activity is elevated (> 2 standard deviations) in 60% of patients, presumably reflecting macrophage activity. It can also be elevated in patients with histoplasmosis, acute miliary TB, hepatitis, or lymphoma and is thus nonspecific. Liver disease slows the metabolic excretion of serum ACE and results in increased ACE activity. Increased CSF ACE may be useful in diagnosing CNS sarcoidosis. Tissue ACE activity is highest in sarcoid lymph nodes rather than in pulmonary tissues.

Bronchoalveolar lavage shows lymphocytosis in most patients with active sarcoidosis but is rarely indicated because patients with hypersensitivity pneumonitis show similar lymphocytosis. However, the CD4/CD8 ratio on bronchoalveolar lavage is elevated in sarcoidosis and reduced in hypersensitivity pneumonitis. Bronchoalveolar lavage analyses were advocated to determine the need for corticosteroid therapy, but recent studies do not support this use.

Whole-body gallium scanning, a sensitive but nonspecific indicator of sarcoidal inflammation, may be used for diagnosis in patients with normal chest x-rays or otherwise atypical presentations. Patients with symmetric increased uptake in mediastinal and hilar nodes (lambda sign) and in lacrimal, parotid, and salivary glands (panda sign) have a pattern pathognomonic for sarcoidosis. Gallium scanning may indicate useful sites for biopsy and may help determine whether radiologic densities represent reversible inflammation or fibrosis in long-standing pulmonary sarcoidosis. Gallium uptake is extremely sensitive to corticosteroids; a negative result in patients taking prednisone is unreliable.

TB, aspergillosis, cryptococcosis, histoplasmosis, coccidioidomycosis, and Hodgkin's disease must be differentiated from sarcoidosis. It is uncertain whether the typical sarcoid granulomas found in 5% of liver biopsies performed for staging of Hodgkin's disease indicate two concurrent diseases or a sarcoid reaction to the neoplasm.

CLINICAL COURSE AND PROGNOSIS

Evaluating treatment is difficult because spontaneous improvement or clearing is common. Even massive hilar adenopathy and extensive infiltrates may disappear in a few months or years. Mediastinal adenopathy may sometimes persist without change for many years. In one study, recovery was observed on x-ray at the end of 5 yr in 82% of Swedish patients with hilar adenopathy alone and in 57% of patients with pulmonary opacities. In another study, recovery was observed at the end of 9 yr in 85% of white patients and 65% of black patients with pulmonary sarcoidosis. Race and extrapulmonary sarcoidosis help predict the likelihood of recovery in patients with pulmonary sarcoidosis: 89.4% in whites with no extrathoracic disease; 69.7% in whites with extrathoracic disease; 76% in blacks with no extrathoracic disease; and 46.4% in blacks with extrathoracic disease.

The prognosis is better for patients who have adenopathy without radiologic evidence of pulmonary disease. The most reliable indicator of a favorable outcome of sarcoidosis is onset with erythema nodosum.

About 10% of patients develop serious disability from ocular, respiratory, or other organ damage, but mortality from sarcoidosis is <>

TREATMENT

Patients with few or no symptoms should not be treated, regardless of radiologic or laboratory abnormalities (except for sustained hypercalcemia). Abnormal ACE activity, gallium scanning, and other laboratory tests are useful in assessing symptoms, but abnormal test results alone do not justify therapy. No available drugs have consistently prevented pulmonary fibrosis.

Corticosteroids accelerate clearance of symptoms, physiologic disturbances, and x-ray changes. However, little difference is demonstrable in long-term outcome between treated and untreated patients, and relapse is common when treatment ends. Corticosteroids should be given to suppress severe symptoms (eg, dyspnea, arthralgia, fever) or hepatic insufficiency, cardiac arrhythmia, CNS involvement, hypercalcemia, ocular disease uncontrolled by local drugs, or disfiguring skin lesions. A good starting dose is prednisone 15 to 20 mg/day po or methylprednisolone 12 to 16 mg/day po. Prednisone 60 mg/day po or methylprednisolone 48 mg/day po is often used when a prompt effect is desired, but such doses are poorly tolerated by many patients. Patients with acute disease (eg, severe erythema nodosum) may need treatment for only a few weeks, but most of those requiring therapy have chronic sarcoidosis and need treatment for >= 1 yr. Maintenance doses of prednisone as low as 5 mg/day po control symptoms and radiologic lesions and may be needed indefinitely in a few patients. Inhaled corticosteroids may provide palliation of mild or moderate respiratory symptoms. Because relapse occurs in 50% of cases, clinical and laboratory examination should be repeated every 2 to 3 mo after the drug is stopped.

About 10% of patients requiring therapy are unresponsive to tolerable doses of a corticosteroid and should be given a 6-mo trial of methotrexate starting at 2.5 mg/wk po and increasing in increments of 2.5 mg/wk to a total of 10 to 15 mg/wk as tolerated by a WBC > 3000/mm3. After 8 wk of methotrexate, the corticosteroid can be reduced and then often discontinued. Serial blood counts and liver enzyme tests should be performed every 6 wk.

