Leading Article

Ind. J. Tub., 2000. 47,3

TUBERCULOSIS AND DIABETES : AN APPRAISAL

Since ancient times, physicians have been aware of the association between tuberculosis and diabetes mellitus: perhaps the earliest to note it was the great Indian physician Susruta, in 600 A.D, while Avicenna (780-1027 A.D.) had commented that phthisis frequently complicated diabetes.1 The global burden of diabetes mellitus was estimated by the World Health Organisation2 in 1998. It has been projected that the prevalence of diabetes among adults world wide will more than double, from 135 million (4%) to 300 million (5.4%), by the year 2025. The major part of this tremendous increase will occur in developing countries, like India and China, wherein a 170% increase, from 84 million to 228 million is projected. With the revision of the criteria for the diagnosis of diabetes (Appendix), by the American Diabetes Association, in 19973, which are simpler to apply compared with those proposed by the National Diabetes Data Group of the National Institute of Health, in 19794, the prevalence rates of diabetes are expected to increase further. Tuberculosis has already been declared a global emergency by the WHO5 in 1992, with an estimated one third of the worlds population infected with Mycobacterium tuberculosis and tuberculosis recognised as the single biggest killer. Now, with diabetes assuming epidemic proportions in the first quarter of the 21st century, it is imperative to take measures for the prevention and control of this deadly duo. Diabetes mellitus is also recognised as an independent risk factor for developing lower respiratory tract infections6. Whereas infections with Staphylococcus aureus, Gram-negative bacteria, and fungi occur more frequently, those with organisms like Streptococcus, Legionella, and Influenza cause significantly more morbidity and mortality7.8. Tuberculosis occurs with an increased frequency in diabetics 9.10 and causes a significantly greater mortality11.12. Increased reactivation of tuberculosis lesions has also been recorded in diabetics13. At the same time, tuberculosis appears to aggravate diabetes, with patients requiring higher than before doses of insulin. The incidence of diabetes as such appears to be higher among tuberculosis patients14-16 as compared to the general population.
Tuberculosis Complicating Diabetes Mellitus

In 1883, Windle autopsied 333 known diabetic subjects and observed pulmonary tuberculosis in more than 50% of them17. In a classic study, Root reported that 2.8% of 1373 hospitalised diabetics had pulmonary tuberculosis. Of the 750 juvenile diabetics, 1.6% had tuberculosis as compared to 0.12% among school children. After studying the association between diabetes and tuberculosis, he made the following observations: (i) The development of tuberculosis occurred ten times more frequently in juvenile diabetics. (ii) In 85% of the patients, tuberculosis had developed after the onset of diabetes. (ii) The occurrence of pulmonary tuberculosis increased with the duration of diabetes. Hence, he concluded that a diabetic patient appeared doomed to die of pulmonary tuberculosis if he succeeded in escaping diabetic coma. Root, however, postulated that the association between the two diseases was one sided i.e., diabetic patients tended to contract tuberculosis but the reverse was rare. The Philadelphia survey revealed that 8.4% of the 3,106 diabetics had pulmonary tuberculosis as compared to 4.3% of the 71,767 presumably healthy industrial workers10. Tuberculosis was present in 17% of the diabetics who had had the disease for more than 10 years compared to 5% in the diabetics with less than 10 years of the disease. A higher prevalence of tuberculosis was found in diabetics requiring more than 40 units of insulin per day. Diabetes mellitus was present in 8.3% of the cases of reactivation tuberculosis in New York city1, the second most common association after alcoholism. A Korean study18 found that pulmonary tuberculosis had developed in 170 patients among 8,015 diabetics (2.1%) as compared to 4,935 patients among 806,698 control subjects (0.6%). Estimated annual incidence rates of bacteriologically confirmed cases of tuberculosis in diabetics and non-diabetics were 281 and 55 per 10,000 respectively. The study concluded that the relative risk of developing pulmonary tuberculosis, bacteriologically confirmed,

