DIABETES MAY IMPAIR TUBERCULOSIS TREATMENT RESPONSE
NEW YORK (Reuters Health) - Patients with tuberculosis and diabetes do not respond as well to tuberculosis therapy as those who are non-diabetic, Dutch researchers report.
The reason for this is unclear, but screening for and aggressively treating diabetes may improve the outcomes of patients receiving tuberculosis therapy, Dr. Reinout van Crevel, from Radboud University Medical Center in Nijmegen, note in the current issue Clinical Infectious Diseases.
The findings stem from a study of 737 Indonesian patients with tuberculosis who were screened for type 2 diabetes, also referred to as adult-onset diabetes, and then followed while receiving tuberculosis therapy.
Overall, 14.8 percent of the subjects had diabetes. Despite initially having more symptoms, the patients with diabetes had tuberculosis that was comparable in severity to that in non-diabetics.
However, after 2 months of treatment, sputum test results were more likely to be positive in diabetic patients --18.1 percent vs. 10.0 percent in non-diabetics. At 6 months, the diabetes were still significantly more likely to have positive sputum test results than the non-diabetic patients, at 22.2 percent vs. 9.5 percent, respectively.
In a related editorial, Dr. Blanca I. Restrepo, from the University of Texas Health Science Center in Houston, comments that the findings "highlight the need for further research aimed at understanding how the current global epidemic of type 2 diabetes mellitus is affecting tuberculosis control and prevention."
SOURCE: Clinical Infectious Diseases, August 15, 2007.
ACTIVE
TUBERCULOSIS SHOULD BE TREATED WITH INSULIN:
--Prof.
P.V.Rao, Nizam's Institute of Medical Sciences,
Hyderabad, India.
Diabetic patients are not only more
susceptible to infection but when infections
do occur they are more severe as the diabetic
is a compromised host. Tuberculosis infection
in diabetes mellitus is usually due to reactivation
of an old focus rather than through fresh
contact. Patients with diabetes mellitus
and tuberculosis present with more advanced
disease and have more changes in the lower
lobes. For these reasons, tuberculosis is
described as a complication of diabetes
mellitus. In U.K. tuberculosis is quoted
first among common infections in diabetes
mellitus, although the last UK publication
on increased frequency of tuberculosis in
diabetes mellitus appeared in 1948. Inspite
of successfully eradicating tuberculosis
in their communities, the American Thoracic
Society and Centers for Disease control
cautiously list diabetes mellitus as a special
situation, and prescribe chemoprophylaxis
with isoniazid in those with diabetes mellitus
and positive Heaf test. In populations of
developing countries, tuberculosis remains
a significant cause of morbidity and mortality
in both types of diabetes mellitus. Vulnerability
of Type I diabetes mellitus is amply evidenced
in many reports from many parts of the world.
The 10-year actual risk of acquiring tuberculosis
was 24.2% for 116 Type I diabetes mellitus
and 4.8 %for the rest in one study from
Chile. It was also reported in one study
that 30% of the young, undernourished, insulin-requiring
and ketosis-resistant diabetics needing
increased insulin. Tuberculosis in Type
II is not uncommon either, as 5-10% have
pulmonary tuberculosis in developing countries.
Though tuberculosis is more prevalent in
Type I diabetes mellitus, the magnitude
of the problem in Type II diabetes mellitus
should be considered with no less concern
in the purview of Type II diabetes mellitus
affecting an overwhelming larger number
of people and also emerging as a serious
public health problem in developing countries.
PANCREATIC
ENDOCRINE DEFICIENCY
A
high proportion of chronic respiratory failure
patients might have intolerance for glucose
loading but a normal insulin secretion pattern.
However in active pulmonary tuberculosis,
immunoreactive insulin, C-peptide and glucose
levels before and after glucagon stimulation
demonstrated absolute insulin deficiency
and more frequent development of severe
diabetes mellitus. Hyperglycemia in a study
of 51 patients with pulmonary tuberculosis
was at first due to relative insulin deficiency
coupled with higher pancreatic functional
reserve as tuberculosis progressed. The
functional disorders of the insular system
of the pancreas were more evident in middle-aged
and elderly patients with pulmonary tuberculosis.
Further, antituberculous therapy (ATT) was
also reported to be detrimental to serum
C-peptide as well as to the insulin sensitivity
in a study. These negative effects on the
inherent insulin resistance and rapid loss
of pancreatic residual function in chronic
tuberculosis warranted exogenous insulin
administration in these diabetics. There
is one report from Chennai, India that even
in a previously not ascertained diabetic,
ATT may affect beta-cell function and unmask
the diabetic state.
