Medicine
Markers of Tuberculosis in Pleural Effusion :-
Interferon gamma > 140 IU
Adenosine deamylase > 40
PCR
Roth Spots :-
seen in the retina of Myeloproliferative, Lymphoproliferatie disorders and Infective endocarditis.
Spiral CT scan :-
for pulmonary embolism
Addison’s disease :-
The patients have microcardia (small heart).
Kikuchi’s disease :-
Mostly in Japan, in young girls, bilateral lymphadenopathy with high grade fever is seen in this disease.
The National Institute for Health and Clinical Excellence (NICE) and the National Collaborating Centre for Chronic Conditions, in conjunction with the British Hypertension Society (BHS) have today (Wednesday 28 June) launched the keenly awaited updated clinical guideline on the management of hypertension:-
The updated recommendations in the guideline include the following:
• In hypertensive patients aged 55 and over, or Black patients* of any age, first choice of initial therapy should be either a calcium channel blocker or a thiazide-type diuretic.
* Black patients are those of African or Caribbean descent, and not mixed race, Asian or Chinese patients
• In hypertensive patients younger than 55, first choice initial therapy should be an ACE inhibitor (or an Angiotensin receptor blocker if an ACE inhibitor is not tolerated).
• If initial therapy was with a calcium channel blocker or thiazide-type diuretic and a second drug is required, add an ACE inhibitor (or an Angiotensin receptor blocker if an ACE inhibitor is not tolerated). If initial therapy was with an ACE inhibitor, add a calcium channel blocker or a thiazide-type diuretic.
• If treatment with three drugs is required, the combination of ACE inhibitor (or an Angiotensin receptor blocker if an ACE inhibitor is not tolerated), calcium channel blocker and thiazide-type diuretic should be used.
The decision not to recommend Beta-blockers for first line therapy is based on evidence that suggests that they perform less well than other drugs, particularly in the elderly, and the increasing evidence that the most frequently used Beta-blockers at usual doses carries an unacceptable risk of provoking type 2 diabetes. The guideline also makes recommendations beyond a 3-drug combination, where, although the evidence is less certain, the GDG took into account existing guidelines and constructed recommendations most compatible with current good practice.
Hypertensive Crisis:-
Only HTN.
Hypertensive Emergency:-
With Complications.
Accelerated Hypertension:-
End Organ Damage.
The young patient with paroxysm of palpitations:-
at rest —-> mostly its paroxysmal svt
after exercise —-> rvot – vt.
Side effects of captopril:-
Angioedema.
Mechanical Valves induce haemolysis.
Regarding contraceptive when a male patient is on thalidomide , the answer is a single barrier method:-
Because of the known human teratogenicity of thalidomide, thalidomide is contraindicated in women who are or may become pregnant and who are not using the two required types of birth control or who are not continually abstaining from heterosexual sexual contact. If thalidomide is taken during pregnancy, it can cause severe birth defects or death to an unborn baby. Thalidomide should never be used by women who are pregnant or who could become pregnant while taking the drug. Even a single dose [1 capsule (regardless of strength)] taken by a pregnant woman can cause birth defects. If pregnancy does occur during treatment, the drug should be immediately discontinued. Under these conditions, the patient should be referred to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure to THALOMID® (thalidomide) must be reported to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436.
Because thalidomide is present in the semen of patients receiving the drug, males receiving thalidomide must always use a latex condom during any sexual contact with women of childbearing potential. The risk to the fetus from the semen of male patients taking thalidomide is unknown.
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Inducers of the P450 system include
antiepileptics: phenytoin, carbamazepine
barbiturates: phenobarbitone
rifampicin
St John’s Wort
chronic alcohol intake
griseofulvin
smoking (affects CYP1A2, reason why smokers require more aminophylline)
Inhibitors of the P450 system include
antibiotics: ciprofloxacin, erythromycin
isoniazid
cimetidine, omeprazole
amiodarone
allopurinol
imidazoles: ketoconazole, fluconazole
SSRIs: fluoxetine, sertraline
ritonavir
sodium valproate
acute alcohol intake
quinupristin
————————————————————
Young people with septic arthritis – gonococcus; older people – Staph aureus
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Using Beta Blockers in Patients with Heart Failure
Compelling evidence now exists to support the safety and efficacy of beta-blocker therapy in patients with heart failure. Guidance on the implementation of beta-blocker therapy in these patients is provided in the following sections.
