Tuberculosis and liver are related in many ways. Liver disease can occur due to hepatic tuberculosis or the treatment with various anti-tubercular drugs may precipitate hepatic injury or patients with chronic liver disease may develop tuberculosis and pose special management problems. Tuberculosis per se can affect liver in three forms.
Can tuberculosis be treated in patients with liver disease?
Tubercular disease of liver occurring along with pulmonary involvement as in disseminated tuberculosis is treated with standard regimen for pulmonary tuberculosis. Granulomatous hepatitis and tubercular liver abscess are treated like any other extra-pulmonary tubercular lesions without any extra risk of hepatotoxicity by anti-tubercular drugs.
How is liver involvement in tuberculosis (TB) characterized?
· Summary of the literature and our data, indications of surgical treatment of hepatic tuberculosis include: (1) isolated tuberculoma, liver tuberculous abscess while anti-TB treatment effect is not obvious; (2) oppression of biliary tract causing obstructive jaundice; (3) concurrent portal hypertension or biliary tract bleeding or acute abdomen; (4) confusion with malignant …
Which medications are used in the treatment of hepatic tuberculosis (TB)?
· The treatment involves taking the two drugs, rifampin and pyrazinamide, or RIF-PZA, for two months. Cases of liver damage -- including the two reported by CDC in April -- developed in some ...
Which TB medicine affect liver?
A combination of isoniazid (INH), rifampicin, pyrazinamide, and ethambutol is the commonly recommended treatment regimen for TB. However, drug-induced liver injury (DILI) is a major adverse event of anti-TB treatment, leading to nonadherence, treatment failure, or development of drug resistance.
Can TB drugs cause liver problems?
Anti-tuberculosis treatment is known to cause liver damage in 4 percent to 11 percent of patients mandating to stop the treatment till the liver enzymes come to normal. In ~0.1 percent cases this could prove fatal.
Which is more hepatotoxic isoniazid or pyrazinamide?
(Review of side effects of drugs for tuberculosis; isoniazid alone leads to hepatitis in 0.5% of patients increasing with age from 0.3% <35, 0.8% >55 years, higher rates when it is combined with other agents; pyrazinamide found to be hepatotoxic in high doses [40 mg/kg/day], but not with lower doses – “So far there has ...
Does isoniazid cause liver damage?
Even with monitoring, isoniazid remains a major cause of acute liver failure due to idiosyncratic reactions, and is associated with several instances of acute liver failure and death or emergency liver transplanation in the United States each year.
Which TB drug is most hepatotoxic?
Among the first-line anti-TB drugs, isoniazid, rifampicin, and pyrazinamide are known to cause hepatotoxicity, but pyrazinamide attribute to a higher percentage for the drug induced liver toxicity compared to the other drugs.
Does rifampin cause liver damage?
Rifampin is associated with transient and asymptomatic elevations in serum aminotransferase and bilirubin levels and is a well known cause of clinically apparent, acute liver disease that can be severe and even fatal.
Which is more hepatotoxic isoniazid or rifampin?
In a meta-analysis, isoniazid was more likely to be associated with hepatotoxicity (odds ratio (OR) 1.6) even in the absence of rifampicin, but the combination of these two drugs was associated with higher rate of hepatotoxicity (OR 2.6) when compared to each drug on its own.
What are side effects of ethambutol?
Headache, loss of appetite, upset stomach, or nausea/vomiting may occur. If any of these effects last or get worse, tell your doctor or pharmacist promptly.
What is drug induced liver disease?
Drug-induced hepatitis is a redness and swelling (inflammation) of the liver that is caused by a harmful (toxic) amount of certain medicines. The liver helps to break down certain medicines in your blood. If there is too much medicine in your blood for your liver to break down, your liver can become badly damaged.
What is the side effect of pyrazinamide?
SIDE EFFECTS: Nausea, vomiting, loss of appetite, or mild muscle/joint pain may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.
Does INH cause elevated liver enzymes?
Severe liver injury is seen in up to 1% of the patients 2, 4. Elevations in ALT and AST can start as early as 1 week and sometimes as late as 9 months after starting treatment with INH. However, in more than half of the patients an ALT increase occurs between 1–6 months 2, 3, 5.