AMRIT GUPTAN AND ASHOK SHAH

was 5.15 times higher in diabetics than in matched controls. Some of the later studies, done in developed countries have failed to demonstrate an epidemiological association between tuberculosis and diabetes19, 20. Perhaps, this is largely due to the low prevalence of tuberculosis in these areas. However, in countries like India, diabetes remains one of the most important risk factors disposing towards tuberculosis, along with malnutrition, alcoholism and HIV infection. The prevalence of pulmonary tuberculosis in diabetics in India varies from 3.3% to 8.3%, about 4 times that of general population. Is Immune Dysfunction in Diabetics a Predisposing Factor ? A probable cause of increased incidence of pulmonary tuberculosis in diabetics could be defects in host defenses and immune cell functions (Table 1) 2 1 . 2 2 . The immune derangements predominantly involve the cell-mediated arm of the immune system. Also, the degree of hyperglycemia has been found to have a distinct influence on the microbicidal function of macrophages, with even brief exposures to blood sugar level of 200 mg% significantly depressing the respiratory burst of these cells.23.24 This is borne out by the observation that in poorly controlled diabetics, with high levels of
Table 1. List of defects in diabetics immunologic makeup and physiologic pulmonary functions
Immunologic abnormalities in diabetics Pulmonary physiologic dysfunctions in diabetics

glycated haemoglobin, tuberculosis follows a more destructive course and is associated with higher mortality. Multiple pulmonary physiologic abnormalities have also been documented in diabetics that contribute to delayed clearance of and spread of infection in the host.22 Infection with tubercle bacilli leads to further alterations in cytokines, monocyte-macrophages and CD4/CD8 T cell populations.25. 26 The balance of the T lymphocyte subsets CD4 and CD8 plays a central role in the modulation of host defenses against mycobacteria and has a profound influence on the rate of regression of active pulmonary tuberculosis.27 Glucose Intolerance in Tuberculosis In the early part of this century, the prevailing view, as suggested by Root9 was that tuberculous patients do not develop diabetes with any greater frequency than the non-tuberculous". However, Nichols14, in 1957, changed this view when he described 178 tuberculous patients of whom 5% had diabetes and a further 22% had an abnormal screening test. In India16, a multicentric study done in 1987 found the prevalence of unsuspected diabetes in tuberculous patients to be of the order of 9.7%: In males above 40 years, the rate was 17.8% compared with 5.1% in those below 40 years. And in females, the respective rates were 23.5% and 4.0%, the overall rates for males and females being 10% and 8.7% respectively. Various other Indian studies have estimated the prevalence of glucose intolerance in tuberculosis to be between 1.5% to 14%. Two recent studies conducted in Africa also had similar findings. In the Tanzanian study,28 done as per WHO criteria, in 506 consecutive patients admitted w i t h sputum positive pulmonary tuberculosis, 9 of whom were known diabetics, diabetes was diagnosed by the consecutive oral glucose tolerance tests (OGTTs), in 11 additional patients giving a crude diabetes prevalence rate of 4%. Impaired glucose tolerance (IGT) was present in 82 patients (16.2%). In comparison, a similar OGTT survey, carried out by the authors in a community, revealed prevalence of 0.9% in respect of diabetes and 8.8% for IGT. The Nigerian study29, done on 54 patients with active pulmonary tuberculosis found that 3 patients had OGTT values in the diabetic range and 20 had IGT.

Abnormal chemotaxis, adherence, phagocytosis and microbicidal function of polymorphonuclear Decreased peripheral monocytes with impaired phagocytosis. Poor blast transformation of lymphocytes. Defective C3 opsonic function

Diminished bronchial reactivity

Reduced elastic recoil and lung volumes. Reduced diffusion capacity Occult mucus plugging of airways Reduced ventilatory response to hypoxaemia and

Adapted from: Infections in Diabetes Mellitus21-22

TUBERCULOSIS AND DIABETES : AN APPRAISAL

An 8 year study, done in Japan30 from 1987 to 1994, revealed that in 2,659 patients the prevalence of diabetes in cases of active tuberculosis was 13.2%: In males above 40 and 50 years of age, the rates were 22% and 21.3% respectively. The prevalence in males was significantly higher than in females. Moreover, the prevalence of diabetes among patients with active pulmonary tuberculosis was significantly higher during 1991-1994 compared with during 1987-1990. Impaired glucose tolerance in tuberculosis is much higher than overt diabetes. Although IGT reverts to normal in a large number of cases with effective chemotherapy, the higher percentage with IGT is significant because, according to the National Diabetes Data Group of NIH, one to five per cent of patients with IGT may progress to overt diabetes, annually. Causes of Glucose Intolerance in Tuberculosis Acute severe stress is an important cause of the development of impaired glucose tolerance. Fever, protracted inactivity and malnutrition stimulate the stress hormones epinephrine, glucagon, cortisol and growth hormone, which acting synergistically raise the blood sugar level in excess of 200 mg%.31 Plasma levels of IL-1 and TNF alpha are also raised in severe illness which can stimulate the anti-insulin hormones32. Age, co-existent illnesses and alcoholism also influence the host response. Tempting though it may be to ascribe the metabolic derangements in tuberculosis to stress, the complex host parasite relationship suggests otherwise. Serum levels of adrenocortico-tropin hormone, cortisol and T3 have been found to be decreased in patients with tuberculosis.33 Clinical and sub-clinical hypoadrenalism has been described frequently in these patients.34 These abnormalities make the patients ability for a stress response doubtful. The endocrine function of pancreas has also been found to be adversely affected in severe tuberculosis, and a higher incidence of chronic calcific pancreatitis occurs in patients w i t h concomitant diabetes and tuberculosis35 leading to an absolute orrelative insulin deficiency state. A family of fatty-acid-transporter proteins in the tubercle bacillus may cause dysregulation of energy homeostasis in the disease.36 The fatty acid transporter protein gene of mycobacterium when expressed in mammalian

