Department of MedicineJOURNAL CLUB

Dr Awadhesh Sharma ,SR

MEDICINE,MLB,MEDICAL COLLEGE,JHANSI(UP)

TROPICAL SPLENOMEGALY SYNDROME

MEDICAL TREATMENT OF ULCERATIVE COLITIS

MEASURING OBESITY TO ASSESS CARDIOVASCULAR RISK - INCH TAPE, WEIGHING MACHINE, OR BOTH?

GUJJAR LUNG

TROPICAL SPLENOMEGALY SYNDROME

Several reports of massive splenomegaly in patients from tropical areas have been published in the last century. Diagnostic criteria were recently established. In 1983, this condition was defined as hyperreactive malarial syndrome (HMS).

Pathophysiology: HMS is prevalent in native residents of malarious regions and visitors to those regions. Patients with HMS have high levels of antibody for Plasmodium falciparum.

Genetic factors, pregnancy, and malnutrition may play a role in the etiology of HMS. Relative protection against HMS is observed in patients with sickle cell trait, as it is with malaria.

Although the exact mechanism is uncertain, evidence suggests that exposure to malaria elicits exaggerated stimulation of polyclonal B lymphocytes, leading to excessive and partially uncontrolled production of immunoglobulin M (lgM) as the initiating event.

IgM is polyclonal and not specific for any particular malarial species.

Defective immunoregulatory control of B lymphocytes by suppressor or cytotoxic T lymphocytes causes an increase in B lymphocytes and a decrease in T lymphocytes in the peripheral blood. Accompanying this process is T-cell infiltration of the hepatic and splenic sinusoids. Serum cryoglobulin and autoantibody levels increase, as does the presence of high-molecular-weight immune complexes. The result is anemia, deposition of large immune complexes in Kupffer cells in the liver and spleen, reticuloendothelial cell hyperplasia, and hepatosplenomegaly.

Antimalarial treatment is effective in decreasing the size of the spleen, but premature discontinuation of treatment may lead to relapse. Effective malarial chemoprophylaxis and eradication measures have been associated with a decrease in the incidence of HMS.

Frequency- HMS occurs only in people who have resided in or visited areas where malaria is endemic.

Exact and accurate assessment of the incidence of HMS is difficult because many conditions that cause splenomegaly and similar symptoms are prevalent in areas where malaria is endemic. These conditions include hemoglobinopathies, lymphoreticular disorders, schistosomiasis, hepatic cirrhosis, leishmaniasis, typhoid, and tuberculosis.

Mortality/Morbidity: HMS is associated with a high mortality rate. However, the natural history of HMS is not well documented. A 5-year mortality rate of 50% was reported in Uganda and New Guinea. A mortality rate of 85% was documented in hospitalized patients with gross splenomegaly. Overwhelming infections are the leading cause of death.

HMS is not considered a premalignant condition, but chronic lymphocytic leukemia has been reported in patients with HMS.

Race: Certain racial and immunologic factors may be important in the pathogenesis of HMS, though results of phenotypic studies of human lymphocyte antigens have not been entirely conclusive.

Sex: HMS is more common in female individuals, especially lactating mothers, than in male individuals. The female-to-male ratio is 2:1.

Age: HMS is most frequently observed in young and middle-aged adults, though the process probably commences during childhood. HMS is uncommon in children younger than 8 years, but it was reported in a 4-year-old patient. These observations support the theory that prolonged chronic antigenic stimulation is an important factor in the development of HMS.

CLINICALHistory

The most common presenting symptoms of HMS are chronic abdominal swelling (64%), pain (52%), and a dragging sensation.

Abdominal swelling may wax and wane. . Many patients do not have any symptoms and are capable of normal daily activity.

Patients rarely have intermittent fever, and persistent, severe fevers should raise the possibility of an alternative diagnosis.

Some patients present with acute abdominal pain.

Patients physiologically adapt well to the chronic evolution of anemia and are symptomatic only when anemia is severe.

Weakness and loss of energy may reflect the degree of anemia.

Nonspecific symptoms include cough, dyspnea, epistaxis, and headache.

Pressure on the abdominal contents may lead to hernias and leg swelling.

A history of chronic long-standing splenic enlargement differentiates HMS from simple malarial splenomegaly.

Bleeding complications are uncommon because thrombocytopenia is usually not severe.

Susceptibility to infections, especially skin and respiratory infections, is slightly increased.

Pregnant women are susceptible to episodes of massive Coombs negative hemolysis, which are usually preceded by febrile episodes.

Physical

The hallmark of HMS is splenomegaly, which is usually moderate to massive.

The spleen is firm and regular, with notches that may be well palpable.

The enlarged spleen may be seen to protrude against the abdominal wall.

A splenic bruit may be audible.

Despite the size of the spleen, splenic rupture is rare.

Approximately 93% of patients have accompanying hepatomegaly.

Pallor is common.

Patients are usually afebrile at presentation.

In general, tachycardia is absent. If it is present, tachycardia indicates a concurrent complication.

Dilatation of the veins, cardiomegaly and flow murmurs reflect hypervolemia.