TUBERCULOUS
PANCREATITIS
Active tuberculosis should
be a leading cause differential diagnosis
in patients with enlarged pancreas when
the usual diagnostic reasoning does not
yield conclusive results. Even a clinical
diagnosis of insulinoma was no exception
for subsequent detection of active abdominal
tuberculosis on laparotomy. Tuberculosis
is one of the rarer causes of pancreatitis,
and only with the development of diabetes
mellitus might a chronic pancreatitis of
probable tuberculous origin reveal itself.
Interestingly, there was a higher prevalence
of pulmonary tuberculosis in patients with
diabetes mellitus secondary to chronic pancreatitis.
Perhaps in most, tuberculosis infections
in the pancreas is dormant, even preceding
diabetes mellitus.
TUBERCULIN
TOXICITY ON PANCREAS
Purified protein derivative
(PPD) of tuberculin is widely used for induction
and study of autoimmunity in vitro-vivo
in animals and humans, and many available
reports described its direct toxic effects
on pancreas. Glucose stimulated insulin-release,
and contents of insulin-release and glucagons
were reported as markedly reduced in isolated
human islets incubated with cytokine-rich
supernatants of blood mononuclear cells
stimulated with PPD f tuberculin. Such supernatants
of blood mononuclear cells stimulated with
purified with PPD of tuberculin were more
potent cytotoxic to human is lets in inhibiting
insulin release than any other known media.
At the 12th International Immunology of
Diabetes Workshop held during April 1993
in Oriando, Florida, one of the reviews
was on the insulitis in the NOD mouse induced
by tuberculin antigen in which diabetes
onset was delayed by insulin administration.
Thioredoxin is a more specific Mycobacterium
tuberculosis protein recently identified
with functional activity.
PITUITARY,
THYROID, AND ADRENAL DEFICIENCIES
Glucose, ACTH, cortisol,
growth hormone (GH), and prolactin (PRL)
in fasting and following insulin -induced
hypoglycemia were reported high in 96 pulmonary
and 15 hematogenous tuberculosis patients
due to stress induced by infections. Higher
levels of anti-insulin hormones exhausted
eventually due to stress induced by infection.
Higher levels of anti-insulin hormones exhausted
due to supramaximal stimulation, as measurements
of C-peptide as well as T3, T4, TSH, ACTH
and the circadian excretion of 17-OCS revealed
high frequency of absolute and relative
insufficiencies of pituitary, thyroid, and
adrenal glucocorticoid functions in pulmonary
tuberculosis. Concomitant thyroid treatment
benefited 92.8% of such 111 patients with
pulmonary tuberculosis suffering from diabetes
mellitus. In adolescents with pulmonary
tuberculosis, reduced levels of somatotrophic
hormone, immunoreactive insulin and 17-keto-steroids
were related to impaired physical development
evaluated using the main anthropometrical
tests. As endocrine insufficiencies in pulmonary
tuberculosis were pronounced, blood plasma
cortisol /insulin ratio was recommended
as a diagnostic marker for dissemination
of pulmonary tuberculosis. Supranormal concentrations
of substances cross-reactive with insulin
(SCIRI) were also frequently associated
with nonmalignant pulmonary tissue proliferation
as in tuberculosis, which might also contribute
to insulin resistance. In all these situations,
exogenous insulin not only offsets the possible
insulin administration was also known to
improve immune responses as demonstrated
in alloxan rats.
WEIGHT
LOSS
The association between
marked weight loss and diabetes mellitus
and/or tuberculosis is uncontrolled. Cachexia
may not always be the effect of diabetes
mellitus or tuberculosis, but also has a
formidable causative role in tuberculosis
infection and its therapy. To this effect,
the clinical evidence abounds. In consonance,
animal experiments demonstrated that loss
of weight was detrimental, and high protein
diet protected from mycobacterium. In diabetes
mellitus with tuberculosis, Ahuja's recommendation
is to allow calories as for standard weight,
or at least 2000-2400 kcal per day irrespective
of their absolute weight to ensure that
patient is not in negative nitrogen balance,
and also to adequately cover the insulin
doses prescribed.
ADVERSE
EFFECTS AND DRUG INTERACTIONS OFANTITUBERCULOSIS
THERAPY
Rifampicin accelerates
the metabolism of oral hypoglycemic agents,
as it is a potent hepatic enzyme-inducing
agent. It was also known to cause early
hyperglycemia in non-diabetic patients with
or without pulmonary tuberculosis, and also
to augment intestinal absorption of glucose.