Although immunosuppressive drugs are often more effective in refractory cases, relapse is frequent after their cessation. The safety of long-term use of drugs other than methotrexate has not been established. Immunosuppressive drugs are frequently required in patients with neurosarcoidosis and other severe forms of the disease. Hydroxychloroquine 200 mg bid po is more effective than corticosteroids for treatment of disfiguring skin sarcoids. Retinal damage is rare, but serial ophthalmologic examination should be performed every 6 mo.

FEB-MAR-APR 2002 EDITION
THYROID DISORDERS - INTRODUCTION

Thyroid disorders include euthyroid goiter, euthyroid sick syndrome, hyperthyroidism, hypothyroidism, thyroiditis, and thyroid cancers. Discussion of the synthesis and physiology of thyroid hormones and of the laboratory testing of thyroid function are prerequisites to a thorough understanding of these disorders.

SYNTHESIS AND RELEASE OF THYROID HORMONES
Iodide, which is ingested in food and water, is actively concentrated by the thyroid gland, converted to organic iodine by thyroid peroxidase, and incorporated into tyrosine in intrafollicular thyroglobulin within the colloid at the basal cell surface of the thyroid follicular cell. The tyrosines are iodinated at one (monoiodotyrosine) or two (diiodotyrosine) sites and then coupled to form the active hormones (diiodotyrosine + diiodotyrosine tetraiodothyronine [thyroxine, T4]; diiodotyrosine + monoiodotyrosine triiodothyronine [T3]. Another source of T3 within the thyroid gland is the result of the outer ring deiodination of T4 by a selenoenzyme: type I 5-deiodinase (5D-I). Thyroglobulin, a glycoprotein containing T3 and T4 within its matrix, is taken up from the follicle as colloid droplets by the thyroid cells.
Lysosomes containing proteases cleave T3 and T4 from thyroglobulin, resulting in release of free T3 and T4. The iodotyrosines (monoiodotyrosine and diiodotyrosine) are also released from thyroglobulin, but only very small amounts reach the bloodstream. Iodine is removed from them by intracellular deiodinases, and this iodine is used by the thyroid gland.
The T4 and T3 released from the thyroid by proteolysis reach the bloodstream, where they are bound to thyroid hormone-binding serum proteins for transport. The major thyroid hormone-binding protein is thyroxine-binding globulin (TBG), which has high affinity but low capacity for T4 and T3. TBG normally accounts for about 75% of the bound hormones. Other thyroid hormone-binding proteins--primarily thyroxine-binding prealbumin, also called transthyretin, which has high affinity but low capacity for T4, and albumin, which has low affinity but high capacity for T4 and T3--account for the remainder of the bound serum thyroid hormones. About 0.03% of the total serum T4 and 0.3% of the total serum T3 are free and in equilibrium with the bound hormones. Only free T4 and T3 are available to the peripheral tissues for thyroid hormone action.
All reactions necessary for the formation of T3 and T4 are influenced and controlled by pituitary thyroid-stimulating hormone (TSH), also called thyrotropin, which stimulates follicular cells in the thyroid gland. TSH binds to its thyroid plasma membrane receptor on the external follicular cell surface and activates the enzyme adenylate cyclase, thus increasing the formation of adenosine 3:5-cyclic phosphate (cAMP), the nucleotide that mediates the intracellular effects of TSH. Pituitary TSH secretion is controlled by a negative feedback mechanism modulated by the circulating level of free T4 and free T3 and by conversion of T4 to T3 in the pituitary thyrotropic cells. T3 is the metabolically active iodothyronine. Increased levels of free thyroid hormones (T4 and T3) inhibit TSH secretion from the pituitary, whereas decreased levels of T4 and T3 result in an increased TSH release from the pituitary. TSH secretion is also influenced by thyrotropin-releasing hormone (TRH), a 3-amino acid peptide synthesized in the hypothalamus. TRH, released into the portal system between the hypothalamus and pituitary, binds to a specific TRH receptor on the thyrotropic cells of the anterior pituitary and causes the subsequent release of TSH. The precise regulation of TRH synthesis and release is not clear, although thyroid hormones do play a role.
About 20% of the circulating T3 is produced by the thyroid. The remaining 80% is produced by monodeiodination of the outer ring of T4 (5D-I), mainly in the liver. Monodeiodination of the inner ring of T4 (5-deiodinase [5D-III]) also occurs in hepatic and extrahepatic sites to yield 3,3,5-T3 (reverse T3 or rT3). This iodothyronine has minimal metabolic activity but is present in normal human serum and in insignificant amounts in thyroglobulin. About 99% of the circulating rT3 is generated by inner ring deiodination of T4 in peripheral tissues. rT3 levels increase in many instances in which serum T3 levels fall because of decreased activity of outer ring 5D-I (eg, chronic liver and renal disease, acute and chronic illness, starvation, and carbohydrate-deficient diets). This increase in rT3 occurs primarily because of decreased outer ring (5D-I) activity, which markedly decreases the clearance of rT3. These states of chronic illness, therefore, result in decreased production of the active hormone, T3, and in increased serum rT3 levels due to decreased rT3 clearance. The decreased production of T3 might be an adaptive response to illness.