Lymphadenopathy is absent, but bilateral parotid swelling has been described.

The patient may be malnourished and jaundiced.

Ascites is uncommon.

Causes

The most important predisposing factor for HMS is residence in or visitation to an area where malaria is endemic.

Other risk factors include malnutrition and an as-yet-undefined genetic predisposition.

DIFFERENTIALS

Brucellosis Felty Syndrome Histiocytosis Infectious Mononucleosis Leishmaniasis Malaria Salmonella Infection Schistosomiasis Sickle Cell Anemia Thalassemia Trypanosomiasis Tuberculosis

Other Problems to be Considered

Hepatic cirrhosis

Banti disease

Lab Studies

Diagnostic criteria far HMS

The mere exclusion of other disease processes causing splenomegaly is insufficient to establish a diagnosis of HMS. Fakunle (1981) was the first to establish diagnostic criteria for the definitive diagnosis of HMS. When these strict criteria are applied, as many as one half of patients with splenomegaly may not have HMS.

Major criteria

Gross splenomegaly 10 cm or more below the costal margin in adults for which no other cause can be found

Elevated serum IgM level 2 standard deviations or more above the local mean

Clinical and immunologic responses to antimalarial therapy

High antibody levels for P falciparum

Minor criteria

Hepatic sinusoidal lymphocytosis

Normal cellular and humoral responses to antigenic challenge, including a normal phytohemagglutination response

Hypersplenism

Lymphocytic proliferation

Familial occurrence

Hematologic manifestations

Normocytic normochromic anemia is almost always present and related to the degree of splenomegaly. Several factors contribute to its etiology, including pooling of RBCs in the spleen, hypersplenism, and increased R8C destruction and turnover, but the major factor is increased plasma volume. The reticulocyte count is increased and reflects erythroid hyperplasia. The anemia is Coombs negative. Deficiency of vitamin B12, folic acid, or glucose-6-phosphate

dehydrogenase has not been demonstrated.

Leukopenia is common. It is sometimes associated with lymphocytosis.

Thrombocytopenia is generally mild. Both neutropenia and thrombocytopenia are due to splenic pooling.

Peripheral smears usually do not reveal the malarial parasite.

Other findings

IgM levels are increased. An elevation of 2 standard deviations above the local mean should be present. Serum IgM levels are correlated with the degree of splenomegaly.

Patients with HMS have high titers of malarial antibodies.

Titers of cold agglutinins, rheumatoid factor, antinuclear factor, cryoproteins, and thyroglobulins may be high.

Imaging Studies

Imaging tests are of limited value. Ultrasonography of the abdomen may help to document and monitor hepatosplenomegaly.

Histologic Findings

Liver biopsy is rarely indicated.

Hepatic sinusoidal lymphocytosis is present in HMS.

In HMS unlike malaria, malarial pigmentation is absent in the macrophages.

Kupffer cell hypertrophy and hyperplasia are also present.

TREATMENT

Medical Care: The mainstays of therapy are antimalarial drugs.

Surgical Care: Splenectomy plays no role in the treatment of HMS. The mortality rate after splenectomy is high because of fulminant and overwhelming infections.

Appropriate consultation with oncologists and metabolic and infectious disease specialists may be sought to rule out diseases that mimic HMS.

Activity is permitted, as tolerated by the patient. A patient's activity may be limited because of severe anemia or the pressure effects of massive splenomegaly.

MEDICATIONAntimalarial drugs are effective therapies for HMS. The specific

choice of drug is based on the pattern and prevalence of drug resistance in the patient's geographic area.

To be effective, treatment should be prolonged and continued regularly. Months may pass before a response is observed, and relapses may occur when therapy is discontinued.

No studies have addressed the duration of adequate treatment, and no researchers have compared antimalarial medications.

Chloroquine and proguanil appear to be equally effective. This observation suggests that eradication of parasitemia is the common pathway for therapeutic responses. Pyrimethamine may be an alternative. Data regarding the usefulness of other antimalarial drugs in HMS are limited.

The role of lifelong prophylaxis for individuals residing in endemic areas is unclear. Treatment may have to be continued for longer than a year, or even longer.

The response to therapy is guided by the size of spleen, a decrease in serum IgM levels, improvement of anemia, and general improvement in the patient's well-being.

Antimalarial agents

Because epidemiologic and other data suggest that HMS is related to malarial infection, antimalarial drugs have been used and have been effective.

Drug - Chloroquine phosphate

Dose - 1 g salt (600 mg base) PO initially and 300 mg base 6,24 and 48 h later; then, 300 mg base qwk for

months to >1 y until response occurs

Drug - Proguanil

Dose - 200 mg/d PO

Drug - Pyrimethamine and sulfadoxine (Fansidar)

Dose - Acute episode : 50-75 mg (based on pyrimethamine component) PO qd for 3 d is curative

Prophylaxis : 25mg (based on pyrimethamine component) PO qwk

FOllOW-UP

Complications Complications include infections that may be serious and that may

result in death. Trapping of hematopoietic elements in the enlarged spleen may

cause thrombocytopenia, anemia, and neutropenia, with resultant problems.

