Isoniazid Toxicity


Article Author:
Madhuri Badrinath


Article Editor:
Savio John


Editors In Chief:
Melissa Max
Danyae Lee
Manouchkathe Cassagnol


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Frank Smeeks
Kristina Soman-Faulkner
Trevor Nezwek
Radia Jamil
Patrick Le
Sobhan Daneshfar
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
2/21/2019 12:31:36 PM

Introduction

Isoniazid (INH) is a potent bactericidal antibiotic used in the treatment of tuberculosis. Treatment with INH therapy has a risk of toxicity, which can be acute or chronic. Acute toxicity manifests as neurological symptoms. Consumption of 2 g of INH can predispose a patient to acute toxicity; while chronic toxicity usually presents as hepatotoxicity and peripheral neuropathy. 

There are 2 known syndromes of hepatotoxicity: 

  1. Mild type manifesting as transient and asymptomatic elevation in serum aminotransferase levels
  2. Severe acute hepatitis which can sometimes be fatal[1]

Peripheral neuropathy is secondary to deficiency of vitamin B6 (pyridoxine).

Etiology

INH is a potent antimycobacterial agent that inhibits cell wall synthesis of Mycobacterium tuberculosis and is used in both therapeutic and prophylactic regimens. Since initially being introduced in 1954, INH has contributed toward the treatment of tuberculosis resulting in a significant decline in tuberculosis-related morbidity and mortality.  The recommended dose of INH in adults is 300 mg (5 mg/kg) daily to 900 mg (15 mg/kg) once or twice weekly. Due to the rapid development of microorganism resistance, treatment regimens often include other antibacterial agents. Most of the regimens include INH alone or with other agents including rifampin, pyrazinamide, streptomycin, and/or ethambutol. Common side effects include gastrointestinal (GI) upset, fever and rash. High doses of INH can cause peripheral neuropathy preventable with concurrent administration of pyridoxine (vitamin B6). The development of hepatotoxicity increases with other contributing risk factors such as increased age, alcohol consumption, concurrent use of medications that induce cytochrome P (CYP) oxidative enzymes, prior or concurrent liver disease like viral hepatitis, previous INH intolerance, female gender, injection drug use, and genetic causes like slow acetylation status.[2]

Epidemiology

Transient asymptomatic liver enzyme elevation due to INH is seen in 15% to 20% of recipients. INH-induced, clinically-apparent, acute liver injury with jaundice is seen in 0.5% to 1% of recipients, and the risk of fatal hepatitis is about 0.05% to 1%.  While the occurrence of mild hepatotoxicity is not related to acetylation status, the occurrence of acute hepatitis can depend on it.[3] The incidence of peripheral neuropathy is 1.1% in the general population and around 6.5% in the elderly.

Pathophysiology

INH is rapidly absorbed from the GI tract and diffuses into all the body tissues. Hepatic metabolism of INH produces multiple metabolites which include: hydrazine, monomethylhydrazine, and toxic-free radicals that are involved in the pathogenesis of INH induced hepatitis. INH is metabolized via N-acetyltransferase 2 gene (NAT2) to form the inactive N1-acetyl-N2-isonicotinohydrazide (AcINH), which is then hydrolyzed to form AcHZ and INA. These metabolites are further acetylated to non-toxic metabolites and excreted in urine. As NAT2 is the primary enzyme involved in the metabolism of INH, its deficiency can cause INH related hepatotoxicity. This is particularly seen in slow acetylators due to the higher concentration of AcHZ. As mentioned above, the incidence of toxic hepatitis increases when INH is used with rifampin, pyrazinamide or barbiturates as these medications are inducers of the CYP system resulting in increased production of toxic INH metabolites.[4] 

INH causes peripheral neuropathy by 2 different mechanisms. First, INH metabolites directly inactivate pyridoxine species. Also acts by inhibiting the enzyme pyridoxine phosphokinase which is a necessary enzyme to convert pyridoxine to its active form of pyridoxal 5' phosphate which is a very important cofactor in many reactions. 

As mentioned above, acute INH toxicity can manifest as seizures, and the important mechanism is a deficiency of gamma-aminobutyric acid (GABA) which is an inhibitory neurotransmitter. The pyridoxine deficiency induced by use of INH leads to reduced production of GABA, as it is usually a product of pyridoxine-dependent decarboxylation reaction. Thus GABA deficiency can manifest as seizures especially in the acute setting of toxicity.

History and Physical

Acute toxicity presents as altered mental status, seizures, and sometimes status epilepticus.[5] Long-term complications include anoxic encephalopathy and dementia.