EFFECTS OF THYROID HORMONES
Thyroid hormones have two major physiologic effects: (1) They increase protein synthesis in virtually every body tissue. (T3 and T4 enter cells, where T3, which is derived from the circulation and from conversion of T4 to T3 within the cell, binds to discrete nuclear receptors and influences the formation of mRNA.) (2) T3 increases O2 consumption by increasing the activity of the Na+, K+-ATPase (Na pump), primarily in tissues responsible for basal O2 consumption (ie, liver, kidney, heart, and skeletal muscle). The increased activity of Na+, K+-ATPase is secondary to increased synthesis of this enzyme; therefore, the increased O2 consumption is also probably related to the nuclear binding of thyroid hormones. However, a direct effect of T3 on the mitochondrion has not been ruled out. T3 is believed to be the active thyroid hormone, although T4 itself may be biologically active.

LAB TESTING OF THYROID FUNCTION
Measurement of serum thyroid-stimulating hormone (TSH): Measuring serum TSH is the best way to determine thyroid dysfunction. Normal test results essentially rule out hyperthyroidism or hypothyroidism, except in hyperthyroidism secondary to a TSH-secreting pituitary adenoma or pituitary resistance to thyroid hormone and in some patients with central hypothyroidism due to disease in the hypothalamus and/or pituitary gland. These conditions are discussed briefly below. The serum TSH level also defines the syndromes of subclinical hyperthyroidism (suppressed serum TSH) and subclinical hypothyroidism (elevated serum TSH), both associated with normal serum T4, free T4, T3, and free T3 levels.
New serum TSH assays using immunometric assay methodology are far more sensitive and accurate than the first-generation assay using radioimmunoassay. This sensitivity allows differentiation between the extremely low or undetectable levels found in true hyperthyroidism and the below-normal levels found in certain patients, eg, patients with euthyroid sick syndrome (see below). Second-generation immunometric assays (IEMAs, IFMAs, and ICMAs) have a functional sensitivity of 0.1 to 0.2 mU/L. Third-generation assays (some ICMAs) have a functional sensitivity of 0.01 to 0.02 mU/L. Fourth-generation assays in development have a functional sensitivity of 0.001 to 0.002 mU/L.

Measurement of total serum T4: Total serum T4 is most commonly measured by immunometric assay using isotopic (IRMA) or nonisotopic labels, including an enzyme (immunoenzymometric assay [IEMA]), a fluorophor (immunofluorometric assay [IFMA]), or a chemiluminescent compound (immunochemiluminometric assay [ICMA]). Immunometric assays measure total T4, both bound and free hormone, although almost all T4 is protein-bound. These assays are simple, inexpensive, and rapid. Total T4 is a direct measurement of T4, unaffected by contaminating non-T4 iodine. However, changes in serum-binding protein levels produce corresponding changes in total T4, even though the physiologically active free T4 is unchanged. Thus, a patient may be physiologically normal but have an abnormal total serum T4 level.
Thyroxine-binding globulin (TBG) is most commonly increased in pregnancy, by estrogen therapy or oral contraceptives, and in the acute phase of infectious hepatitis. TBG may also be increased genetically by an X-linked abnormality.
TBG is decreased primarily by anabolic steroids, including testosterone, and by excess amounts of corticosteroids. TBG may also be decreased genetically. Finally, large doses of drugs such as phenytoin and aspirin and their derivatives displace T4 from its binding sites on TBG, thereby falsely lowering the total serum T4 level.

Direct measurement of free T4: Since free thyroid hormones are available to peripheral tissues, directly measuring serum free T4 avoids the pitfalls of interpreting total T4 levels, which are influenced by the level of the binding proteins. Thus, serum free T4 levels more accurately diagnose true thyroid function than total T4. Direct measurement of serum free T4 level is most accurately assessed by equilibrium dialysis, which is time-consuming, expensive, technically demanding, and unavailable in most commercial laboratories. This method separates bound from free hormone. The gold standard for measuring serum free T4 is overnight equilibrium dialysis of serum containing 125I-T4; the percentage of free T4 is calculated by determining the total counts in the dialysate divided by the total 125I-T4 added to the serum multiplied by the total T4 concentration. A simplified version is available in kit form; free T4 is measured in the dialysate by immunoassay.
Indirect estimation of free T4: These measurements are readily available, are simpler, and compare extremely well with the methods for measuring direct free T4 mentioned above. Index methods require two independent tests, one measuring total serum T4 and the other measuring thyroid hormone-binding ratio or T3 resin uptake. The free T4 index is then calculated using the total T4 and the TBG level, the thyroid hormone-binding ratio, or T3 resin uptake. The index is directly proportional to the free T4 level. Immunoassay methods are standardized against a direct measurement of free T4 by equilibrium dialysis, thus results are reported in absolute units (ng/dL or pmol/L). The two most commonly used methods are a two-step and a one-step immunoassay method using a T4 analog. These assays are not completely free of the influence of binding proteins or substances in serum that may result in false increases or decreases in the free T4 levels.