A predisposition to develop malignancy remains unproven.

Prognosis HMS is a chronic disease that can be fatal because of infections and

bleeding complications. Appropriate treatment with antimalarial medications can result in a

good outcome. Splenectomy should be avoided because it increases the risk of

fulminant infections. The risk of malignancy is ill defined.

Patient Education

The importance of antimalarial prophylaxis during visits to endemic areas should be emphasized to travellers.

Symptoms should be promptly attended to and evaluated, even if they occur in travelers who received prophylaxis and even if they appear months after they left the endemic area.

MEDICAL TREATMENT OF ULCERATIVE COLITISLove Dalal

Bakersfield Digestive Disease Center, Bakersfield, California, USA.

INTRODUCTION

Ulcerative colitis is an idiopathic inflammatory bowel disease characterized by colonic mucosal inflammation and a chronic relapsing course. It affects about 11 in 100,000 persons in the United States. One house to house survey conducted in North India found the incidence of ulcerative colitis not much less than reported from the western world. The exact etiology of ulcerative colitis is not known, but it appears to be triggered by a dysregulated immune response, perhaps to. a currently unknown pathogen. Patients with ulcerative colitis usually present with diarrhea, rectal bleeding, tenesmus, passing of mucus and abdominal pain. Diagnoses are made on the basis of clinical, endoscopic and histopathological findings.

Usually, ulcerative colitis is mildly active, but it can be life threatening - during severe attacks because of colonic and systemic complications. It is also well established that patients with long-term ulcerative colitis are at an increased risk of developing colorectal cancer.

Pharmacological Agents

Efforts at managing ulcerative colitis are directed at decreasing or eliminating mucosal inflammation and symptoms, thereby improving the patient's quality of life. Accomplishing these goals requires careful selection of therapeutic agents based on symptom severity and drug side effects. The therapeutic options vary depending upon the anatomic extent of the colonic involvement and clinical severity of an ulcerative colitis attack.

5-Aminosalicylic Acid Compounds

5-Aminosalicylic acid (5-ASA) compounds, also. known as aminosalicylates are the cornerstone of medical therapy far active ulcerative colitis.

SULFASALAZINE

Sulfasalazine possesses both anti-inflammatory (5-ASA) and antibacterial (sulfapyridine) properties. Taken orally, the drug is delivered intact into the right colon and subsequently is degraded by coliform bacteria into 5-ASA, the active moiety and sulfapyridine, which helps transport 5-ASA to target areas. A major drawback to its use, however, is that the most effective doses also tend to be associated with intolerable toxicity; nearly one out of every three sulfasalazine-treated patients will develop adverse reactions. Common adverse effects include nausea, headache, vomiting, dyspepsia and anorexia, while less frequent, but more serious adverse effects include agranulocytosis, megaloblastic or hemolytic anemia, pancreatitis and sperm abnormalities. Patients with sulfaallergies should avoid sulfasalazine. Folic acid supplementation is recommended because sulfasalazine inhibits folate absorption.

NEWER AMINOSALICYLATES

Newer aminosalicylates deliver 5-ASA to the distal bowel without the sulfapyridine, thus allowing us to administer higher doses of the medication while limiting adverse effects and systemic toxicity. In equimolar doses, the oral 5-ASA preparations are equivalent in efficacy to sulfasalazine and their safety profile is similar or superior to that of placebo. Orally ingested 5-ASA alone undergoes rapid absorption in the jejunum and is therefore of limited efficacy in patients with colonic disease. Two main types of delayed release formulations have been developed to overcome this deficiency. The most commonly used aminosalicylate, is Mesalamine, 5-ASA enveloped in a coating that dissolves at pH of 7 in the distal ileum and colon. The next preparation is a controlled release capsule which consists of 5-ASA encapsulated by ethylcellulose microgranules. This preparation will allow gradual release of 5-ASA from the jejunum to the colon. Rectal (topical) therapies are also available as mesalamine suppositories or enemas. The other two 5-ASA preparations which are available are Olsalazine and Balsalazide.

The former consists of two 5-ASA molecules linked by a diazo bond and the latter consists of 5- ASA molecule linked by a diazo bond to an inert, unabsorbed carrier molecule. Both these formulations require colonic bacteria to break down the diazo bond and release 5-ASA moiety. Thus, they are also mainly active in the colon. The most recent advance in 5-ASA oral therapy includes recently FDA approved delayed and extended release formulation which is MMX mesalamine. This method employs a gastro resistant polymer to delay release of the active drug until it reaches the terminal ileum and the MMX drug delivery technology is believed to extend delivery of 5-ASA consistently throughout the entire colon. The medication is prescribed as once a day dosage. Aminosalicylates are usually well tolerated, but can cause mild and transient side effects like headache and abdominal discomfort. Olsalazine causes watery diarrhea in about 10% of patients. Other side effects like pneumonitis, pericarditis, pancreatitis and thrombocytopenia are rare.

In last few years, several trials have demonstrated that 5-ASA therapy can prevent the development of dysplasia and cancer in patients with long standing ulcerative colitis. Educating patients about this potential benefit may increase their adherence to treatment.