What is latent tuberculosis?
Latent tuberculosis occurs when a patient is exposed to the bacterium that causes tuberculosis and carries the infection, but is not infectious to others or actually sick with symptoms.
How long have TB drugs been used?
The drugs under scrutiny have been used for 30 years to treat active TB -- when patients are actually sick with the disease -- with few problems, but have been used to treat latent TB only for the past year. Officials still do not know why these problems have suddenly developed with the treatment of latent infection.
Can you take alcohol with liver disease?
Those with a history of alcoholism, liver disease or who are taking medications that pose a danger to the liver should not take these two drugs, the CDC said.
How to diagnose tuberculosis in the liver?
As in other organs, the final diagnosis of liver tuberculosis rests on the demonstration of acid-fast bacilli on direct examination or culture of tissue specimens. In needle liver biopsies, epithelioid granuloma formation can be demonstrated in 80% to 100% of cases; and caseation necrosis in 30% to 83%. Nine percent to 60% of cases show the presence of acid-fast bacilli on culture of biopsy material, more in the presence of caseating necrosis; Ziehl-Neelsen staining on tissue sections demonstrates bacilli in 0% to 45% cases. Polymerase chain reaction assays from paraffin embedded liver tissue have a sensitivity of 58% to 88% and a specificity of 96% to 100% for the detection of mycobacterial DNA 42,43; however, polymerase chain reaction (PCR) has its own limitations. Some patients with tuberculosis may have negative PCR results from liver tissue because of the paucity of mycobacteria or because of the possible reactive nature of liver granulomas. 43
What is the liver biopsy for hepatic tuberculosis?
Liver biopsy in hepatic tuberculosis shows an expansile granuloma with central caseating necrosis.
What is the hallmark of hepatic tuberculosis?
The histologic hallmark of hepatic tuberculosis is the formation of epithelioid granulomas, often accompanied by caseation and giant cells (Fig. 38-25 ). The granulomas are usually small, but may coalesce to form large nodules or masses with central liquefactive necrosis. 122 Old lesions may show fibrosis, calcification, and occasionally amyloid. 123 Hepatic tuberculosis is often accompanied by reactive hepatitis. Mycobacteria are usually difficult to detect on special stains; thus, culture and PCR assays are of significant value.
How do hepatic bacilli get into the liver?
The tubercle bacilli gain access to the liver through the hepatic artery, portal vein, or lymphatic system. 189 Hepatic tuberculosis has been classified into three forms. 189 The miliary form occurs during the course of generalized miliary tuberculosis typically without signs or symptoms referable to the liver. Tuberculous (granulomatous) hepatitis may result in unexplained fever, jaundice, and hepatomegaly. Localized hepatic tuberculosis, with signs and symptoms referable to the liver, may occur with or without biliary involvement. Hepatic parenchymal manifestations include solitary or multiple nodules, tuberculoma, or tuberculous hepatic abscess. Obstructive jaundice may result from compressive lymphadenopathy or inflammatory strictures due to tuberculous involvement of the biliary ductal epithelium.
Is tuberculosis endemic in developing countries?
Tuberculosis is endemic in developing countries. An increase in tuberculosis in the West is largely related to the increased number of immunocompromised patients, predominantly due to AIDS. 97,189,190 Mycobacterium tuberculosis and mycobacterium avium-intracellulare are the two most commonly responsible organisms. 190 Mycobacteremia with granulomatous hepatitis has been reported after intravesical instillation of bacillus Calmette-Guérin for treatment of bladder carcinoma. 191
What are the symptoms of hepatic TB?