The onset of INH induced hepatotoxicity is insidious, ranging from 2 weeks to 6 months. It usually affects adults older than 35 years of age with the highest frequency amongst those above 50 years of age. The symptoms are similar to viral hepatitis with prodromal symptoms of nausea, anorexia, fatigue, abdominal discomfort with right upper quadrant pain, generalized flu-like symptoms, dark urine, and jaundice.

Neuropathy symptoms are usually sensory which include numbness, tingling, burning sensation in all the extremities. Rarely seen are central features like ataxia, nystagmus.

Evaluation

The pattern of elevation of liver enzymes is consistent with hepatocellular injury with marked alanine aminotransferase (ALT) elevations (greater than 10 times the upper limit of normal) and minimal alkaline phosphatase (ALP) elevations. The injury is mostly self-limited except for 10% of the cases where it can progress to acute liver failure with clinical manifestations of coagulopathy, ascites, edema, and encephalopathy.[6] Liver biopsy reveals morphologic changes similar to viral hepatitis such as bridging necrosis along with increased numbers of eosinophils and prominence of cholestasis. INH therapy can induce production of antinuclear antibodies (ANA). These can be present during acute hepatic injury phase but usually in very low titers. As ANA can also be positive in autoimmune hepatitis, absence of arthralgia and hyperglobulinemia can help differentiate it from INH induced hepatotoxicity. Recently, antibodies to INH have also been detected in INH recipients, but their presence has not been linked to liver injury yet.

Treatment / Management

Acute toxicity is approached by strict airway management, activated charcoal if the patient presents early, seizure management with the use of benzodiazepines, and pyridoxine administration. This helps with rapid restoration of GABA stores.[7]

Elevated serum aminotransferase levels develop during the first few weeks of therapy and are termed as mild INH hepatotoxicity. In most cases, such toxicity is self-limiting, and the adaptive response allows continuation of the agent as long as patients remain asymptomatic without progressive elevation in aminotransferase levels. However, it is very important to know that INH should be immediately discontinued if there are hepatitis related symptoms or progressive elevation in aminotransferase levels. The onset of any symptoms of hepatitis such as anorexia, nausea, jaundice, and fatigue in a patient with abnormal liver biochemical tests should prompt cessation of INH forthwith.

The exact level of aminotransferases at which INH should be discontinued is unclear. It is generally recommended that if the total bilirubin is greater than 3 mg/dL and liver enzymes are over 5 times the upper limit of normal, INH (including other anti-tuberculosis medications) should be discontinued. If the bilirubin is less than 3 mg/dL and liver enzymes are less than 5 times the upper limit of normal, therapy can be continued, but liver enzymes should be checked in 3 days for reassessment. If liver enzymes continue to worsen or patients develop symptoms of hepatitis, therapy should be discontinued; otherwise, close monitoring is recommended. Once the liver enzymes return to baseline (or less than twice normal), the potential hepatotoxic drugs can be restarted one at a time with careful monitoring between resuming each agent. Rechallenge with INH may be done cautiously with serial monitoring of liver biochemical tests in patients with a strong indication for therapy and who have not had a severe hepatoxicity with INH. Many public health programs that require INH prevention for a positive tuberculin skin test or a blood test for diagnosing Mycobacterium tuberculosis infection include monthly liver enzyme monitoring; although, there is limited evidence of benefit for such practice. Monitoring of liver biochemical tests while on therapy is generally recommended in patients with chronic liver disease or age above 50 years as these individuals are at a higher risk for developing hepatotoxicity.

Though there are no specific therapies for INH induced liver damage, some studies have shown a mortality benefit in using corticosteroids and N-acetylcysteine early in the course of liver injury. In rare instances, the hepatotoxicity from INH can be very severe prompting the need for an emergency liver transplant.[8]

Peripheral neuropathy is avoided and treated with daily pyridoxine administration along with INH.

Enhancing Healthcare Team Outcomes

With rising rates of tuberculosis, the prescription of isoniazid has also increased. And sometimes, isoniazid toxicity occurs because of multiple or inadvertent dosing. Isoniazid toxicity is usually managed by a multidisciplinary team that consists of an emergency department physician, nurse practitioner, toxicologist, poison control, neurologist and an internist. In all cases of isoniazid toxicity, the offending agent must first be discontinued. The treatment is generally supportive with hydration and monitoring. If there is evidence of liver damage, small case studies suggest use of N-acetyl cysteine and corticosteroids. In rare cases, a liver transplant may be required. Today, peripheral neuropathy is rarely seen because most patients are prescribed pyridoxine at the initiation of isoniazid therapy. [9][10](Level V)

 

 

 


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Isoniazid Toxicity - Questions

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A patient is placed on isoniazid for 9 months to treat his tuberculosis. He reports of painful tingling in his arms and legs. The tingling has been getting intense on a daily basis. Which of the following can be used to reverse the side effects of isoniazid?