CORTICOSTEROIDS

Corticosteroids are potent, rapidly acting oral, rectal or parenteral agents used for acute treatment of patients with moderate to severe relapses of ulcerative colitis. They are potent anti-inflammatory agents acting through inhibition of several inflammatory pathways. The short term side effects of steroids include acne, moon face, edema, mood disturbance, dyspepsia and glucose intolerance. The long-term side effects include cataracts, osteopenia/ osteoporosis, osteonecrosis, myopathy and susceptibility to infection. Effects during withdrawal include adrenal insufficiency, a syndrome of myalgia and arthralgia or raised intracranial pressure. Complete steroid withdrawal is facilitated by early introduction of agents like Azathioprine (AZA) or timely surgery.

Corticosteroid enemas are beneficial in patients with left sided distal ulcerative colitis. The foam preparation may facilitate retention and thus may be more effective than the liquid preparations. Some systemic absorption occurs, but serious side effects like adrenal suppression, etc. are uncommon. Budesonide is a poorly absorbed corticosteroid with limited bio-availability due to extensive first-past metabolism (degraded by the liver and red blood cells that can produce therapeutic benefit with reduced systemic side effects). It is designed to deliver steroids to the distal small bowel and proximal colon. The ileal-release preparations of budesonide are indicated for the treatment of patient's with ileal and right-sided colonic Crohn's disease. The efficacy of enterically coated budesonide in treatment of ulcerative colitis has not been established. However controlled trials have demonstrated that budesonide enemas are effective for inducing remission ill left-sided ulcerative colitis.

IMMUNOMODULATORS

Azathioprine (AZA) and 6-Mercaptopurine (6-MP) are chemically related immunomodulators.

AZA is nonenzymatically metabolized to 6-MP and subsequently to 6-thioguanine nucleotides. These drugs are useful for patients who are refractory to, or cannot be weaned from oral steroids. Although their slow onset of action (three to six months are required for optimization of benefit) may limit their utility in active therapy, AZA and 6-MP have each demonstrated efficacy in maintaining remission.. Recent studies have shown that these immunosuppressive agents have a more favorable adverse effect profile than was originally believed. Fewer than 10% of patients stop therapy due to reversible bone marrow suppression and fewer than 3% develop pancreatitis or allergies characterized by abdominal pain, fever and rash. Pancreatitis is a contrailldication to continued use of these drugs. One large retrospective review failed to find a significant association between Azathioprine and the development of lymphoma or leukemia. However one recent meta analysis showed a significant increase in risk of lymphoma in inflammatory bowel disease patients treated with AZA or 6-Mp.

It is advisable to obtain a complete blood count every two weeks during the initial treatment phase and every three months for patients on maintenance treatment. It has been suggested that direct measurement of 6-MP metabolites like 6-thioguanine (6 TG) and 6-Methylmercaptopurine (6-MMP) could be useful for optimizing the efficacy and minimizing the toxicity related to 6-MP.

While Methotrexate has been found effective for inducing remission or preventing relapse in Crohn's disease, no comparable trials have addressed the role of methotrexate in induction or maintenance of remission in ulcerative colitis.

INFLIXIMAB

Infliximab is a chimeric anti-tumour necrosis factor alpha monoclonal antibody with potent anti inflammatory effects and is classified as one of the biological agents for treatment of ulcerative colitis. Tumor necrosis factor (TNF) has a central role in the pathogenesis of mucosal inflammation in Crohn's disease.

The efficacy in Crohn's disease provided the rationale for clinical trials of infliximab and other anti TNF agents in patients with ulcerative colitis. Two recent randomized, double blind, placebo controlled trials (ACT 1 and ACT 2) demonstrated efficacy of infliximab in the induction and maintenance of mild to moderate ulcerative colitis. USFDA recently approved the use of this drug to treat patients with moderate to severe ulcerative colitis who have not completely responded to other treatments.

The medication is administered intravenously at the dose of 5 mg/kg at 0, 2 and 6 weeks, followed by 5 mg/kg every 8 weeks thereafter. Because infliximab is associated with four or five fold increase in risk of tuberculosis, all patients should have chest x-ray to exclude past or present infection. Infusion reactions are rare and usually respond to slowing the infusion rate or treatment with antihistaminics and sometimes corticosteroids. Anaphylactic reactions have been reported. A delayed reaction consisting of myalgia, fever and joint pain may occur if there has been an interval of more than one year following a previous infusion.

The formation of antibodies to infliximab may also be a problem and has been associated with reduced efficacy and infusion reactions. This can be avoided by using this medication at recommended regular intervals. The use of immunomodulators (like AZA and 6-MP) is also reported to reduce development of antibodies to infliximab and some authorities recommend starting of the immune modulators before the patient is put on infliximab. Long-term data on use of infliximab in ulcerative colitis is not 'yet available and at this time it is best considered for patients with acute steroid refractory disease who are reluctant to undergo colectomy.