Measurement of total serum T3 and free T3: Since T3 is tightly bound to TBG (although 10 times less than T4) but not to transthyretin, total serum T3 levels measured by the same methods described above for total T4 will be influenced by alterations in the serum TBG level and by drugs that affect binding to TBG. Free T3 levels in the serum are measured by the same direct and indirect methods described above for T4.

Testing with thyrotropin-releasing hormone (TRH): Serum TSH is measured before and after an IV injection of 500 g synthetic TRH. Normally, there is a rapid rise in TSH levels of 5 to 25 U/mL, reaching a peak in 30 min and returning to normal by 120 min. The rise is exaggerated in primary hypothyroidism. The TRH test may be useful in distinguishing pituitary from hypothalamic hypothyroidism. Patients with hypothyroidism secondary to a pituitary deficiency have an absent or impaired TSH response to TRH. Patients with a hypothalamic disorder who have deficient TRH reserve and a normal pituitary reserve will usually release normal amounts of TSH in response to TRH, although the release may be delayed and prolonged, resulting in a shift in the time of release. In hyperthyroidism, TSH release remains suppressed, even in response to injected TRH, because of the inhibitory effects of the elevated free T4 and free T3 on the pituitary thyrotroph cell. However, with newer TSH assays, the TRH test is rarely needed to diagnose thyroid dysfunction because the basal serum TSH is proportional to the TSH response to TRH.

Measurement of thyroid autoantibodies: Autoantibodies to thyroid peroxidase and, less commonly, to thyroglobulin are present in almost all patients with Hashimoto's thyroiditis, and thyroid peroxidase autoantibodies are usually detected in patients with Graves' disease. Both these antibodies are commonly measured by enzyme immunoassays; a thyroid peroxidase autoantibody test has replaced the older tanned red cell agglutination test for thyroid antimicrosomal (M) autoantibodies. Hyperthyroidism in Graves' disease is caused by an autoantibody directed against the TSH receptor on the thyroid follicular cell (TRAb). Two general methods are used to measure TRAbs. TSH binding-inhibition assays determine the ability of serum IgG to inhibit the binding of 125I-TSH to solubilized TSH receptors. Thyroid-stimulating antibody assay measures the ability of these IgGs to stimulate cAMP generation or 125I uptake in different biologic systems, ie, monolayer cultures of isolated thyroid cells, cultured rat thyroid follicular cells (FRTL-5), or thyroid cells from human or porcine tissue. Finally, antibodies against T4 and T3 may be found in patients with autoimmune thyroid disease and may affect T4 and T3 measurements but are almost never clinically significant.

Measurement of thyroglobulin: The thyroid is the only source of this iodinated high molecular weight glycoprotein, which is readily detectable in normal patients and is usually elevated in patients with nontoxic and toxic goiter. The principle use of serum thyroglobulin is in evaluating patients after near-total or total thyroidectomy with or without 131I ablation for differentiated thyroid cancer. Normal or elevated serum thyroglobulin values indicate the presence of residual normal or malignant thyroid tissue in patients receiving TSH suppressive doses of L-thyroxine or after withdrawal of L-thyroxine. The major problem with the current immunometric assay and radioimmunoassay methods in measuring serum thyroglobulin is the presence of thyroglobulin antibodies, which usually results in an underestimation of serum thyroglobulin.

Testing for radioactive iodine uptake: This test has disadvantages in cost, time, and patient inconvenience. The isotope of choice is 123I, which exposes the patient to vanishingly small radiation. It is valuable in the differential diagnosis of hyperthyroidism, which is discussed below. The thyroid 123I uptake varies widely with iodine ingestion and will be low in patients exposed to excess iodine. The thyroid 123I uptake may be helpful in calculating the dose of 131I in the treatment of hyperthyroidism.

Scanning of the thyroid: Scanning with radioiodine or technetium-99m is not routine. It is useful in delineating structural abnormalities of the thyroid and in evaluating modular thyroid disease, especially a solitary nodule, to determine its functional state, ie, hot vs. cold.

JAN 2002 EDITION

DYSPHAGIA

A subjective awareness of difficulty in swallowing caused by impaired progression of matter from pharynx to stomach.

The usual complaint is that food "gets stuck" on the way down, which may be accompanied by pain. Dysphagia is caused by impeded transport of liquids and solids by organic lesions of the pharynx, esophagus, and adjacent organs or by functional derangements of the nervous system and musculature. The cause of dysphagia should always be carefully sought.

PREESOPHAGEAL DYSPHAGIA
Difficulty emptying bolus material from the oral pharynx into the esophagus.