Beta-blocker therapy is appropriate in patients with New York Heart Association class II or class III symptoms resulting from left ventricular systolic dysfunction.Patient Selection
Beta blocker therapy is appropriate in patients with NYHA class II or class III symptoms resulting from left ventricular systolic dysfunction. Unless contraindicated, beta blockers should be considered a mainstay of therapy in these patients to improve symptoms and mortality and to decrease hospitalizations.
None of the trials described in this article tested the use of beta blockers in patients with NYHA class I disease. Many asymptomatic patients with left ventricular dysfunction have had a myocardial infarction sometime in the past. Data on the administration of beta blockers subsequent to myocardial infarction are compelling enough to justify the use of these agents, if tolerated, in patients with NYHA class I disease. Many of these patients have other comorbid conditions, such as hypertension or angina, for which beta blockers may also be indicated.
When beta blockers are used in patients with heart failure, they should be considered disease-modifying agents rather than “rescue” agents. Their utility lies in blocking the neurohormonal cascade that leads to progression of the disease, not in providing immediate symptomatic relief.
None of the published trials have included sufficient numbers of patients with NYHA class IV symptoms to justify the safety or efficacy of beta blockers in this group. BEST was designed to better address this issue, but the trial included relatively few patients with NYHA class IV symptoms and was stopped early. The COPERNICUS trial may provide guidance once data become available. Pending release of the COPERNICUS trial results or other data, beta blockers should not be used in patients with NYHA class IV symptoms; however, these agents may be started or resumed once NYHA class IV symptoms resolve and patients are hemodynamically stable.
When beta blockers are used in patients with heart failure, they should be considered disease-modifying agents rather than “rescue” agents. Their utility lies in blocking the neurohormonal cascade that leads to progression of the disease, not in providing immediate symptomatic relief. Thus, patients should be hemodynamically stable when beta-blocker therapy is initiated. This approach provides certain pragmatic difficulties in dealing with patients who may already be taking a number of medications and may be resistant to the thought of adding another medication at a time when they seem well. In this setting, however, the risks of polypharmacy seem to be justified when compared to the mortality benefit of beta-blocker therapy.
Beta blockers appear to be effective irrespective of the etiology of the heart failure. Similarly, no age-specific phenomena have been reported. Preliminary data from BEST imply that racial differences may exist in the response of patients with heart failure to beta blockers; however, conclusions about this issue must await release of the trial results.
Carvedilol is the only agent labeled by the FDA for use in patients with heart failure. It is also the only agent that is available in the appropriate starting dosage (3.125 mg twice daily). The starting dosages for metoprolol tartrate, metoprolol succinate and bisoprolol require that the tablet in the smallest available dose size be split into fourths, which may be a cumbersome task for some patients. In addition, dividing the metoprolol succinate tablet into fourths may disrupt the delivery system, although it is not known if tablet division would have an adverse clinical impact. Metoprolol tartrate and bisoprolol are the least expensive of these agents (Table 6).
Once the patient has tolerated the starting dosage of the selected beta blocker, the dosage should be doubled every two to four weeks as tolerated. While the dosage is being titrated, the patient should be monitored for signs of worsening heart failure, hypotension or bradycardia. If symptoms develop, the dosage may need to be held at the current level or decreased; in some patients, the drug may need to be stopped. Otherwise, the dosage should be increased until the target dosage is achieved or the patient is receiving the maximal tolerated dosage, if below the target level. Once the desired dosage has been reached, no further adjustments need to be made. Even if the patient’s symptoms stabilize or the ejection fraction normalizes, most experts recommend continuing beta-blocker therapy indefinitely.
Other Pharmacologic Therapy
In all of the published mortality trials, beta blockers were added to background therapy with ACE inhibitors, diuretics and, sometimes, digoxin (Lanoxin). All patients for whom beta-blocker therapy is indicated should also be taking an ACE inhibitor as tolerated, unless contraindications exist. Diuretics should be titrated as needed for symptoms of volume overload. Digoxin may be used to improve symptoms, but it has never been shown to improve mortality. Spironolactone (Aldactone) has recently been shown to improve mortality in heart failure and its use is indicated in patients with systolic dysfunction who have symptoms at rest or a recent history of symptoms at rest.13
The long list of potential medications poses challenges for both the physician and the patient. Close surveillance for volume, electrolyte and hemodynamic changes is essential. The frequency of office monitoring is based on the characteristics and needs of the individual patient.