CYCLOSPORINE

Cyclosporine is a potent immunosuppressive which has a rapid onset of action (more rapid than AZA or 6 MP). Many open studies confirm that intravenous cyclosporine in a short-term data, at a dose of 2-4 mg/kg per day induces clinical improvement in more than 75% of the patients suffering from severe ulcerative colitis.

Intravenous cyclosporine often demonstrates clinical efficacy within one week of the onset of treatment. Oral maintenance with cyclosporine is not very popular because of its toxicity and long-term failure rate. One of the immunomodulators (AZA or 6-MP) is usually started concurrently with initiation of treatment with cyclosporine with the hope that AZA or 6-MP will be effective within three to six months and hence cyclosporine is rarely continued for more than 3-6 months. Measurement of blood pressure, full blood count, renal function and cyclosporine serum levels are advisable at 0, 1 and 2 weeks and then every month. Measurement of serum cholesterol and magnesium are appropriate before starting therapy because the risk of convulsions increases in patients with low cholesterol or magnesium. The other minor side effects include tremor, paresthesia, malaise, headache and abnormal liver functions. Major complications include renal impairment and infections. Prophylaxis against Pneumocystis carinii pneumonia is advised in all patients on cyclosporine. Cyclosporine enemas are not effective in left-sided ulcerative colitis.

Other Experimental Approaches

Probiotics, as well as oral antibiotics have not shown any efficacy in the treatment of active ulcerative colitis. The use of fish oil showed some promising results; however, the lack of long-term effectiveness, bad taste, and the dosage requiring 15-18 capsules per day make this medicine not actively being used in clinical settings. Several epidemiologic studies have suggested a protective effect of cigarette smoking on the activity of ulcerative colitis. While two placebo control trials of use of nicotine patch in mild active ulcerative colitis showed a beneficial effect of nicotine therapy, the same therapy has not been found to be effective in maintaining the remission. Interesting case reports showing unexpected benefit in the activity of colitis with the use of heparin suggested initiation of a few placebo control trials using subcutaneous or intravenous heparin. The overall results were negative.

Therapy

Ulcerative colitis is usually classified into severity in two different ways. The first one is according to the extent of involvement. The second one is according to the symptoms. By definition, the rectum is involved in at least 95% of the patients suffering from ulcerative colitis. If the disease is limited only to the rectum, it is known as proctitis; proctosigmoiditis refers to disease limited to the rectum and sigmoid colon and left-sided ulcerative colitis involves the descending colon, sigmoid colon, and rectum. When the term pancolitis is used, it suggests involvement of the whole colon or most of the colon. In the past, the severity of disease was determined clinically into categories of mild disease, severe disease, and fulminant disease. However, in the present era of colonoscopy based diagnosis and follow up, it is easy to manage these patients according to the anatomically defined severity. If you take a generalized approach, the extent of colonic involvement usually collaborates with the severity of clinical symptoms.

TREATMENT OF PROCTITIS

For the patient whose disease is limited to the last 10- 12 cm of the

rectum, it is usual practice to begin treatment using 1,000 mg. 5-ASA

suppository once a day or a steroid suppository which is

recommended twice a day. Symptomatic improvement can be seen

within a few days. Suppositories are never effective for the disease

beyond upper rectum (about 15-20 cm above the anal verge). For

maintenance of remission, long-term treatment using 5-ASA

suppositories should be carried out. Less than once a day

maintenance therapy (such as every other day) is not recommended.

If the symptoms are not controlled, the alternatives are 5-ASA enema

or hydrocortisone foam or enema. In the rare situation when the

patient is not willing to try any of these local therapies, he can

receive ora1 5-ASA preparation.

TREATMENT OF PROCTOSIGMOIDITIS AND LEFT-SIDED COLITIS

Topical (rectal) treatments like 5-ASA enemas are superior to oral preparations in the treatment and maintenance of remission of proctosigmoiditis and left sided colitis. Topical corticosteroid enemas or foams are effective as active therapy, but not in remission. The topical therapy generally has a quicker response time and a less frequent dosing schedule. Meta-analysis has clearly demonstrated that 5-ASA enema is superior to topical corticosteroids in the management of distal ulcerative colitis. For proctosigmoiditis, the standard recommendation is to begin treatment with 4 gm 5-ASA. enema every night. The response is usually seen within four to six weeks. If the patient does not respond, additional morning 5- ASA or hydrocortisone enema can be considered. Once the patient goes into remission, frequency of enema should be tapered to every night or even on alternate nights. For patients who do not respond to or tolerate rectal preparation, an oral 5-ASA medication should be used.

Combination therapy consisting of rectal, as well as oral 5- ASA preparation has been found to be more effective than either alone. Oral therapy with sulfasalazine, mesalamine, olsalazine or balsalazide is beneficial in achieving and maintaining the remission. These drugs are maximally effective within four weeks of initiation of treatment and are effective in more than two-thirds of the patients. In case of an inadequate response, the drug should be raised to its maximum therapeutic dosage. Oral corticosteroids are typically reserved for patients who do not respond to oral 5-ASA agents with or without rectal agents or for patients who need rapid improvement. The starting dose of Prednisone is usually 40-60 mg a day depending on the severity of symptoms and weight of the patient. This dose is generally effective within two weeks and should be then tapered, usually by 5 mg per week. As mentioned before, there is no scientific evidence to support use of chronic steroid therapy in maintaining the remission and the longer the patient gets these preparations, the more significant the toxicities are.