Some of the adverse effects of Rifampicin
in Type I diabetes mellitus as detailed
below may well be applicable to the altered
glycemic control in Type II diabetes mellitus,
as well. Rifampicin per se, and not tuberculous
infection, Isoniazid, or Pyrazinamide, was
attributed to the increased insulin requirement
in a 54 -year old woman with Type I diabetes
mellitus.
Chronic rifampicin treatment
manifesting hypercortisolism and unstable
glycemic control led to a misdiagnosis of
Cushing 's syndrome due to occult ectopic
ACTH secretion with long-standing Type I
diabetes mellitus and active tuberculosis.
However, after withdrawal of rifampicin,
his urinary cortisol excretion returned
to normal within two weeks, as well as the
24-hour profile and dynamic tests.
Malabsorption of rifampicin
was also reported in poorly controlled diabetes
mellitus in a 14-year old year old boy with
INH resistance. Apart from causing pancreatic
hypofunction and peripheral insulin insensitivity,
long-term administration of ATT interfered
with hydrolysis and absorption of carbohydrates
in small intestine in 106 newly detected
persons with pulmonary tuberculosis.
A chemotherapeutic regimen
supplemented with insulin, glucocorticoids,
and folic acid, in particular, improved
intestinal carbohydrate absorption in them.
The epidemiological, paraclinical and therapeutical
viewpoints in 68 diabeticpatients clearly
established the efficiency of ATT in annulling
the negative influence of the diabetes mellitus
-tuberculosis morbid association.
Unfortunately, the liability
of these diabetic patients persisted in
spite of the best control of tuberculosis
by tuberculostatics. Isoniazid antagonizes
sulphonylureas and impairs insulin release
and action, and rifampicin shortens the
plasma half-life of sulphonylureas.
HEPATIC
DISEASE
In addition to the hepatotoxicity
of isoniazid, rifampicin, pyrazinamide the
ethambutol, the association of hepatic disease
with pulmonary tuberculosis and diabetes
mellitus is ubiquitous. Comprehensive examination
of 50 patients with pulmonary tuberculosis
and diabetes mellitus, confirmed chronic
active hepatitis in 3, chronic persistent
hepatitis in 8, non-specific reactive hepatitis
in 4, live cirrhosis in 3, fatty degeneration
in 10 and fibrosis of the liver in 22 patients.
CONTRAINDICATIONS
FOR ORAL ANTIDIABETIC DRUGS
Sulphonylureas are not
indicated in tuberculosis, as it is more
chronic and serious of all infections in
diabetes mellitus. They are not indicated
in diabetes mellitus associated with destruction
of pancreas either, which is the extra-pulmonary
manifestation of active tuberculosis in
many instances. Biguanides are contraindicated,
as metformin produces weight loss indicating
the role of malabsorption, particularly
in high doses, and it is also an anorectic.
Biguanides as well as sulphonylureas are
contraindicated in hepatic disease, which
is a common adverse effect of ATT. Marked
weight loss, increasing age, longer duration
of diabetes mellitus, higher insulin and
caloric needs in tuberculosis are other
important indications for withholding oral
antidiabetic therapy in diabetes mellitus.
AGING
Usual signs and symptoms
in tuberculosis may be absent or show only
a mild toxic reaction, with absence of fever
or cough. Thus, masking of serious infection
is likely in diabetes mellitus, and autonomic
neuropathy and aging facilitating it. As
non-respiratory tuberculosis presentations
are atypical or relatively insidious, delayed
diagnosis may be crippling or even potentially
life threatening. Less favorable course
and outcomes of the disease, related to
older age and late diagnosis of pulmonary
tuberculosis, were registered in 40 cases
of Type II as compared to 110 Type I diabetes
mellitus. Pulmonary tuberculosis in Type
II often runs asymptomatically and slowly,
specific changes in the lungs seem limited,
and foci of destruction are solitary and
large. Adverse reactions to respiratory
drugs such as isoniazid were also known
to increase with age. The prevalence of
tuberculosis infection was 11.3% in 228
Type II diabetes mellitus at a Spanish Health
Centre, and the average age of them was
62.6+11.4 years. As the risk tuberculosis
increases with age and years of evolution
of the disease, protocol use of PPD test
in diabetes mellitus and chemoprophylaxis
if necessary, was recommended. Elderly individuals
aged 60 and older have four to five times
the case rate of tuberculosis, and some
of their immune deficits of aging could
be the cause of tuberculosis, and some of
their immune deficits of aging could be
reversed by GH and / or IGF-1 treatments
demonstrated in humans and primates.