Contraindications to Beta Blockers
Beta blockers should not be administered to patients with heart failure who have bradycardia, heart block or hemodynamic instability. Patients hospitalized for heart failure may receive beta blockers only after they have been stabilized. Patients with severe asthma should not be given beta blockers, although those with milder symptoms may be able to tolerate these medications.
Members of various medical faculties develop articles for “Practical Therapeutics.” This article is one in a series coordinated by the Department of Family Medicine at the University of Michigan Medical School, Ann Arbor. Guest editor of the series is Barbara S. Apgar, M.D., M.S., who is also an associate editor of AFP.
Long-term benefits of using Beta blowckers :-
• improved survival
• improved control of heart failure
• reduced need for hospitalisation
• improved quality of life
• improved left ventricular ejection fraction
Mechanism of action
The benefit of beta blockers almost certainly depends on blockade of beta-1 receptors. This action is consistent with the large body of data documenting high plasma catecholamines in severe heart failure, and more sophisticated studies demonstrating increased cardiac sympathetic activity and catecholamine release. Possible mechanisms for beta receptor blockade improving survival include:
• antiarrhythmic action
• anti-ischaemic action
• attenuation of catecholamine toxicity
• reduced cardiac remodelling.
Metoprolol and bisoprolol are both cardioselective beta blockers acting primarily on beta-1 receptors. By comparison, carvedilol is a non-selective beta blocker with additional alpha-receptor blocking and antioxidant properties. Based on the unequivocal treatment benefits seen in the CIBIS2 and MERIT3 studies, the principal mechanism by which these drugs improve outcome in heart failure is likely to be via their beta-1 receptor blocking action. We will not know if the additional properties of carvedilol are important, and whether carvedilol actually produces a larger benefit than standard beta blockers, until the results of current head-to-head comparisons are reported.
Indications other than systolic heart failure
There are two other types of heart failure where use of beta blockers provides clear benefits and little risk.
Atrial fibrillation
In some patients, atrial fibrillation with rapid ventricular response is a major factor which worsens the severity of their heart failure. In this situation, controlling the ventricular response alone can produce a major improvement in heart failure. Digoxin is usually effective in this situation. Beta blockers are also effective in slowing the ventricular rate, and rarely worsen the situation providing ventricular systolic function is reasonably well preserved.
Diastolic heart failure
Possibly as many as one third of patients with heart failure have normal ventricular systolic function. In these patients, the primary cardiac abnormality leading to heart failure is an abnormality of ventricular filling. They have so-called ‘diastolic heart failure’. In this situation, beta blockers can also produce improvement with little risk of the patient deteriorating. The drugs slow the heart rate and allow a longer period for diastolic filling, particularly if atrial fibrillation is also present. Patients with mitral stenosis are the best example. Beta blockers can also facilitate diastolic filling by improving abnormal myocardial relaxation, for example in patients with diastolic failure due to severe left ventricular hypertrophy. This is generally in patients with severe, long-standing, poorly-controlled hypertension.
Clinical trials in systolic heart failure
Patients with primarily systolic heart failure with low ejection fraction may deteriorate when given a beta blocker. Paradoxically, it is this very group of patients that had unequivocal long-term benefits in recent trials (see box).
Carvedilol trials
In the meta-analysis of beta blockade1, there were eight trials of carvedilol, with a total of 1657 patients. Carvedilol appeared to reduce total mortality by 49%. However, only one of the eight individual carvedilol trials produced a statistically significant reduction in total mortality. This trial markedly influences the overall estimate of the treatment benefit of carvedilol. The ANZ trial was the largest of the carvedilol trials (415 patients). Although it found a 27% reduction in total mortality and a 30% reduction in hospitalisation, neither result was statistically significant. None of the carvedilol trials were sufficiently powered to be able to detect a significant difference in these end-points.
It was pooled data from a number of relatively small trials of carvedilol which convinced the Therapeutic Goods Administration to approve carvedilol for systolic heart failure in 1998. Carvedilol requires an authority prescription under the Pharmaceutical Benefits Scheme.