The most common presentation of hepatic TB is abdominal pain, hepatomegaly, jaundice, fever, and chills. Alkaline phosphatase elevations and hyponatremia usually are prominent features. 114,116,117 In 65% to 78% of patients with hepatic TB, respiratory symptoms or chest radiographs suggest pulmonary TB as well. 111,114,116,117 Abdominal imaging shows liver calcifications in approximately half of patients. 111,112,118 Caseating granulomas are a hallmark of hepatic TB, particularly miliary TB in the setting of primary infection; in reactivation TB, noncaseating granulomas may be present instead ( Fig. 10-15 ). The granulomas may reside in the lobules or in portal tracts. Acid-fast stains or cultures are positive in 0% to 59% of cases, but organisms are more likely to be found with caseating necrosis. 114-116 PCR for M. tuberculosis DNA has a 53% to 88% sensitivity and a 96% to 100% specificity for detecting hepatic TB. 111,119,120 Immunocompromised patients may present with a wasting syndrome in which multiple organs, including the liver, contain necrotic miliary nodules surrounded by histiocytes that do not aggregate into well-formed granulomas. Acid-fast stain shows numerous organisms in these lesions. 121
Can hepatic granulomas be caused by TB?
Tuberculosis. Worldwide, M. tuberculosis is one of the most common causes of hepatic granulomas. The organisms may reach the liver hematogenously from the lungs, through the portal circulation in the setting of gastrointestinal tuberculosis, or via lymphatics.111 Tuberculosis (TB) can affect the liver in several forms.
What is the cause of tuberculosis?
Tuberculosis is caused by bacteria that spread from person to person through microscopic droplets released into the air. This can happen when someone with the untreated, active form of tuberculosis coughs, speaks, sneezes, spits, laughs or sings.
What is the drug that is resistant to tuberculosis?
Drug-resistant strains of tuberculosis emerge when an antibiotic fails to kill all of the bacteria it targets. The surviving bacteria become resistant to that drug and often other antibiotics as well. Some TB bacteria have developed resistance to the most commonly used treatments, such as isoniazid and rifampin (Rifadin, Rimactane).
Can anyone get tuberculosis?
Anyone can get tuberculosis, but certain factors can increase your risk, including:
Why is TB a killer?
Tuberculosis also remains a major killer because of the increase in drug-resistant strains. Over time, some TB germs have developed the ability to survive despite medications. This is partly because people don't take their drugs as directed or don't complete the course of treatment.
Is tuberculosis contagious?
Although tuberculosis is contagious, it's not easy to catch. You're much more likely to get tuberculosis from someone you live or work with than from a stranger. Most people with active TB who've had appropriate drug treatment for at least two weeks are no longer contagious.
Can you get TB from other conditions?
These are often indications of TB but can also result from other conditions. Also, see your doctor if you think you've been exposed to TB. The Centers for Disease Control and Prevention recommends that people who have an increased risk of tuberculosis be screened for latent TB infection.
Can TB cause back pain?
When TB occurs outside your lungs, signs and symptoms vary according to the organs involved. For example, tuberculosis of the spine might cause back pain, and tuberculosis in your kidneys might cause blood in your urine.
How long does it take to cure tuberculosis?
In particular, in cases of resistant tuberculosis, the WHO generally recommends a standard treatment duration of at least 18 months, as there ...
What is the pathogenesis of hepatotoxicity?
The pathogenesis of hepatotoxicity is not entirely clear but INH and RMP induced damage may involve oxidative stress, lipid peroxidation, choline deficiency leading to lowering of phospholipids protein synthesis with alteration in cell wall configuration, reduced glutathione level and activation of CYP2E1.
How much hepatotoxicity is in Indian patients?
A higher risk of hepatotoxicity has been reported in Indian patients (up to 11.5%) than in their western counterpart (up to 4.3%). The only measure available for managing hepatotoxicity is stopping the offending agents, once there is an evidence of liver damage and reintroducing the same after normalization of liver enzymes.
Can anti-tuberculosis cause liver damage?
Anti-tuberculosis treatment is known to cause liver damage in 4 percent to 11 percent of patients mandating to stop the treatment till the liver enzymes come to normal. In ~0.1 percent cases this could prove fatal. A trial conducted by botanical research group in India on Tuberculosis cases proved the efficacy of two Ayurvedic herbs taken as adjuvant, to prevent serious liver damage entirely even in high risk and immunocompromised patients and to enhance efficacy of conventional drugs on tuberculosis.
What is cirrhosis in medicine?
Cirrhosis—a state of immune system dysfunction
What is RIF in liver?