For small numbers of steroid refractory and/ or steroid dependent patients with left-sided colitis, azathioprine or 6-MP should be considered if symptoms of disease continue despite use of steroids for six months. Control trials have shown that Budesonide enemas are effective for inducing remission in left-sided ulcerative colitis. The efficacy of this drug was comparable to conventional corticosteroids. But 5-ASA enemas were significantly better than conventional rectal steroids and hence it is recommended that budesonide enemas should generally be reserved for patients who failed 5-ASA enemas.

PANCOLITIS (EXTENSIVE COLITIS)

Topical therapy alone is not adequate in achieving remission when the disease extends proximal to the splenic flexure. Therefore, oral mesalamine is preferred for treatment of mild to moderate colitis extending proximal to the splenic flexure both for active disease and for maintenance of remission. Nevertheless, topical therapy is a useful adjunct to oral mesalamine in extensive colitis.

Those who demonstrate severe disease or those who fail to respond to oral as well as rectal 5 ASA therapy should be started on oral Prednisone (40-60 mg a day). The dose of oral sulfasalazine should be titrated up to 4-6 gm per day or alternatively mesalamine in the dose up to 4.8 gm per day. Responses are dose related. Up to 80% of the patients who receive daily doses of 4-6 gm of sulfasalazine or equivalent aminosalicylate manifest complete clinical remission or significant improvement in four weeks and approximately half achieve sigmoidoscopic remission. Azathioprine or 6 MP should be considered in patients in this category who are refractory to maximal doses of 5-ASA medications and require corticosteroids to control the symptoms. These drugs are not good options for patients who are unlikely to comply with regular monitoring, and are unwilling to accept the risk of toxicity or have dysplasia or other indications for colectomy. The use of infliximab is recommended for severe ulcerative colitis, especially when it is steroid refractory in a patient who is reluctant to undergo colectomy and in whom cyclosporine is contraindicated.

If the patient improves, the maintenance regimen should consist of sulfasalazine or one of the newer aminosalicylate preparation. As a rule, patients should not be treated chronically with steroids. Azathioprine or 6-MP may be useful as steroid sparing agents for steroid dependent agents and for maintenance of remission not adequately sustained by aminosalicylates, and occasionally for patients who are steroid-refractory, but not acutely ill. In patients whom remission was achieved with Azathioprine, continuation of the active drug reduced the twelve month relapse rate to 36%, compared to 59% on placebo.

SEVERE OR FULMINANT COLITIS

Patients who have failed to respond to maximum oral treatment with combination of 5-ASA preparation and steroids with or without topical therapy or those presenting with symptoms of severe disease (bloody stools up to 10-15 per day, fever, abdominal pain, dehydration and anemia) should be admitted for intensive intravenous therapy and monitoring.

Close liaison with a surgeon should be maintained. The mainstay of therapy at this point is an intravenous steroid in a daily dose equivalent to 400 mg of hydrocortisone or 60 mg of methylprednisolone. Broad spectrum intravenous antibiotic may be added with signs of toxicity or with worsening symptoms despite maximal medical therapy. Studies have not demonstrated clinical benefit of an oral or rectal aminosalicylate so it is generally withheld.

Patients who have severe colitis and/ or megacolon with toxic signs (fever, leukocytosis, or worsening of symptoms) and who do not improve significantly within seven days of maximal medical therapy are unlikely to benefit from prolongation of a medical regimen and should either be referred for colectomy or offered treatment with intravenous cyclosporine. For patients responding to cyclosporine, the medication should be switched to oral preparation (8 mg/kg per day) and should be continued for three to four months. At the same time, azathioprine or 6-MP should be introduced.

A recent randomized double blind trial comparing infliximab with placebo for rescue therapy in severe to moderately severe ulcerative colitis showed significant benefit for the patients on infliximab. Infliximab may turn out to be a good alternative to cyclosporine which has significant side effects and requires very close monitoring. To date no large clinical trial comparing cyclosporine with infliximab has been reported.

Indications for Surgery

Urgent surgery is needed for severe colitis not responding to five to seven days of adequate medical treatment and for toxic megacolon after 48-72 hours of ineffective treatment. Emergency surgery is mandatory for any perforation, massive hemorrhage or development of multiorgan failure.

CONCLUSION

The goal of therapy in inflammatory bowel disease is to induce and maintain remission in order to realize the best quality of life. In ulcerative colitis disease activity is almost always associated with presence of diarrhea or bloody stool and can be easily assessed by sigmoidoscopy. The principal goals of maintenance therapy are avoiding disease progression and relapse and obviating corticosteroids and surgery. Consistent adherence to the maintenance therapy is very important and should be emphasized at each follow up consult. Ulcerative colitis is often a lifelong, multifaceted disorder that extends beyond disease related symptoms. The medical management of ulcerative colitis is a constantly moving field and recent evolutions will undoubtedly change clinical practice in years to come.