CIBIS-II
CIBIS stands for Cardiac Insufficiency Bisoprolol Study.2 Bisoprolol is a beta-1 selective blocker not available in Australia. A total of 2647 patients, mostly in Class III heart failure, had either bisoprolol or a placebo added to optimal therapy. (Most patients were taking a loop diuretic and ACE inhibitor in reasonable doses, and 50% were taking digoxin.) The trial was stopped early because of an unequivocally statistically significant reduction in total mortality of 34%. There were also significant reductions in sudden death (44%) and in hospitalisation for congestive cardiac failure (20%).
MERIT-HF
MERIT-HF stands for Metoprolol Randomised Intervention Trial in Heart Failure.3 Metoprolol is a beta-1 selective blocker which has been available in Australia for many years. However, this trial used a slow-release formulation not currently available in Australia. A total of 3991 patients, with predominantly Class III heart failure, were randomised to have either a placebo or metoprolol, added to the optimal conventional therapy of a loop diuretic and ACE inhibitor. The trial was stopped early because of an unequivocally statistically significant reduction in total mortality of 34%. There was also a significant reduction in sudden death (41%).
COPERNICUS
This stands for Carvedilol Prospective Randomized Cumulative Survival Trial. This trial compared carvedilol with placebo in 2289 patients with severe Class III/IV heart failure and ejection fraction of less than 25%. Carvedilol or placebo was added to optimal conventional therapy for heart failure. The trial has been stopped prematurely because of a beneficial effect of carvedilol on the primary end-point of all cause mortality. The results have been presented at an international meeting, but have not yet been published. Carvedilol was associated with a 35% reduction in total mortality.
In COPERNICUS, the annual mortality in the placebo group (18.6%) was higher than in either the MERIT (11.0%) or CIBIS (13.2%) studies. This reflects a generally sicker group of patients in COPERNICUS with more severe heart failure. As a result, the same relative risk reduction has resulted in a larger absolute mortality benefit and a smaller number needed to treat. However, the relative risk reduction was similar between the three studies.
Unresolved issues
Severity of heart failure
Both the CIBIS and MERIT trials enrolled predominantly patients with Class III heart failure. The number of patients with more severe Class IV heart failure was small (17% and 3% respectively) and the treatment benefit was not statistically significant in this sub-group. Nevertheless, on average, the magnitude of benefit was not different in the patients with more severe failure. The COPERNICUS study enrolled more patients with Class IV heart failure, yet produced virtually the same relative reduction in total mortality. It must be emphasised that patients with very severe heart failure are a much more difficult group in which to start beta blockers because of the risk of exacerbating their already severe heart failure.
Co-medication
Digoxin
Approximately 50% of patients in both the CIBIS and MERIT studies were taking digoxin. Randomisation was not performed in relation to digoxin, but there was no difference between the treatment benefit from beta blockade in those taking and those not taking digoxin. Given that there is no mortality benefit from digoxin4, it seems logical to recommend that patients in sinus rhythm should have a beta blocker added to optimal therapy before digoxin is introduced. However, this recommendation is not based on any definitive data.
Spironolactone
In the recently published RALES trial5 there was a highly significant 30% reduction in total mortality when a low dose of spironolactone (25 mg daily) was added to conventional therapy in patients with very severe heart failure. Only 10% of the patients were taking beta blockers. The patients in this study had much more severe heart failure than in most of the beta blocker studies. As a result of this trial, many physicians are now including low dose spironolactone as part of ‘optimal conventional therapy’ in patients with very severe heart failure before introducing a beta blocker.
Antiarrhythmics
There is no consensus on the role of conventional antiarrhythmics in severe heart failure. What is clear is that the beta blocker trials have shown a clear reduction in the very substantial risk of sudden death. This is assumed to be because they prevent ventricular tachyarrhythmias. It seems logical to recommend that, in the absence of documented sustained ventricular tachycardia, beta blockers should be used before any consideration of antiarrhythmic drug therapy.
Recommendations
A beta blocker should be considered for all patients with systolic heart failure who are stable on optimal doses of a diuretic and ACE inhibitor. If patients are not stable on optimal treatment, then digoxin and perhaps spironolactone should be added before a beta blocker.
Which beta blocker to use?
Both carvedilol and standard beta-1 blockers appear to be effective. There are currently multiple trials in progress of carvedilol in various different groups of heart failure patients. The results should tell us if carvedilol is more effective than standard beta-1 blockers. Carvedilol has the advantage of a lower dose formulation for starting treatment. However, carvedilol is also much more expensive than standard beta blockers (up to 10 times the cost of the standard form of metoprolol).
What dose for starting therapy?