RIF is a bactericidal agent which inhibits mycobacterial DNA-dependent RNA polymerase. RIF is primarily metabolized by acetylation and glucuronidation; metabolites are excreted in the bile. Hepatotoxicity associated with RIF is usually idiosyncratic.31RIF may occasionally cause dose-dependent interference with bilirubin uptake due to competition with bilirubin for clearance at the sinusoidal membrane, resulting in mild, asymptomatic unconjugated hyperbilirubinemia or jaundice without hepatocellular damage. Conjugated hyperbilirubinemia probably results from RIF inhibiting the major bile salt exporter pump, impeding secretion of conjugated bilirubin at the canalicular level.43This may be transient and occurs early in treatment or in some individuals with preexisting liver disease.44,45Occasionally RIF can cause hepatocellular injury and can potentiate hepatotoxicity of other ATD.43In patients with primary biliary cirrhosis, in whom baseline transaminases were significantly elevated, clinically significant hepatitis was attributed to RIF in 7.3 and 12.5% of patients.45RIF can cause hepatocellular changes such as centri-lobular necrosis, associated with cholestasis. Histopathological findings range from spotty to diffuse necrosis with more or less complete cholestasis. Bridging necrosis, lymphocytic infiltration, focal cholestasis, increased fibrosis, and micronodular cirrhosis have been seen in patients with RIF- and PZA-induced hepatotoxicity.23
Can ATT be used to reduce viral load?
A case can be made for decreasing viral load using antiviral therapy against HBV with high-potency, high genetic barrier drugs such as entecavir and tenofovir in patients with HBV infection needing ATT to prevent the development of liver dysfunction. Hepatotoxicity related to ATT was more common in HBV positive patients who were seropositive for hepatitis B e antigen (HBeAg) than among those who were seronegative for HBeAg (relative risk [RR] = 11.38, CI = 5.49–23.59, P < 0.001).58Most episodes of liver dysfunction were usually preceded by an increase in HBV-DNA levels.55At least one case report describes that treatment with lamivudine enabled isoniazid and rifampicin treatment in a patient with pulmonary tuberculosis and hepatitis B co-infection.59However, more data need to be generated before a firm recommendation can be made on this issue.
Can ATT be used for liver disease?
The management of patients with liver disease who develop tuberculosis varies from center to center since no guidelines have been proposed for the use of ATT in the presence of preexisting liver disease. The need for such guidelines is beyond dispute. Once established and accepted, they will help to introduce uniformity in the management of tuberculosis in liver diseases, and in the management of patients with latent and overt tuberculosis infection awaiting liver transplantation. Agreement on uniform management of tuberculosis in liver diseases is also an essential requirement for collaborative studies.
Does INH cause liver damage?
Asymptomatic, self-limited increase in aminotransferase levels is observed in the majority of patients treated with INH, which does not progress to more serious forms of liver injury.27Presence of jaundice, encephalopathy and the presence of severe hepatitis (aminotransferase levels >10-fold) are associated with a poor outcome.30Approximately 5–10% of patients who have clinical symptoms of severe hepatitis including jaundice develop acute liver failure.31Age appears to be the most important factor in determining the risk of INH-induced hepatotoxicity. Hepatic damage is rare in patients less than 20 years old; it is observed in 0.3% of those in the 20–34 years age group, increasing to 1.2% in the 35–49 years age group and 2.3% in those older than 50 years of age.26,27,32–34Up to 12% of patients receiving INH may have elevated plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities.32,33Recent treatment studies have reported significant transaminase elevation in 1–4% of those treated with INH for latent tuberculosis infection.33–36A meta-analysis of six studies estimated the rate of clinical hepatitis in patients given INH alone to be 0.6%.21A large survey estimated the rate of fatal hepatitis to be 0.023%, but more recent studies suggest the rate is substantially lower.36–38
Is anti-tuberculosis therapy safe for liver disease?