MEASURING OBESITY TO ASSESS CARDIOVASCULAR RISK - INCH TAPE, WEIGHING MACHINE, OR BOTH?

V Mohan, M Deepa

Chairman and Chief of Diabetology, Madras Diabetes Research Foundation and Dr. Mohan’s Diabetes Specialities Centre 4, Conran Smith Road, Gopalapuram, Chennai

Asian Indians have an increased predisposition not only to diabetes but also to premature coronary artery disease. This has been attributed to the so called 'Asian Indian Phenotype characterized by less of generalized obesity as measured by body mass index (BM!) but greater central body obesity as shown by greater waist circumference (WC) and waist-to-hip ratios (WHR). This leads to unique biochemical and hormonal changes including higher plasma insulin levels, greater insulin resistance, lower HDL cholesterol, higher triglyceride levels, increased small dense LDL cholesterol as well as small dense HDL cholesterol and C-reactive protein and leptin levels but decreased adiponectin levels. Thus many Asian Indians fit into the category of metabolically obese, normal weight individuals.

While it is clear that obesity measured by any index almost always correlates with cardiovascular disease risk (CVD) risk factors, there are differences in the relationship of these anthropometric measures and CVD risk factors in different ethnic groups. The report on a large series of 1800 urban subjects with an aim of correlating the BMI, WC and WHR with multiple cardiometabolic risk factors. They show a positive correlation between BMI, WC and WHR with systolic and diastolic blood pressure, fasting glucose and LDL cholesterol and a negative correlation with physical activity and HDL cholesterol in both men and women. All three parameters correlated with diabetes, hypertension and metabolic syndrome while WHR was additionally correlated with dyslipidemia. While the findings are neither unexpected nor novel, there is very little data from India based on well carried out population based studies and the study results add new data from northern India on CVD risk factors and hence the study is a welcome addition to the growing volume of literature on this subject from within the subcontinent.

Since different indices [ie. body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR)] are used to define obesity, the debate as to which is the best to assess CVD risk continues. While direct assessment of fat mass may be a better index of obesity-related to health risk, it is difficult to measure this accurately in large epidemiological studies particularly in the field setting. Thus, anthropometry still remains the most widely used method for clinical and epidemiological purposes. Each obesity index has its own implications in relation to health risk in general and CVD risk in particular. In the study the importance of BMI, WC and WHR are all shown to be important for estimating CVD risk due to their positive association with various CVD risk factors. Survey of the literature also shows that no single obesity index can be recommended for this purpose from a global standpoint. The recent INTERHEART study showed that waist-to hip ratio was a much better predictor of CVD events than BMI and the accompanying Lancet editorial is provocatively titled. A farewell to body mass index?.

Indeed, INTERHEART also showed for the first time that not only is waist a 'risk' factor, but that hip is an independent 'protective' factor. Hence the WHR becomes an even stronger marker because the numerator (waist) is a 'risk' factor while the denominator (hip) is a 'protective' factor and therefore the ratio is, at least theoretically, a stronger predictor than either alone. However, while waist itself is difficult to standardize, measuring hip is even more challenging as one needs to undress the subject and, in the case of women, this could pose cultural and logistic problems ego finding enough privacy, women health workers to perform measurements etc. Moreover, many studies report that WC is as good if not better than using WHR and it is much simpler as it needs standardization of only one measurement. While proponents of BMI would point out the difficulties in standardization of WC and WHR, we would argue that measuring BMI needs not only a weighing machine, but also a stadiometer to measure height.

Standardization of the latter is a major problem particularly in

rural areas where even the floor is not uniform, while calibration

of weighing machines, particularly the spring balance which in

commonly used, would always remain an. epidemiologist's

nightmare. Moreover, the sheer convenience of carrying a

measuring tape in one's pocket or purse for doing opportunistic

screening e.g. during an event, in an office, etc., as compared to

carrying a stadiometer and a weighing machine around, is pretty

obvious. Therefore, even if the waist (±WHR) was only equal to

BMI in its usefulness to assess or predict diabetes and/ or CVD

risk, it would still come out as a clear winner for purposes of

opportunistic screening.

Defining obesity either by BMI or WC is purely arbitrary, and the risk assessment can vary widely based on the cut points used. Thus, data from different ethnic groups using different obesity index cut points should be interpreted with caution. To illustrate this point, a very recent study on a representative population of 2,350 subjects in Chennai reported that the age standardized prevalence of obesity using the international (western) definition of BMI 30 kg/ m2 was 4.0%, using BMI 27.5 kg/m2, it was 9.9%, while using the Asia Pacific definition of obesity BMI 25 kg/m2, it was 26.5%, and finally using the most recent definition of BMI 23 kg/m2, it was 45.9%. Thus the prevalence of generalized obesity ranged from 4% to 45.9% in the same population studied depending on the cut points used. Similarly, using different cut points for WC or WHR would also lead to varying prevalences of central or abdominal obesity in any population.