Preesophageal dysphagia occurs with abnormal function proximal to the esophagus, most often in patients with neurologic or muscular disorders that affect skeletal muscles (eg, dermatomyositis, myasthenia gravis, muscular dystrophy, Parkinson's disease, oculogyric crises associated with phenothiazine therapy, amyotrophic lateral sclerosis, bulbar poliomyelitis, pseudobulbar palsy, other CNS lesions). The patient frequently presents with nasal regurgitation or tracheal aspiration followed by coughing.

ESOPHAGEAL DYSPHAGIA
Difficulty passing food down the esophagus, possibly caused by obstructive or motor disorders.

Esophageal dysphagia is sometimes associated with obstructive disorders (eg, cancer, benign peptic stricture, lower esophageal ring). Obstructive disorders usually produce dysphagia for solids alone by mechanically reducing the esophageal lumen. Meat and bread are often singled out as the major offenders, but some patients cannot tolerate any solids, only liquids. Patients who complain of dysphagia in the lower esophagus are usually correct in terms of origin, whereas patients who complain of dysphagia in the upper esophagus are often incorrect. Dysphagia can be intermittent (eg, from lower esophageal ring), progress rapidly over weeks to months (eg, from esophageal cancer), or progress over years (eg, from peptic stricture). In cases of peptic stricture, dysphagia is preceded by a prominent history of gastroesophageal reflux disease (GERD).

Dysphagia caused by obstructive disorders has extrinsic and intrinsic causes. Extrinsic obstruction results when tumors or adjacent organs compress the esophagus, which may occur with an enlarged left atrium, aortic aneurysm, aberrant subclavian artery (Dysphagia Lusoria), substernal thyroid, bony exostosis, or extrinsic tumors--most commonly lung. Diagnosis is usually made on x-ray, and prognosis depends on the cause. Intrinsic obstruction is usually caused by esophageal cancer. Mechanical obstruction may also be caused by esophageal involvement by lymphoma, leiomyosarcoma, or (very rarely) metastatic cancer.

Esophageal dysphagia is sometimes associated with motor disorders (eg, achalasia, symptomatic diffuse esophageal spasm, scleroderma). Motor disorders involve dysfunction of the smooth muscle of the esophagus. They produce dysphagia for both solids and liquids by impairing esophageal peristalsis and lower esophageal sphincter function, thus interrupting the smooth esophageal transport of a bolus. The presence of dysphagia for both liquids and solids accurately distinguishes motor from obstructive causes.

Dysphagia should not be confused with globus sensation (globus hystericus), a feeling of having a lump in the throat, which is unrelated to swallowing and occurs without impaired transport. Often noted in association with anxiety or grief, globus sensation is mainly emotional in origin.

DEC 2001 EDITION

HEADACHE

Headache (cephalalgia) is a common symptom, often associated with disability, but rarely life threatening. Headaches may be a primary disorder (migraine, cluster, or tension headache) or a secondary symptom of such disorders as acute systemic or intracranial infection, intracranial tumor, head injuries, severe hypertension, cerebral hypoxia, and many diseases of the eyes, nose, throat, teeth, ears, and cervical vertebrae. Sometimes no cause is found.

Headaches may result from stimulation of, traction of, or pressure on any of the pain-sensitive structures of the head: all tissues covering the cranium; the 5th, 9th, and 10th cranial nerves; the upper cervical nerves; the large intracranial venous sinuses; the large arteries at the base of the brain; the large dural arteries; and the dura mater at the skull base. Dilation or contraction of blood vessel walls stimulates nerve endings, causing headache. The cause of most headaches is extracranial rather than intracranial. Stroke, vascular abnormalities, and venous thromboses are uncommon causes of headache.

Diagnosis
The frequency, duration, location, and severity of the headache; the factors that make it better or worse; associated symptoms and signs, such as fever, stiff neck, nausea, and vomiting; and special studies help identify the cause of headache.

Secondary headaches may have specific characteristics. An acute whole-cranial, severe headache associated with fever, photophobia, and stiff neck indicates an infectious process, such as meningitis, until proved otherwise. Subarachnoid hemorrhage also causes acute headache with symptoms and signs of meningeal irritation. Space-occupying lesions often cause subacute, progressive headache. New-onset headache in an adult > 40 yr always requires thorough evaluation. With space-occupying lesions, the following may occur: headache on awakening or at night, fluctuation of headache with postural changes, and nausea and vomiting. Additional neurologic complaints, such as seizure, confusion, weakness, or sensory changes, may occur late and are ominous.

Tension headache tends to be chronic or continuous and commonly originates in the occipital or bifrontal region, then spreads over the entire head. It is usually described as a pressure sensation or a viselike constriction of the skull. Febrile illnesses, arterial hypertension, and migraine usually cause throbbing pain that can occur in any part of the head.

Useful tests include CBC, STS, serum chemistry profile, ESR, CSF examination, and, for specific symptoms, ocular tests (acuity, visual fields, refraction, intraocular pressure) or sinus x-rays. If the cause of recent, persistent, recurrent, or increasing headache remains in doubt, MRI and/or CT is appropriate, especially if abnormal neurologic signs are present.