The treatment of tuberculosis in patients with significant liver disease is challenging for several reasons. The ability to tolerate anti-tuberculosis therapy (ATT) and its potential hepatotoxicity are major concerns in patients with advanced cirrhosis or end-stage liver disease since most of the first-line ATD may demonstrate hepatotoxicity as an adverse effect and can result in treatment discontinuation due to associated morbidity. Firstly, in the presence of preexisting liver disease, the likelihood of drug-induced hepatitis may be higher.1,20,21Secondly, the outcome of drug-induced hepatitis in patients with marginal hepatic reserve may be serious, even fatal. Thirdly, monitoring of drug-induced hepatitis may be confounded in the presence of underlying liver disease due to fluctuating liver function tests related to the preexisting liver disease. Lastly, derangement in liver function tests caused by tuberculosis may improve with ATT.21–23There are no data related to safe use of ATD in patients with underlying chronic liver disease. Park et al found that independent risk factors for ATT drug-induced liver injury were female gender, number of hepatotoxic ATD administered and baseline ALP levels but not cirrhosis itself.24Different ATD have varying hepatotoxicity, and different regimens of ATD may be used depending upon severity of liver disease. Padmapriyadarsini et al25observed that an increase in hepatic transaminase values to more than 2 times the upper limit of normal (>80 IU) occurred in 24% of HBV and 20% of HCV co-infected patients who received concurrent ATT either as preventive regimen or as treatment regimen for tuberculosis, which is far higher than the hepatotoxicity seen in patients without liver disease.
Is ATD safe for HCV seropositive patients?
Kwon et al62demonstrated that drug-induced hepatitis occurred more frequently in HCV-seropositive patients (13%) than in control subjects (4%). ATD reintroduction after the liver transaminase level returned to baseline was safe and successful. These findings suggest that treatment for tuberculosis in HCV-seropositive patients could be pursued in the usual manner, using standard short-course regimens, with the condition that monthly liver function tests are carefully performed.62,63
How long does it take for liver enzymes to increase after TB treatment?
There has been an assumption that the majority of elevations during TB treatment will occur within the first 2 to 4 weeks of therapy. One recent paper reported that over half of the patients who developed elevated liver enzymes within 2 weeks of starting treatment had good specificity for predicting hepatotoxicity later during treatment using a monitoring schedule of regular testing for the first 2 weeks of treatment [ 16 ]. The BTS and ATS [ 6, 13] both recommend pre-treatment baseline blood tests followed by clinical assessment in all patients. In patients deemed by the physician to be at higher risk of DILI or with existing liver disease or age > 35 years old, the ATS recommends a further blood test between 2 and 4 weeks after initiating therapy [ 6 ]. The BTS advises a policy of further weekly blood tests for 2 weeks and 2-weekly blood tests for the first 2 months for patients with known liver dysfunction. Current guidance from the World Health Organization does not include regular monitoring for hepatotoxicity, and instead symptoms are used to detect liver dysfunction [ 21 ].
How many patients completed TB treatment without ALT elevation?
In this paper, we have shown that 94% of patients completed their course of standard TB therapy without clinically significant ALT elevations detected. There were similar proportions of 95% in the isoniazid arm and 96% in the ethambutol arm.
What is liver withdrawal?
Liver-related withdrawals were defined as patients withdrawn from treatment following a peak ALT or AST ≥ 3 × ULN with only liver-related adverse events (either clinical or relating to biochemical tests) recorded between their peak elevation and the time of withdrawal. Patients who met these criteria were counted for all three treatment arms.
How long does it take to measure hepatic enzymes?
Hepatic enzymes were measured at 0, 2, 4, 8, 12 and 17 weeks and as clinically indicated during reported adverse events. Patients included were those receiving at least one dose of drug and with two or more hepatic enzyme measurements.
Does isoniazid raise enzymes?
Older patients on standard therapy, HIV-positive patients, Asian patients and those receiving isoniazid were at higher risk of elevated enzyme levels. Monitoring hepatic enzymes during the first 2 months of standard therapy detected approximately 75% of patients with a peak enzyme elevation ≥3 × ULN, suggesting this should be a standard of care. These results provide evidence for the potential of moxifloxacin in hepatic sparing.
What is the name of the TB infection that infects the liver?
TB infection of the liver, called hepatic TB , is an extrapulmonary manifestation of an active infection.
Why is monitoring hepatic TB important?