Starting a beta blocker can make heart failure worse, so low doses are used. For most patients you can cautiously start with carvedilol 3.125 mg twice a day or metoprolol 12.5 mg twice a day. Patients with very severe heart failure should probably start on only a morning dose.
How rapidly can the dose be increased?
The dose can be doubled every 2-4 weeks providing the patient is stable. If the heart failure has deteriorated, the doses of diuretic, ACE inhibitor or digoxin should be adjusted first before any further increase in beta blocker. The dose of beta blocker may need to be reduced, particularly if there is undue bradycardia or worsening cardiac conduction.
What is the target dose?
For carvedilol, the target dose is 25 mg twice a day. For metoprolol it is 100 mg twice a day. Many patients will not reach these doses. Substantial benefits are almost certainly achieved with doses which are lower than these targets.
What about patients who are already taking a beta blocker?
Some patients who have been taking beta blockers long term for other indications such as angina or hypertension will develop heart failure. The clinician must first determine why the patient has developed heart failure (for example, new atrial fibrillation, silent myocardial infarction). Both the underlying cause and the heart failure must be treated appropriately. In many patients the degree of heart failure may not be too severe, and the beta blocker will be able to be continued. In other patients it may be necessary to either reduce the dose or even withdraw the beta blocker completely until the heart failure is under control. Once this has been achieved, the beta blocker should be cautiously reintroduced.
Who should manage the patient?
These patients are extremely fragile and difficult to treat. Occasional patients will deteriorate markedly after starting a beta blocker and may even require intensive or coronary care with intravenous beta agonist support. In Australia carvedilol can only be started in hospital patients. General practitioners should always consider involving a physician or cardiologist before starting or changing beta blocker therapy.
———————————————————–
MONITORING FOR
HEPATOTOXICITY DURING
ANTITUBERCULOSIS TREATMENT
GENERAL RECOMMENDATIONS
A consensus statement of
the Tuberculosis Control Coordinating Committee of
the Hong Kong Department of Health and
the Tuberculosis Subcommittee of
the Coordinating Committee in Internal Medicine of
the Hospital Authority, Hong Kong
April 2002
AUTHORS
TAM Cheuk-ming * FRCP(EDIN), FHKAM(Medicine)
YEW Wing-wai # FRCP(EDIN), FHKAM(Medicine)
LEUNG Chi-chiu * MRCP(UK), FHKAM(Medicine)
CHAN Yuk-choi @ FRCP(EDIN), FHKAM(Medicine)
* TB & Chest Service, Department of Health, Hong Kong SAR, China
# Department of Respiratory Medicine, Grantham Hospital, Hong Kong SAR, China
@ Department of Respiratory Medicine, Wong Tai Sin Hospital, Hong Kong SAR, China
Corresponding Author: TAM Cheuk-ming
Address: Wanchai Chest Clinic, 99 Kennedy Road, Hong Kong
April 2002
ACKNOWLEDGEMENT
This statement is prepared by a Working Group consisting of the above authors on behalf of
the Tuberculosis Control Coordinating Committee of the Hong Kong Department of Health
and the Tuberculosis Subcommittee of the Coordinating Committee in Internal Medicine of
the Hong Kong Hospital Authority. The authors would like to thank the members of the two
Committee/ Subcommittee. The members are: Dr. CK Chan, Dr. HS Chan, Dr. KS Chan, Dr.
WM Chan, Dr. WNK Chen, Dr. MT Cheung, Dr. K Choo, Dr. CM Chu, Dr. DLK Dai, Dr. SS
Ho, Dr. DSC Hui, Dr. KM Kam, Dr. CW Lam, Dr. CY Tam, Dr. KWT Tsang, Dr. ML Wong, Dr.
WKS Yee, Dr. WC Yu, and Dr. RWH Yung.
[Extracted from Annual Report (Suppl) 2002, TB & Chest Service, Department of Health, Hong Kong]
Background
Treatment of tuberculosis (TB) involves several drugs in combination for six
or more months. An updated set of guidelines has been published by a working
group of the Tuberculosis Control Coordinating Committee/ Tuberculosis & Chest Subcommittee of the Department of Health and the Hospital Authority
(TBCCC/TBSC).1 In view of the concern about the risk of hepatotoxicity, this short paper has been prepared to address the issue in greater depth.