Treatment
Many headaches are of short duration and require no treatment other than mild analgesics (eg, aspirin, acetaminophen) and rest.

Treatment of primary headaches is discussed under the specific disorders, below. Alternative approaches, such as biofeedback, acupuncture, dietary manipulations, and some less conventional modes, have been advocated for these disorders. None of these treatments has shown clear-cut benefits in rigorous studies. However, to the extent that an alternative treatment poses little risk, it may be tried, with the idea that effective headache management is multidimensional.

Treatment of secondary headaches depends on treatment of the underlying disorder. For meningitis, prompt antibiotic therapy is critical. Subsequently, symptoms can be relieved with analgesics, including acetaminophen, NSAIDs, or opioid narcotics. Certain disorders require more specific treatment; eg, temporal arteritis is treated with corticosteroids, and headache due to benign intracranial hypertension is treated with acetazolamide or diuretics and weight loss. Subdural hematomas or brain tumors may be treated surgically.

Stress management taught by a psychologist often reduces the incidence of headaches. However, most patients are helped by an understanding physician who accepts the pain as real, sees the patient regularly, and encourages discussion of emotional difficulties, whether they are the cause or the result of chronic headaches. The physician can reassure the patient that no organic lesion is present and recommend environmental readjustments and the removal of irritants and stresses. For particularly difficult problems, a team composed of a physician, psychotherapist, and physiotherapist is most effective in managing chronic headache.

CLUSTER HEADACHE

Headache that lasts 15 to 180 min, is severe, is unilateral, is located periorbitally and/or temporally, occurs up to 8 times per day, and is associated with at least one of the following: tearing, red eye, stuffy nose, facial sweating, ptosis, or miosis.

Men have cluster headache more often than women. Triggers include alcohol, sleep, and barometric pressure change. The pathophysiology is unknown but may be similar to that of migraine.

Diagnosis is based on symptoms and the exclusion of intracranial pathology. Treatment is prophylactic, abortive, or analgesic. The calcium channel blocker verapamil and the serotonin antagonist methysergide are used for prophylaxis. Sumatriptan and ergots are used for abortive treatment. Indomethacin is uniquely effective for cluster headache.

TENSION HEADACHE

Headache that lasts 30 min to 7 days and is nonpulsating, mild to moderate in severity, bilateral, not aggravated by exertion, and not associated with nausea, vomiting, or sensitivity to light, sound, or smell.

Tension headache can be thought of as a state of cranial hyperalgesia with reduced endogenous pain modulation and enhanced pain potentiation. It has many causes; comorbid migraine, mood disorders, sleep dysfunction, and anxiety states contribute.

Treatment with mild analgesics is helpful: acetaminophen 650 mg po q 4 h, aspirin 300 to 600 mg, or another NSAID, such as ibuprofen or naproxen. For chronic or recurrent headache, many physicians empirically supplement analgesics with tricyclic antidepressants (eg, amitriptyline 10 to 125 mg/day po) or, occasionally, benzodiazepines (eg, diazepam 2 to 5 mg po qid), but regular use may cause habituation.

More disabled patients require a multidimensional approach as described above. Recognition of comorbid illness is essential. Migraine is often associated with chronic tension headaches, so treatments overlap.

NOV 2001 EDITION

MIGRAINE HEADACHE

Headache that lasts 4 to 72 h, is throbbing, is moderate to severe in intensity, is unilateral, becomes worse with exertion, and is associated with nausea, vomiting, or sensitivity to light, sound, or smell.
Only three or four of the above criteria must be present for accurate diagnosis.
About 24 million Americans have migraines. Migraines may occur at any age but usually begin between ages 10 and 40, more often in women than in men. Headaches often partially or completely remit after age 50. More than 50% of patients have a family history of migraine.

Etiology and Pathophysiology
The cause is unknown, and the pathophysiology is not fully understood. Changes in brain and scalp arterial blood flow occur, but whether vasodilation and vasoconstriction are a cause or an effect of the migraine is unclear. Cortical spreading depression (fundamental changes in the brain cortex in which a crest of hyperpolarization is followed by depolarization) may induce neurogenic inflammation, with vasodilation, activated WBCs and permeable capillaries. The inflammation leads to irritation of perivascular trigeminal sensory fibers. A cascade of events follows, causing changes in blood flow and the severe headache. Intracranial vascular malformations are a rare cause of migraine-like headaches.
The mechanism for migraines is not well defined, but several triggers are recognized. Cycling estrogen, a significant trigger, may explain why there are three times as many women with migraines as men. Evidence of estrogen's role as a trigger includes the following: During puberty, migraine becomes much more prevalent in females than in males; migraines are particularly difficult to control in the premenopausal period; and oral contraceptives and estrogen replacement therapy often make migraine worse. Other triggers include insomnia, barometric pressure change, and hunger. The association of diet and migraine is usually overstated. No prospective study has proved an association.