Monitoring hepatic TB patients is important to ensure response to treatment and detect complications. Hepatotoxicity, or drug-induced liver injury (DILI), is the most common adverse effect among patients receiving isoniazid, rifampin, and pyrazinamide [ 71, 72 ]. However, the incidence and management of DILI among hepatic TB patients has been poorly studied. Managing hepatic TB in HIV co-infected patients involves additional challenges, and may require the assistance of an infectious diseases specialist. The WHO recommends initiating antiretroviral therapy (ART) 2–8 weeks after starting anti-TB therapy [ 69 ]. In addition to complex drug-drug interactions of concurrent ART and anti-TB therapy, clinicians should be aware of DILI and TB-related immune reconstitution inflammatory syndrome (TB-IRIS). Both entities can cause a worsening clinical picture and elevated liver enzymes after initiating ART, and can be difficult to distinguish [ 73 ]. TB-IRIS is an inflammatory reaction to TB antigens by the host immune system while receiving ART. Approximately one-sixth of co-infected patients starting ART will develop TB-IRIS [ 73 ]. Hepatic TB-IRIS presents with hepatomegaly (56% of patients), right upper quadrant pain, fever, nausea/vomiting, and elevated liver enzymes [ 73 ]. However, patients with hepatic TB-IRIS do not typically present with jaundice [ 73 ]. Differentiating DILI from hepatic TB-IRIS can be challenging in the absence of a liver biopsy [ 73 ]. Making this distinction is critical since DILI is managed with treatment cessation and drug rechallenge, while TB-IRIS requires persistence of treatment with the possible addition of corticosteroids [ 74, 75 ].
What countries have TB granulomas?
TB was the most common etiology of hepatic granulomas in TB-endemic countries [ 36, 38, 39 ]. In Iran, India, and Saudi Arabia, TB was the cause of hepatic granulomas among 51% (37/72), 55% (28/51), and 43% (26/61) of cases, respectively [ 36, 38, 39 ]. In Turkey, TB was among the most common causes of hepatic granulomas (15%) [ 40 ]. Therefore, in TB-endemic countries, presence of hepatic granulomas was highly suggestive of hepatic TB. 11 In low-prevalence TB regions and among patients with no risk factors for TB, non-communicable causes, such as primary biliary cirrhosis or sarcoidosis, may be more common etiologies for hepatic granulomas [ 35, 37 ].
What are granulomas in TB?
The characteristic histological feature of both miliary and local forms of hepatic TB is the granuloma [ 11, 34 ]. Hepatic granulomas are due to cell-mediated immunological responses to TB antigens and consist of focal aggregates of macrophages, including Kupffer cells that may coalesce to form Langerhans giant cells with surrounding lymphocytes and fibroblasts [ 34 - 37 ]. Granulomas may be necrotizing or non-necrotizing, and caseating (where necrotic tissue appears cheese-like on gross examination) or non-caseating. Hepatic granulomas in response to TB tend to be necrotizing with central caseation [ 34 ]. In three large case series, caseating granulomas were found in 51-83% of hepatic TB patients [ 18, 20, 29 ]. Multiple granulomas may coalesce to form a large tuberculoma, and caseation and liquefaction necrosis of a tuberculoma may lead to a tubercular abscess [ 11 ].
Where does TB spread?
Tuberculous bacilli can reach the liver via hematogenous dissemination, generally from the lungs, or by local spread from the gastrointestinal tract (Table 2) [ 2, 3, 31, 32 ]. Among reported hepatic TB cases, miliary form accounted for 79% of cases, while local hepatic TB accounted for 21% of cases (Table 1 ). TB infection of the biliary tree, or biliary TB, is another form of TB infection in the liver and is considered rare [ 2, 33 ].
Why has the proportion of extrapulmonary TB increased in the last 30 years?
The proportion of extrapulmonary TB, which includes hepatic TB, has increased in the last 30 years [ 22 ], due largely to increases in the global prevalence of HIV/AIDS [ 11, 21 - 26 ].
Why is a systematic review of hepatic TB important?
There have been no prior systematic reviews of hepatic TB to facilitate this understanding; therefore, the aim of this systematic review is to synthesize the existing data on the epidemiology, pathophysiology, clinical features, diagnosis, and treatment of hepatic TB, and to highlight additional considerations in HIV co-infection.