Many of the commonly used anti-TB drugs are associated with significant
potential of causing hepatotoxicity. While the occurrence of drug-induced hepatitis is difficult to predict, it has been observed that certain patients are at higher risk of developing drug-induced hepatitis during the course of anti-TB chemotherapy.
These include patients with pre-existing liver diseases, particularly those associated with chronic viral infection due to Hepatitis B, Hepatitis C, and HIV, the alcoholics, the elderly and the malnourished.2-4
The exact role of regular monitoring of liver function tests in patients
receiving antituberculosis drugs remains controversial. Certain guidelines only emphasize the need of clinical monitoring without mentioning regular biochemical monitoring,5,6 while a number of authorities recommend routine biochemical monitoring among the high risk groups.7-9
Transient changes in alanine transaminase and bilirubin levels are relatively
common during antituberculosis chemotherapy and do not signify true hepatotoxicity.
However, progressive rise in alanine transaminase and bilirubin levels is much more ominous. Existing data do not allow reliable prediction of the exact clinical course of asymptomatic patients with moderate degree of biochemical derangement.
Opinions therefore differ as at what cut-off level of liver dysfunction should
modification of treatment regimen be initiated. For the alanine transaminase level, some recommend stopping the hepatotoxic drugs three times or above that of normal,8-12 while others recommend five times.6,7,13 The recommendations regarding the level of bilirubin are also not uniform.13
Furthermore, opinions on the frequency and duration of biochemical
monitoring also differ. While more frequent testing may be more likely to pick up those cases with rapid progression, cost-effectiveness and patient acceptance are practical issues among those without clinical symptoms. Whether monitoring should be performed throughout the whole course of anti-TB treatment, or just during the initial treatment phase also requires deliberation. More recently, a number of fatal cases of drug-induced hepatitis have been
reported during the course of treatment of latent TB infection (LTBI) since the publication of the guidelines for the treatment of LTBI by ATS/CDC.14 Although the absence of data on the denominator precludes an accurate assessment of the risk, an updated statement has been promulgated recommending more vigilant measures in liver function and clinical monitoring.13
A recent study in Hong Kong showed that among patients treated with
anti-TB drugs, the incidences of liver dysfunction and symptomatic hepatitis were
rather high among Hepatitis B carriers compared with non-carriers2 (Table 1).
Another local study also quoted a significant rate at 12% of clinically symptomatic
hepatic dysfunction among 1,181 hospital patients who received rifampicin, isoniazid
with or without pyrazinamide and other drugs.15 Although the definitions employed
for those hepatitic reactions are not exactly similar, the rates of liver dysfunction
found in these local studies are clearly higher than those reported elsewhere.16,17
Recommendations
Basing on the available clinical information, international guidelines, and
experiences from local experts, a consensus statement has been prepared by a working
group of the TBCCC/TBSC on clinical and biochemical monitoring of hepatotoxicity
during anti-TB treatment in the local setting:
(a) For all patients undergoing treatment with potentially hepatotoxic anti-TB drugs,
health education should be provided to alert them of the symptoms suggestive of
hepatitis, which include loss of appetite, nausea, vomiting, fever, and jaundice.
They should be advised to report such symptoms promptly to the nursing or
medical staff should these arise.
(b) During medical consultations in the course of anti-TB treatment, all patients
should be assessed clinically for symptoms and signs suggestive of hepatitis.
(c) Directly observed treatment (DOT), apart from ensuring treatment adherence,
also allows health care workers to monitor the patients closely for such
symptoms and signs.
(d) Patients developing symptoms suspicious of hepatitis should have liver function
tests checked, and in the case of clinical suspicion of significant hepatitic
reactions, the anti-TB drugs may have to be stopped even before the availability
of the test results.
5
(e) Patients at risk of developing drug-induced hepatitis should be identified at the
beginning of the treatment course. Patients with pre-existing liver diseases, the
alcoholics, the elderly and the malnourished constitute the most clearly defined
risk groups. Liver function tests should therefore be checked before the start of
anti-TB treatment.
(f) For those who belong to the risk groups as mentioned in (e), it would be
desirable to monitor liver function tests once every two weeks during the initial
two months of treatment, or more frequently as clinically indicated.
(g) In view of the high Hepatitis B carrier rate and the high incidence of
drug-induced hepatic dysfunction among them locally, it is also desirable to
check the HBsAg status of patients who need to receive anti-TB treatment.
Close clinical and biochemical monitoring should also be considered for
hepatitis B carriers as in (f).