hepatocytes increases preferentially the uptake of long chain fatty acids (LCFAs). The LCFAs are an important source of energy for most organisms and also function as blood hormones regulating key functions such as hepatic glucose metabolism.36 Derangements of lipid metabolism have been described in patients with tuberculosis.37 Effect of Anti-tuberculosis Drugs on Blood Sugar Level Rifampicin is a powerful inducer of the hepatic microsomal enzyme system and frequently interacts with other drugs. It lowers the serum levels of sulphonyl ureas and biguanides.38 Hence, patients with co-existing diseases should have their doses of oyal anti-diabetic dnigs adjusted upwards according to plasma glucose concentration. Takayasu et al39 observed that Rifampicin induced an early phase hyperglycemia which he attributed to augmented intestinal absorption. However, no case of overt diabetes was observed and it was felt that Rifampicin was not diabetogenic. Rifabutin, a newer rifamycin, also induces hepatic metabolism but is not as potent an inducer as is Rifampicin.40 Although its interactions with Zidovudine, Fluconazole and Clarithromycin have been studied extensively, the effects of concomitant administration of oral hypoglycemics have still to be clarified. Other anti-tuberculosis drugs interfere very rarely with blood sugar level. An overdose of INH41 may cause hyperglycemia while in rare circumstances, diabetes may become difficult to control in patients on Pyrazinamide.42 Hypoglycemia may rarely be seen in patients on Ethionannde.43 Clinical Aspects of Concomitant Tuberculosis and Diabetes Symptoms of one disease often mimic those of the other. Loss of weight, loss of appetite and lassitude are common to both the diseases. The association is more common among those above 40 years of age and males appear to be at a somewhat greater risk compared with females. Holden and Hiltz43 described 106 patients with tuberculosis and diabetes in which diabetes appeared first in 48, while tuberculosis appeared first in 40 and the two conditions were diagnosed simultaneously in 18 patients, as did Sumrova come to similar findings.17

AMRIT GUPTAN AND ASHOK SHAH

Patients of tuberculosis who develop diabetes have greater clinical severity at the onset, a greater degree of lung involvement and residual changes. The diabetics who develop pulmonary tuberculosis have higher blood sugar levels and develop complications like coma and diabetic microangiopathies.17
Radiological Aspects of Concomitant Tuberculosis and Diabetes

2. 3. 4. 5.

The radiological aspects of concomitant tuberculosis and diabetes were first described by Sosman and Steidl 4 4 . They reported that diabetic tuberculosis has a special radiological pattern consisting of confluent, cavitary, wedge shaped lesions spreading from the hilum towards the periphery, predominantly in lower zones, to the extent of around 20%.I4-4S Marias46 observed lower lung field tuberculosis in 29% of patients with diabetes, as compared to 4.5% in the non-diabetic patients. However, in other studies 47 , cavitary disease and multi-lobe involvement was found to be more common in patients with pulmonary tuberculosis and diabetes. A study48 to evaluate the CT features of pulmonary tuberculosis in immunocompromised and diabetic patients compared with patients with no underlying disease was done in Japan. Diabetics and immunocompromised patients had a higherprevalence of nonsegmental distribution (30%) and multiple small cavities (44%). Unusual localisation of the disease including basal segment of lower lobe, anterior segment of upper lobe or right middle lobe occurred equally in both the groups (17% and 18%). Earlier studies17-43 had also noted that these patients have a greater extent of lesion and more frequent cavitation. Besides, there is more frequent tuberculous pleural effusion 49,51.52 Since the association of diabetes only and none of the other factors was found to be statislically significant, such radiographic presentations should be first investigated for the presence of diabetes.
Principles of Management of Co-existent Tuberculosis and Diabetes53,54

6.