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A patient is started on four medications for active tuberculosis. Which of the following is least likely to cause hepatotoxicity?



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Which drug is known to cause peripheral neuropathy in patients who are slow acetylators?



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Which of the following can reverse the side effects of isoniazid?



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Which of the following reverse the neurotoxic effects of isoniazid?



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What can be used to reverse the neuropathic side effects of isoniazid?



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A patient is receiving isoniazid (INH) to treat pulmonary tuberculosis. The patient should be monitored for which one of the following reactions?



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A vegetarian being treated for tuberculosis develops peripheral neuropathy. Which of the following is the best therapy for this condition?



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You are a student in the emergency department. The ED doctor is seeing a patient who had been having nausea, vomiting, slurred speech, and dizziness that progressed to stupor and seizures. The family reveals he had recently begun treatment for tuberculosis. What diagnosis do you suspect?



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A 25-year-old male with no known liver disease was recently started on isoniazid, rifampicin, ethambutol, and pyrazinamide for the management of pulmonary tuberculosis. He drinks one to two alcoholic beverages weekly. He is noted to have mildly elevated liver enzymes on labwork done this morning and is asymptomatic. What is the next step in management?



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Isoniazid Toxicity - References

References

Hayashi PH,Fontana RJ,Chalasani NP,Stolz AA,Talwalkar JA,Navarro VJ,Lee WM,Davern TJ,Kleiner DE,Gu J,Hoofnagle JH, Under-reporting and Poor Adherence to Monitoring Guidelines for Severe Cases of Isoniazid Hepatotoxicity. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2015 Sep     [PubMed]
Severe isoniazid-associated liver injuries among persons being treated for latent tuberculosis infection - United States, 2004-2008. MMWR. Morbidity and mortality weekly report. 2010 Mar 5     [PubMed]
Lewinsohn DM,Leonard MK,LoBue PA,Cohn DL,Daley CL,Desmond E,Keane J,Lewinsohn DA,Loeffler AM,Mazurek GH,O'Brien RJ,Pai M,Richeldi L,Salfinger M,Shinnick TM,Sterling TR,Warshauer DM,Woods GL, Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: Diagnosis of Tuberculosis in Adults and Children. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2017 Jan 15     [PubMed]
Saukkonen JJ,Cohn DL,Jasmer RM,Schenker S,Jereb JA,Nolan CM,Peloquin CA,Gordin FM,Nunes D,Strader DB,Bernardo J,Venkataramanan R,Sterling TR, An official ATS statement: hepatotoxicity of antituberculosis therapy. American journal of respiratory and critical care medicine. 2006 Oct 15     [PubMed]
Weber WW,Hein DW, Clinical pharmacokinetics of isoniazid. Clinical pharmacokinetics. 1979 Nov-Dec     [PubMed]
Farrell FJ,Keeffe EB,Man KM,Imperial JC,Esquivel CO, Treatment of hepatic failure secondary to isoniazid hepatitis with liver transplantation. Digestive diseases and sciences. 1994 Oct     [PubMed]
Lheureux P,Penaloza A,Gris M, Pyridoxine in clinical toxicology: a review. European journal of emergency medicine : official journal of the European Society for Emergency Medicine. 2005 Apr     [PubMed]
de' Clari F, The paradoxical anticonvulsive and awakening effect of high-dose pyridoxine treatment for isoniazid intoxication. Archives of internal medicine. 1992 Nov     [PubMed]
Freiman JM,Jacobson KR,Muyindike WR,Horsburgh CR,Ellner JJ,Hahn JA,Linas BP, Isoniazid Preventive Therapy for People With HIV Who Are Heavy Alcohol Drinkers in High TB-/HIV-Burden Countries: A Risk-Benefit Analysis. Journal of acquired immune deficiency syndromes (1999). 2018 Apr 1;     [PubMed]
Denholm JT,McBryde ES,Eisen DP,Penington JS,Chen C,Street AC, Adverse effects of isoniazid preventative therapy for latent tuberculosis infection: a prospective cohort study. Drug, healthcare and patient safety. 2014;     [PubMed]

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