Several studies have examined appropriate cut points to define overweight and obesity in Asian populations. A study done in urban adult populations from six cities in India reported a BMI 23 kg/ m2 and WC of 85 cm for men and 80 cm for women as the optimal cut point values. We recently derived obesity index cut points for urban Indians; the optimal BMI cut point for identifying any two cardio-metabolic risk factors was 23 kg/m2 in both sexes while that of WC was 87 cm for men and 82 cm for women. These cut points are marginally lower than those recommended in the WHO Asia Pacific guidelines, with the exception of WC for women. Studies on north Indian populations have also reported a lower cut point for WC and BMI. These studies clearly illustrate the limitations of applying uniform BMI and WC cut points to assess the health risk of individuals globally. The rising prevalence of obesity in developing countries calls for longitudinal studies defining the role of obesity (generalized and abdominal) in Asians (as identified by BMI, WC or WHR), in predicting diabetes and/ or CVD events.

In addition, there is an urgent need for deriving appropriate cut points for obesity in children as all the current cut points are based on adult data. Population based distribution of BMI, WC and WHR in children need to be derived both for urban and rural populations. One of the challenges in doing this in children is that we will not have any cardiovascular endpoints to determine the appropriate cut points in children. Percentiles of population can be derived, but even these are moving targets, as the population as a whole can be expected to get more obese with time. The need of the hour therefore, is well planned longitudinal, preferably multi-centric, studies in India to address these very important scientific issues.

GUJJAR LUNGG Hassan*, GQ Khan**, W Qureshi+,

RA Rashid++, T Masood***, Gazanfar Ali****Incharge Consultant, **Former Professor and Head, ***Senior Consultant,

Department of Medicine, Government Medical College associated General Hospital, Sanat Nagar, Srinagar Kashmir.

This recently introduced entity in the literature, is a chronic lung disease due to prolonged exposure to indoor air pollution with pine wood smoke occurring in Gujjar Community - a social and ethnic group of population residing at hilly regions of the Indian sub continent (Jammu and Kashmir, Himachal Pradesh, Rajasthan, Pakistan, Pakistan-occupied-Kashmir and Gilgit). These people live in poorly ventilated mud houses called' Kothas' and use pinewood as a fuel for cooking and heating purposes. A high oleoresin containing portion of the wood called' Lash' is used as a source for lighting in the dwellings creating dense smoky atmosphere and adding further to the indoor air pollution.

All family members residing in kothas are exposed to this smoky atmosphere for 12 to 16 hours daily, more during winter months.

The disease is characterized clinically by progressive cough and dyspnea, usually appearing beyond fourth decade of life, varying radiological pattern of miliary mottling, reticulonodular shadows with or without features of chronic bronchitis or corpulmonale - the picture mimicking pulmonary tuberculosis. On histopathological examination of lungs, anthracotic nodules with carbon-laden macrophages (mainly perivascular in distribution) and fibrogenic reactions are seen.

The term 'Gujjar Lung' was first introduced in 1991 by Dhar and Pathania from Kashmir when they observed miliary and reticulonodular shadows in chest radiographs of Gujjar community who were empirically given anti-tuberculosis treatment keeping in view the high prevalence of pulmonary tuberculosis in this group of population; but the shadows remained unchanged or progressed despite adequate dosage of the drugs and duration of treatment.

Pulmonary function testing revealed restrictive or obstructive pattern. Finally, lung biopsy performed in 36 of the 46 patients of their study group revealed evidence of anthracotic nodules, carbon laden macrophages and fibrosis. Other radio diagnostic modalities like high resolution computed tomography (HRCT) were not available. Subsequently in 2000, Raison and co workers observed similar radiological findings confirmed by HRCT and similar histopathological features in a Kashmiri baker working in Saudi Arabia who had significant history of exposure to pinewood smoke inhalation from early age, and, the radiograph was obtained by chance for immigration purposes. The occurrence of this lung disease was attributed to indoor air pollution with pine wood smoke, which is supported by earlier studies conducted on rabbits by Thorning and co-authors to see the effect of pine wood smoke on airways and the lung parenchyma.

They observed predominantly large airway injury occurring

beyond 24 hours of exposure to pine wood smoke in the form of

disruption of surface epithelium, sloughing and necrosis with

marked edema in subepithelial cells accompanied by increase in

the number of extravasated erythrocytes and polymorphonuclear

cells; whereas there are additional studies demonstrating injury of

more distal airways and gas exchange units as well. Pine wood on

combustion gives rise to sulphurdioxide, benzopyrene, carbon

monoxide, nitrogen oxides and low-molecular weight aldehydes

including acrolein and albeitic acid. These gases individually or

alongwith carbon are considered to be responsible for lung injury

with eventual fibrogenic reaction.

The disease usually manifests beyond fourth decade with

dyspnea and cough productive of blackish sputum. Males and

females are involved almost equally and no case has been

detected in the pediatric or teenage group so far. Further studies

involving large samples of Gujjar population are going on and

prevention of the occurrence of this disorder may need to change

the living standard of these people in order to prevent exposure

to pinewood smoke inhalation.

10th Oct 07