Symptoms, Signs, and Diagnosis
Migraine may be preceded by a short prodromal period of depression, irritability, restlessness, or anorexia and may be associated with an aura (in 10 to 20% of occurrences). An aura usually precedes the headache by no more than 1 h but is often concurrent. An aura is a transient, reversible neurologic visual, somatosensory, motor, or language deficit. Most persons report visual auras, including flashing lights, scintillating scotoma, and fortification spectrums.
Symptoms usually follow a pattern in each patient, except unilateral headaches may not always occur on the same side. The patient may have attacks daily or only once every several months. Diagnosis is based on the symptom patterns when there is no evidence of intracranial pathologic changes. Migraine is more probable when the patient has a family history of migraine or of visual prodromata. No diagnostic tests are useful, except to exclude other causes.

Treatment
Treatment depends on the frequency of attacks and the presence of comorbid illness. In general, treatment can be classified as prophylactic, abortive, or analgesic.
If a person has more than one migraine a week, long-term prophylaxis should be considered. -blockers, calcium channel blockers, tricyclic antidepressants, or anticonvulsants may be used. The choice is empiric but is guided by the presence of comorbid illness. For example, if hypertension coexists, -blockers or calcium channel blockers would be most efficient. If depression or sleep dysfunction coexists, tricyclic antidepressants should be tried first.
Abortive drugs are used for acute treatment. A new class of drugs that activate serotonin receptors (5-hydroxytryptamine [5-HT] 1B/1D agonists) block neurogenic inflammation and can abort migraine pain in about 70% of patients. Sumatriptan, the prototype, is available in oral and subcutaneous injection forms. Subcutaneous dosing is more effective but has more adverse effects, which include flushing, nausea, esophageal constriction, and, rarely, coronary artery constriction. Caution is advised in prescribing sumatriptan to men > 55 yr, postmenopausal women, or persons with a history of heart disease. The next generation of 5-HT 1B/1D agonists (eg, eletriptan, naratriptan, rizatriptan, zolmitriptan) promises to increase the benefits and reduce the adverse effects. Ergot alkaloid derivatives, such as ergotamine tartrate and dihydroergotamine, in oral and parenteral preparations can be used effectively. Dopamine antagonist antiemetics, such as metoclopramide and prochlorperazine, are effective, even if nausea is not prominent.
Analgesics should be used sparingly. They are effective in some patients but cause rebound headache with dose escalation in others. NSAIDs are probably best for mild to moderate headaches. Opioids should be avoided except under special circumstances and strict guidelines


PREVIOUS MCQs OF THE MONTH

DEC 2001 EDITION

>Ramesh, a 30 yrs old chronic asthmatic, on oral theophylline comes with symptoms of Respiratory tract infection. Which of the following antibiotics should not be used in this patient?

1. Amoxicillin
2. Erythromycin
3. Doxycycline
4. Cephalexin
5. Levofloxacin

ERYTHROMYCIN-THEOPHYLLINE COMBINATION CAN CAUSE SEIZURES. (JUST THINK HOW?)


>Ramani, 30 years old lady presents to the casualty with acute onset of severe abdominal pain. She also gives history of two spontaneous abortions in the past. She has been taking Oral Contraceptive pills of late. A diagnosis of Ischemic colitis was made based on the barium study. The classical appearance is termed as

1. cobblestone appearance
2. applecor appearance
3. Eagle claw appearance
4. thumbprint appearance
5. coffee bean appearance

ISCHEMIC COLITIS ON BARIUM STUDY IS CLASSICALLY DESCRIBED TO HAVE A THUMB-PRINT APPEARANCE

>Which of the following ATT drugs should not be used in a HIV positive patients taking Indianvir, Didanoside and AZT?

1. INH
2. Rifampicin
3. Ethambutol
4. Pyrazinamide
5. Streptomycin

USE OF RIFAMPICIN IS CONTRAINDIACTED WITH MANY PROTEASE INHIBITORS


>Which of the following beta blockers have minimal
metabolic side effects?

1. Propranolol
2. Nadolol
3. Acebutalol
4. Pindolol
5. Timolol

THE ANSWER IS ACEBUTALOL. ACEBUTALOL IS A CARDIOSELECTIVE BETA BLOCKER WITH PARTIAL AGONIST ACTIVITY. THOSE BETA BLOCKERS WITH PARTIAL AGONIST ACTIVITY HAVE LESS METABOLIC SIDE EFFECTS THAN PURE ANTAGONISTS. THE USUAL METABOLIC SIDE EFFECTS ARE INHIBITION OF LIPOLYSIS AND A DECREASE IN THE HDL/LDL RATIO.


>Which is the DNA virus that can multiply entirely in
the cytoplasm of the cell without entering the
nucleus?

1. Hepatitis B virus
2. Adenovirus
3. Pox virus
4. Herpes virus
5. Parvovirus B19

POX VIRUSES ARE DNA VIRUSES THAT HAVE THEIR OWN DNA POLYMERASE ENZYME AND ALSO REPLICATE IN THE CYTOPLASMOF THE CELL WITHOUT ENTERING THE NUCLEUS.


