Hepatic damage isoniazid

Mild hepatic dysfunction, detected as an elevation in serum transaminases, is now well recognized as an adverse effect of isoniazid and occurs in 10% to 20% of patients. Possibly, as many as 1 % of these cases progress to severe hepatic damage, and it has been suggested that this latter, more severe form, of hepa to toxicity may have a different underlying mechanism. However, the greater incidence of hepatotoxicity reported in rapid acetylators has since been questioned. It seems that the incidence of the mild form of isoniazid hepatotoxicity is not related to the acetylator phenotype, but the incidence of the rarer, more severe form is more common in slow acetylators. 

Allergic reactions are rare. Polyneuropathy is not caused by hypersensitivity, and can be prevented and if need be treated by administration of vitamin B5. In cases of existing liver damage isoniazid may be an additional burden, because it is metabolized in this organ. Some cases of liver damage by isoniazid are clinically difficult to differentiate from virus hepatitis (Garibaldi et al. 1972 Thomas et al. 1979). 

A fatal case of hepatic necrosis was described in detail by Vanderhoff and Ament (6 ). The patient, a 15-year-old girl, had been severely ill over a period of two years with ulcerative colitis and polyarthritis and had been treated with salicylates and steroids in the period immediately preceding the start of isoniazid therapy. Evidence of hepatic damage was first noted about 3 weeks after isoniazid was started. Her condition rapidly deteriorated and she died from hepatic failure approximately 2 weeks later. 

A minor asymptomatic increase in liver aminotransferase is seen in 10 to 20% of patients, whereas fatal hepatitis is seen in fewer than 1% of isoniazid recipients. Risk factors for hepatitis include underlying liver disease, advanced age, pregnancy, and combination therapy with acetaminophen. Early recognition and prompt discontinuation of the drug is recommended to prevent further damage to the liver. 

Both these substituted hydrazine drugs may cause liver damage after therapeutic doses. With isoniazid, a mild hepatic dysfunction may occur in 10% to 20% of patients and a more severe type in less than 1%. Both isoniazid and iproniazid yield hydrazine metabolites (acetylhy-drazine and isopropylhydrazine, respectively), which are responsible for the hepatotoxicity after activation by cytochrome P-450. Isoniazid undergoes acetylation, which in humans is polymorphic. Slow acetylators are more at risk from the hepatotoxicity because acetylhy-drazine is detoxified by acetylation. 

Adverse effects. Isoniazid is in general well tolerated. The most severe adverse effect is liver damage which may range from moderate elevation of hepatic enzymes to severe hepatitis and death. It is probably caused by a chemically reactive meta-bolite(s), e.g. acetylhydrazine. Most cases develop within the first 8 weeks of therapy and liver function tests should be monitored monthly during this period at least. 

Liver damage usually appears 1-2 months after the start of therapy. In children, raised liver enzymes are common during the first few months of treatment, but withdrawal is seldom necessary. A careful watch should be kept for early symptoms of isoniazid-induced hepatitis, such as malaise, fatigue, nausea, and epigastric distress. The dangers of continuing isoniazid after the onset of symptoms of toxicity have been highlighted (30). The earhest symptoms of isoniazid toxicity should be clearly described to the patient, particularly to hepatitis B carriers, who may be more susceptible to hepatotoxicity (26). 

Liver damage is the most common adverse effect of pyrazinamide (6). It varies from asymptomatic alteration of hver function detectable only by laboratory tests, through a mild syndrome characterized by fever, anorexia, malaise, hver tenderness, hepatomegaly, and splenomegaly, to more serious reactions with clinical jaundice, and finally the rare form with progressive acute yellow atrophy and death. As most patients take a combined regimen of pjrazinamide with isoniazid and rifampicin, it is difficult to determine which of the three drugs causes the hepatotoxicity it could be due to a combined effect (7). As with isoniazid and rifampicin, hepatic function should initially be monitored every few weeks. 

Mitchell et al. (1975) made a blind, prospective evaluation in 358 psychiatric patients during 1 year of tuberculosis prevention with isoniazid. Most of the patients who developed abnormal serum transaminases recovered completely while continuing their isoniazid therapy. No serum antibodies against isoniazid could be demonstrated and no correlation was found between the presence of antinuclear antibodies or elevated isoniazid plasma concentrations and the occurrence of hepatic injury. These data support the view that hepatotoxic metabolites of isoniazid may be responsible for the liver damage. 

Warrington et al. (1978) found that the lymphocyte transformation test was positive after stimulation with isoniazid, isonicotinic acid, and conjugates of these compounds in 95% of patients who developed isoniazid hepatitis. Healthy controls and isoniazid patients who did not develop liver damage showed a negative test. There was no correlation between the degree of lymphocyte transformation and the severity of liver damage. The appearance of liver damage after isoniazid seems to depend on the presence of cellular hypersensitivity to this medicament. 

Liver Isoniazid-induced Uver damage is histologically indistinguishable from viral hepatitis and is related to individual susceptibility in patients who hydrolyse the drug to isonicotinic add at different rates. Histologically proven isoniazid hepatotoxicity in complicated tuberculous salpingitis has been reported [70 ]. 

---