Anti-Tuberculosis : Treatment in Liver Cirrhosis

• Cirrhosis is a widely prevalent disease that leads to immunosuppression and a higher prevalence of TB than in the general population
• However, treatment in patients with underlying cirrhosis is complicated by poor tolerance, higher incidence of hepatotoxicity, no consensus regarding monitoring and treatment regimens, and higher chances of multidrug-resistant (MDR) TB

Disseminated Liver TB

• The liver is frequently involved in disseminated TB.
• Signs and symptoms include diffuse abdominal pain or pain localizing to the right upper quadrant, nausea, vomiting, and diarrhea
• Histopathologic sections of involved liver demonstrate scattered granulomatous lesions that on gross examination have the appearance of millet seeds
• Liver function test abnormalities are common, including elevated alkaline phosphatase and transaminases in 83 and 42 percent of patients, respectively, in one series
• Cholestatic jaundice is also well documented in miliary TB.

Choice of Drugs

• There is no consensus regarding the use of antitubercular drugs in patients with cirrhosis and the potential hepatotoxicity of antitubercular drugs is a major concern
• In the setting of pre-existing liver disease, the likelihood of developing drug-induced hepatitis may be higher.
• Outcome of drug-induced hepatitis in patients with compromised liver function may be poor.
• Monitoring of drug-induced hepatitis may be confounded in the presence of underlying liver disease due to fluctuating liver function tests related to the pre-existing liver disease

Isoniazide

• A meta-analysis of six studies estimated the rate of clinical hepatitis in patients given isoniazid alone to be 0.6%
• Hepatotoxicity due to isoniazid therapy seems to be idiosyncratic in most patients and does not recur with rechallenge, hence, it can be reintroduced after complete clinical recovery

Rifampicin

• Transient elevation of hepatitis enzymes are however routinely observed in these patients
• Conjugated hyperbilirubinemia probably results from rifampicin inhibiting the major bile salt exporter pump, impeding secretion of conjugated bilirubin at the canalicular level

Pyrazinamide

• was considered the most hepatotoxic antitubercular drug.
• When the drug was first introduced in the 1950s, a high incidence of hepatotoxicity was reported and was related to the high dosage of 40-70 mg/kg used at that time.
• Toxicity is rare when pyrazinamide is used at a daily dose of < 35 mg/kg

Ethambutol

• Hepatotoxic effects of this agent are not clinically significant

TB in Compensated Cirrhosis

• have more treatment options and better tolerability
• has been no study to date comparing the full antitubercular therapy course with regimens containing only two potentially hepatotoxic drugs.
• At currently used doses, pyrazinamide has not been shown to be more hepatotoxic as compared to isoniazid or rifampicin
• Pyrazinamide is generally substituted with a fluoroquinolone or an aminoglycoside as per the clinician preference.
• It is prudent to use only two hepatotoxic drugs in treating compensated cirrhosis until a randomized controlled trial (RCT) proves the safety of low-dose pyrazinamide-containing combinations of three potentially hepatotoxic drugs 
• Proposed regimen
• rifampicin, isoniazid, pyrazinamide and ethambutol for 2 mo followed by 4 mo rifampicin and isoniazid
• rifampicin, isoniazid, fluoroquinolone/aminoglycoside and ethambutol for 2 mo followed by 4 mo rifampicin and isoniazid
• rifampicin, isoniazid, and ethambutol for 2 mo followed by 7 mo rifampicin and isoniazid.

Decompensated Cirrhosis

Child’s status	Treatment
A	Two hepatotoxic drugs can be used namely isoniazid and rifampicin with/without pyrazinamide (low dose). Duration 6-9 mo
B	Ideally one hepatotoxic drug is used in combination. Pyrazinamide generally avoided Duration generally 9-12 mo
C	No hepatotoxic drugs to be used. Can use second-line drugs like streptomycin, ethambutol, fluoroquinolones, amikacin, kanamycin for extended duration of 12 mo or more. Role of aminoglycosides may be limited due to reduced renal reserve in these patients

 References:

1. www.uptodate.com 
2. Antitubercular therapy in patients with cirrhosis: Challenges and options. World J Gastroenterol. 2014 May 21; 20(19): 5760–5772. 
3. A Guide to the Management of Tuberculosis in Patients with Chronic Liver Disease. J Clin Exp Hepatol. 2012 Sep; 2(3): 260–270.