>Which of the following aneurysm are associated with a
inherited disease characterised by multiple cysts in
the kidney and liver?

1. Renal artery aneurysm
2. Abdominal aorta aneurysm
3. Berry aneurysm
4. Dissecting aneurysm of aorta
5. Mycotic aneurysm of the Aorta between the renal
artey and the coeliac plexus

POLYCYSTIC KIDNEY DISEASE IS ASSOCIATED WITH BERRY ANEURYSM OF THE CIRCLE OF WILLIS.


>In the absence of N-acetyl transferase enzyme, intake
of one of the following drugs will result more
commonly in a lupus like syndrome. Which is the drug?

1. Procainamide
2. Rifampicin
3. Probucol
4. Fenfluramine
5. Indapamide

LACK OF N-acetyl transferase RESULTS IN DECREASED CONVERSION OF Procainamide TO N-acetyl procainamide
(NAPA). THIS RESULTS IN SLE LIKE SYNDROME.OTHER DRUGS CAUSING SIMILAR SYNDROME ARE INH AND HYDRALLAZINE


>Which of the following NSAIDs is better tolerated by
Acid peptic disease patients?
1. Piroxicam
2. Nabumetone
3. Indomethicin
4. Propionic acid derivatives
5. Phenylbutazone derivatives

NABUMETONE IS A KETONE NSAID THAT IS CLAIMED TO HAVE MUCH LESS INCIDENCE OF GI SIDE EFFECTS THAN OTHER NSAIDs.


>Which of the following diseases have the
characteristic pathologic feature of Ballooning
degenration of cells

1. Pemphigus
2. Epidemolysis Bullosa
3. Steven Johnson Syndrome
4. Herpes simplex
5. Dermatitis herpetiformis

BALLOONING DEGENRATION IS CHARACTERISTIC OF HERPES SIMPLEX INFECTION.

>BCYE agar is the specific media for which of the following microbes?

1. Leptospira icterohemorrhagica
2. Campylobacter jejuni
3. Bacillus anthracis
4. Legionella pneumophila
5. Bacillus cereus

BCYE AGAR IS SPECIAL MEDIUM FOR LEGIONELLA PNEUMOPHILA

NOV 2001 EDITION

>Examination of the carotid pulse of a patient revealed two impulses or peaks during the ventricular systole. which of the following physical findings probably would be associated with this finding?

1. diastolic murmur beginning after an opening snap.
2. decrease in systolic arterial pressure during inspiration
3. systolic murmur increasing during Valsalva manoeuver.
4. Right sided third heart sound.

ANSWER IS <3> WHICH IS CHARACTERISTIC FINDING IN HOCM WHICH ALSO HAS PULSUS BISFERIENS THAT IS DESCRIBED IN THE QUESTION. THE OTHER DISEASE WHERE THE MURMUR INCREASES DURING VALSALVA IS MVP

>On examining the eyes of a patient for refractive errors in a dark room using a concave mirrorplaced at 1 m distance from the patient's eye positioned so as to reflect the light from a source just above the patient's head onto the patient's eye, the medical student finds that on moving the mirror to one side, the shadow in the patient's pupil also moved to the same side. The correct interpretation of this finding is?

1. emmetropia
2. hypermetropia > 1D
3. hypermetropia <> 1D
6. myopia < myopia =" 1D.">A 38 year old man came to casualty with alleged history of having been mugged by a group of naxalites and was hit with logs of wood and iron rods on the chest, back, buttocks. After initial resuscitation, Xrays were taken. He was found to have multiple fractures involving the forearm bones, scapula, ribs, iliac bone, etc. He was stable and was shifted to the Orthopedics ward. In the ward after 2 days he became restless, irritable, developed tachypnea and dyspnea. His pulse was 120/min. On examination, he was found to have a peculiar rash occuring particulary on the nondependant areas . His Hb was 9.8gm% and platelet count = 40,000/cu.mm. of blood. What is the most likely diagnosis?

1. Pulmonary pneumothorax
2. Hemopneumothorax
3. Fat embolism
4. Sepsis with DIC
5. Hemolytic Uremic syndrome

THIS IS A TYPICAL CASE HISTORY OF A PATIENT WITH FAT EMBOLISM. THE RASH IN THE NONDEPENDANT AREAS IS SUPPOSED TO BE CHARACTERISITIC OF FAT EMBOLISM

>Which of the following is an absolute indication for Caeserian section in pregnancy associated with heart disease?

1. Pulmonary stenosis
2. Coarctation of Aorta
3. Eisenmenger's syndrome
4. Ebstein's anomaly

SURPRISED? COARCTATION OF AORTA IS !!

>Pappe's rule is associated with?

1. burns
2. bullet injury
3. illegal abortion
4. Pupil in post mortem state

PAPPE RULE HELPS IN FINDING OUT THE SEQUENCE OF GUN SHOTS THROUGH THE SKULL!