DEFECTIVE
LUNG DEFENCE
The lungs of diabetics with tuberculosis
show defective defence mechanisms in the
form of dystrophy of alveolar macrophages,
type II alveolocytes and fibroblasts, generalized
affection of pulmonary vessels, intensive
fiber formation and disorganization of the
pathological process. Diabetes mellitus,
and tuberculosis also increase the likelihood
of severe laryngeal injury.
RARER
MANIFESTATIONS OF TUBERCULOSIS
Papulonecrotic tuberculid
tuberculosis of maxilla, zygoma and sinus,
spindle cell pseudotumors in the lungs,
visceral neuropathy, hyperosmolar hyperglycemic
nonketotic coma, and ketoacidosis are some
of the rare presentatations recorded in
compromised diabetic hosts. Cutaneous infections
caused by Mycobacterium chelonae after self-injection
of insulin using jet injector were another
rare report of Mycobacterium related complications
in diabetes mellitus. The lesions are painful,
indurated, purplish, multiple at the injection
sites, and the culture of pus eventually
grows the atypical Mycobacterium resistant
to usual ATT. In diabetes mellitus, a superinfection
is rarely missed or a misdiagnosis of tuberculosis
is not uncommonly made for silicosis, adrenal
or disseminated histoplasmosis, meliodosis,
aspergilillosis, or coccidiodomycossis.
Such overzealous diagnosis of tuberculosis
is most certainly justified in Indian context.
The dictum that if diabetes mellitus is
not controlled, look for tuberculosis and
if tuberculosis is not controlled, look
for diabetes mellitus, still holds good.
Risk
of developing TB disease
The
following figures show the risk of developing
TB disease for three different groups of people.
Figure
1.6
TB infection and no risk
factors(about 10% over a lifetime)
TB infection and
diabetes(about 30% over a lifetime)
TB infection andHIV infection(a
very high risk over a lifetime)
For people with
TB infection and no risk factors ,
the risk is about 5% in the first
two years after infection and about
10% over a lifetime.
For people with
TB infection and diabetes, the risk
is 3 times as high, or about 30% over
a lifetime.
For people with
TB infection and HIV infection , the
risk is about 7% to 10% PER YEAR,
a very high risk over a lifetime.
In
an HIV-infected person, TB disease can develop
in either of two ways. First, a person who
has TB infection can become infected with
HIV and then develop TB disease as the immune
system is weakened. Second, a person who
has HIV infection can become infected with
M. tuberculosis and then rapidly
develop TB disease.
CONCLUSIONS:
The recommendations are
that diabetes mellitus and tuberculosis
should be treated with insulin injection,
or in case a diabetic with tuberculosis
is on oral hypoglycemic agents, it is necessary
to switch to insulin.
DIABETES MELLITUS,
TUBERCULOSIS AND INSULIN
-- Dr.P.V.RAO
Chronic and severe
tuberculous infection
· Increased susceptibility in diabetes
mellitus
· Reactivation of old focus of
infection
· More cavitations, smear-or-culture
positivity
· Deceptively mild or absent toxic
symptoms and signs
· Ineffective chemotherapy in hyperglycemia
Loss of tissue and
function of pancreas ·
Pancreatic endocrine deficiency
· Tuberculous pancreatitis
· Tuberculin toxin on the pancreas
Requirement
of high calorie, high protein diet
· Counter negative nitrogen balance
· Facilitate tuberculous therapy
· Prevent further infection, reactivation
Interactions
and adverse effects of antituberculous
drugs
· Rifampicin accelerates the metabolism
of antidiabetic drugs
· Rifampicin per se may
increase insulin requirements
· Isoniazid antagonizes sulphonylureas
· Isoniazid may rarely cause pancreatitis
· Interference with intestinal
absorption of carbohydrates
Associated hepatic
disease
· With tuberculosis and/or diabetes
mellitus
· Induced by antituberculous therapy
Contraindications
for oral antidiabetic drugs
For sulphonylureas
Tuberculosis, a serious intercurrent
illness
Pancreatic disease
Hepatic disease
For bigunides
Loss of appetite
Loss of weight
Glucose malabsorption
Aging
· Augments susceptibility to tuberculosis
· Masks tuberculous infection
· More severe Beta-cell dysfunction
· Long duration of diabetes mellitus
· Labile diabetic control
Other factors
in diabetes mellitus -tuberculosis association
· Anti-insulin stress hormone induced
by infection
· Requirement for thyroid or glucocorticoid
supplement
· Supernormal concentrations of
insulin antagonists
· Possible improvement of immune
deficits by insulin
· Defective lung defence mechanisms,
laryngeal injury
· Commonality of rare forms of
tuberculosis.