7.

8. 9.

Patients with poor diabetic control should be hospitalised for stabilizing their blood sugar level. Ideally, insulin should be used to control blood sugar levels. Oral hypoglycemics should be used only in cases of mild diabetes. Drug interaction with Rifampicin should be kept in mind. Glycaemic equilibrium is essential for the success of anti-tuberculosis therapy and must be achieved in every patient with co-existent disease. The goals of therapy are: fasting plasma glucose < 120 mg% and glycated Hb <7%. Vigorous and good chemotherapy is essential. Monitoring for adverse effects, particularly of hepatic and nervous systems should be done. Use of potentially neuropathic agents (INH) in patients with peripheral neuropathy demands special consideration with mandatory administration of pyridoxine. Duration of chemotherapy is entirely dependent upon the control of diabetes and response of the patient to treatment. A longer treatment course may be needed. Supportive therapy for diabetes must be actively pursued. Management of co-existent illnesses, malnutrition and rehabilitation of the alcoholic diabetic remain of prime concern.

PROPHYLAXIS

1. Proper care.

All diabetics require regular medical examination and bi-annual chest radiograph. This should be followed more rigorously in patients who are more than 40 years of age or with weight less than 10% of the ideal body weight. Any diabetic- who suddenly develops cough, loss of weight, abnormal chest radiograph or needs increasing doses of insulin to control blood glucose should be investigated for presence of tuberculosis. The American Thoracic Society recommended, in 198656, that diabetics, particularly poorly controlled IDDM patients, should be given INH chemoprophylaxis. Although, primary chemoprophylaxis may be useful in certain communities with high prevalence rates of diabetes and tuberculosis, like the Oglala Sioux natives of North America, there seems to be no reason for using primary chemo-

TUBERCULOSIS AND DIABETES : AN APPRAISAL

prophylaxis in well controlled diabetic patients, in general. Secondary chemoprophylaxis in tuberculin positive diabetic patients is generally recommended, although some investigators have questioned the actual benefit to the diabetic patient.56 Amrit Guptan & Ashok Shah Department of Respiratory Medicine, Vallabhabhai Patel Chest Institute, University of Delhi, Delhi REFERENCES
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patients who had no underlying disease. A J R 1992. 159, 1175 Kuaban C, Fotsin JO K o u l l a Shiro S et. al. Lower l u n g field tuberculosis in Yaounde, Cameroon. Central Afr J Mcd 1996, 42, 62 Boucot K. Diabetes m e l l i t u s and pulmonarv tuberculosis. J Chronic Di.i 1957, 6, 256 Spencer D, Yagan R, Blinkhorn R, Spagnuolo P.I Anterior segment upper lobe tuberculosis in the adult Occurrence in primary and reactivation disease. Chest 1990, 97, 493. W ilcke JT, Askgaard DS, NyboJensen B, Dossing M. Radiographic spectrum of adult pulmonary tuberculosis in a developed country. Respir Mcd 1998, 92, 493 Shah A : Tuberculosis and diabetes. Ann Indian Med A.isoc Accid Med Specialities 1991, 5, 54 American Diabetes Association : Standards of medical care for patients with diabetes mellitus (Position Statement). Duiheie.i Care 1997, 20 (Suppl 1) s8 American Thoracic Society. Treatment of tuberculosis and tuberculosis infection in adults and children. Am Rev Re.ipir Dix 1986, 134, 355 Rose D, S i l v e r A, Schechter C. Tuberculosis chcmoprophylaxis for diabetics : Are the benefits of isoma/id worth the risk? Mount Sinai Med J 1985, 52, 253.

APPENDIX Criteria for the Diagnosis of Diabetes Mellitus*

1. Symptoms of diabetes plus casual2 plasma glucose of > 11.1 mmol/L(200mg/dL) or 2. Fasting 3 plasma glucose of > 7.0 mmol/L (126 mg/dL)
or

3. 2h plasma glucose of > 1 1.1 mmol/L (200 mg/dL) during an OGTT with 75 g anhydrous glucose * Adapted from the report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, l997. 1. The classic symptoms of diabetes include polyuna. polydipsia and unexplained weight loss. 2 Casual is defined asalany time of the day without rcgaid to time since last meal 3 Fasting is defined as no caloric intake for at least 8 hours. In the absence of unequivocal hypcrglycaemia with acute metabolic decompensation, these c r i l e n a should be confirmed In repeat testing on a di Herein day. The third measure is not lecommendcd for routine clinical use.