(h) Regarding the cut-off levels of liver dysfunction for withholding potentially
hepatotoxic anti-TB drugs in patients without symptoms, the followings are
recommended:
(i) Alanine transaminase level rising to three times or above the upper limit of
normal;
(ii) Bilirubin level rising to two times or above the upper limit of normal.
Discussion and conclusions
Biochemical monitoring is not a replacement for close clinical monitoring.
Clinical heterogeneity dictates that each case should be assessed individually with the
monitoring procedures tailored accordingly. More frequent and intensive
biochemical monitoring may be indicated in situations where the patient’s condition
or the liver enzyme levels change rapidly. If the anti-TB drugs are given for the
treatment of latent TB infection, the standard for safety monitoring is clearly higher
than that for the treatment of active disease.18
Not uncommonly, mildly elevated pretreatment liver enzymes are
encountered among TB patients without any other evidence of liver disease. When
these patients are given the full treatment regimen,1 their enzyme levels are often
observed to revert to normal and this phenomenon is presumably related to the
6
resolution of hepatic TB microgranulomas. However, for those patients with
evidence of underlying chronic liver diseases, anti-TB drugs should be started
carefully. Depending on the nature of the underlying liver problem, it may be
necessary to begin with a potentially less hepatotoxic combination of drugs, and then
modify the regimen according to tolerance.
If significant drug-induced hepatitis develops, careful balance of all factors
is required to decide on when and how to resume treatment. In case of doubt,
experts in the field should be consulted. It should be noted that patients with active
TB disease would develop detrimental consequences if the TB is left untreated,
particularly if the disease is extensive. Hence, the decision on when to resume
treatment with anti-TB drugs should be made not only by the time the liver function
tests reverting to the normal or pretreatment level, but also on the rate of TB disease
progression and the disease severity. Sometimes, a regimen with less hepatotoxic
drugs or a combination of drugs without potential hepatotoxicity may have to be tried
first, with the more potent but potentially hepatotoxic drugs added subsequently one
after the other (Table 2). It is generally desirable to include both isoniazid and
rifampicin in the final regimen whenever possible, so that the duration of treatment
does not need to be excessively prolonged. During resumption of the treatment, the
liver chemistry should be closely monitored, and the frequency of monitoring usually
depends on the severity of the liver dysfunction that has had occurred and the drugs
on trial. It has to be noted that the cause of that hepatitis, apart from being
drug-induced, could be due to alternatives such as viral infections, or induction by
other drugs used at the same time. Resumption of treatment utilizing the original full
drug regimen may rarely be possible.
Although there has been substantial progress in the treatment of certain liver
diseases, like chronic viral hepatitis, the implications of these advances on the
treatment of tuberculosis have not yet been fully clarified. The above guidelines and
recommendations need to be reviewed periodically with the availability of future
updates in scientific data and medical literature, as well as further accumulation of
local experience.
7
Table 1. Rate of liver dysfunction and symptomatic hepatitis among patients given
anti-TB drugs, among HBV carriers as compared with non-carriers, and among HBV
carriers not given anti-TB drugs2
HBV carriers given
anti-TB drugs Non-carriers given
anti-TB drugs
HBV carriers not
given anti-TB drugs
Total number 43 276 86
Liver dysfunction * 15 (34.9%) 26 (9.4%) 7 (8.1%)
Symptomatic
hepatitis #
7 (16.3%) 13 (4.7%) 1 (1.2%)
* Liver dysfunction is defined as an increase in ALT levels to 1.5 times above the upper limit of
normal on at least 2 consecutive occasions within 4 weeks. For patients with increased
pretreatment ALT, the elevation in ALT had to be greater than 1.5 times the baseline level.
# Symptomatic hepatitis is defined as the presence of malaise, nausea, vomiting, lethargy and/or
right upper quadrant discomfort together with the presence of liver dysfunction irrespective of the
severity of the biochemical abnormality.
Table 2. Anti-TB drugs and potential for hepatotoxicity
Potentially hepatotoxic drugs
Isoniazid
Rifampicin, Rifabutin
Pyrazinamide
Ethionamide, Prothionamide
Para-aminosalicylic acid
Drugs with much lower or little potential for hepatotoxicity
Streptomycin, Kanamycin, Amikacin, Capreomycin
Ethambutol Ofloxacin, Levofloxacin, Ciprofloxacin
Cycloserine
