Acute medication hepatitis

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Acute hepatitis refers to the presence of liver lesions characterized by inflammation and important necrosis or hepatocyte degeneration

Hepatic lesions can be determined by:
a) Immunoallergic genesis reactions
b) Reactions for metabolic idiosyncrasy

In more severe cases, zonal or bridge necrosis or massive hepatic (panlobular) necrosis are evident; these lesions may be associated with fulminating or sub-fulminant hepatic failure. Acute hepatitis is responsible for about 50% of cases of adverse reaction to drugs with liver involvement, and there are many substances that can determine it. Drug Hepatitis may or may not be associated with clinical and laboratory manifestations compatible with drug allergy (immunoallergic reactions).

The forms not associated with these manifestations could be due to metabolic idiosyncrasy; often there are partial dose-dependence and histological and ultrastructural manifestations typical of chemical toxicity. As an example of acute immunoallergic hepatitis we have the reaction from nitrofurantoin, while as an example of metabolic idiosyncrasy that from isoniazid. Other relatively frequent examples of drug hepatitis, such as granulomatous reactions and chronic hepatitis, will then be briefly discussed.

Drugs responsible for hepatitis with immunoallergic genesis

Nitrofurantoin, a synthetic compound based on furan, is a urinary antiseptic with a wide spectrum of adverse reactions. During the first (few) weeks of therapy it is frequent to notice abnormal liver function tests, of dubious importance. The spectrum of hepatopathies associated with nitrofurantoin include acute hepatitis, sometimes with cholestatic manifestations, hepatic granulomas, chronic hepatitis with autoimmune phenomena, acute liver failure and cirrhosis. Causality has been demonstrated by re-administration. The damage is not dose-related; Cases were described following ingestion of milk from cattle treated with nitrofurantoin. The frequency of liver injury from nitrofurantoin ranges from 0.3 to 3 cases per 100,000 exposed subjects and increases with age, particularly after age 64. Two-thirds of the acute cases occur in the female sex and the male: female ratio for chronic hepatitis is 8: 1. Laboratory hepatic tests may show marked increases in ALT blood levels (see enzymes), but more often there is a mixed picture with an increase in alkaline phosphatase levels or relatively non-specific liver test changes. In other cases the results are indicative of cholestasis. Blood levels of bilirubin tend to be increased in proportion to the severity of the reaction. Unlike many types of acute drug hepatitis, albuminemia is often low. The increase in serum globulins is more likely in chronic hepatitis. In 33% of cases eosinophilia is present. In some cases of acute hepatitis and in 80% of cases of chronic hepatitis, antinucleus antibodies are evident. Anti-smooth antibodies are also present in most patients with chronic nitrofurantoin hepatitis. Unlike autoimmune hepatitis, nitrofurantoin hepatitis is not associated with HLA-B8 and DRw3 antigens of the major histocompatibility complex.

Methyldopa was one of the first drugs for which cases of immunoallergic hepatitis have been reported. Currently, cases of methyldopa hepatitis are rare, thanks to the availability of better anti-pertensive drugs. Hepatic reactions to methyldopa include the detection of impaired liver tests, severe acute hepatitis, granulomas, cholestasis and chronic hepatitis with bridge necrosis and cirrhosis.

Epidemiological, clinical, laboratory, course characteristics and extrahepatic manifestations are similar to those described for nitrofurantoin. Phenytoin causes a severe form of acute hepatitis in less than 1 subject per 10000 exposed. There is no prevalence of sex and children can also be affected. The frequency can be higher in black subjects. Rash, fever, eosinophilia, lymphadenopathy, similmononucleosic syndrome and other allergic manifestations are common. Although these manifestations are indicative of immunoallergic reaction, a familial enzyme deficiency for the elimination of the phenytoin oxide artery was also identified in patients with phenytoin reactions, so that metabolic factors could predispose to phenytoin reactions. L-asparaginase is an antileukemic drug that frequently causes hepatotoxicity. The toxicity is generally reversible, but may lead to liver failure with diffuse microvescicular steatosis. Phosphorus is one of the few direct hepatotoxins, but hepatotoxicity is rarely observed because phosphorus is no longer used in the production of rat or mouse poisons. The clinical picture is characterized by vomiting and hepatorenal insufficiency.

Cocaine, phencyclidine and 5-methoxy-3,4-methylene-dioxo-methamphetamine (MDMA, ecstasy) are voluptuous drugs that can cause liver failure, with some evidence of dose-dependence. However, the direct relationship between drugs and hepatotoxicity is controversial. Cocaine is hepatotoxic in the mouse but not in many other animal species. In humans severely intoxicated with cocaine, liver damage is usually secondary to other factors, such as hypoxia, hypotension and hyperthermia. Phencyclidine (angel dust, angel powder) has been associated with liver injury in cases of severe toxicity with hyperthermia, rhabdomyolysis and respiratory failure and acute renal failure. Ecstasy has been associated with several cases of severe hepatic failure; some of these were fatal and others were liver transplanted. Hepatomegaly, jaundice, pruritus, severe hyperbilirubinemia and disproportionate increase in AST blood levels compared to ALT were found, and liver biopsy revealed the presence of acute hepatitis of varying severity.

Liver injury is not always dose-related; it has been hypothesized that at the base there may be an underlying abnormality of the muscular metabolism similar to that associated with the malignant hyperthermia syndrome. CYP2D6 is the major pathway of hepatic oxidation of ecstasy and similar drugs, but it has not yet been verified whether the subjects in which this enzyme is deficient (and therefore show a slow metabolizing phenotype of debrisoquine) are at risk of damage hepatic from ecstasy. The evidence of altered laboratory liver tests and hepatomegaly in a young subject should lead to investigate the possible use of drugs. Amiodachin, an antimalarial 4-aminoquinolone, has been associated with fatal hepatotoxicity and agranulocytosis. A possible correlation with the total dose has been noted. Amiodachin should be reserved for the active treatment of Plasmodìum falciparum chlorochino-resistant malaria, scrupulously respecting the recommended doses. Icantone is an antisistosomal drug whose hepatotoxicity is favored by concomitant administration of phenothiazines or estrogens and any pre-existing hepatopathy or bacterial infection. The main risk factor, however, is the dose.

Drugs responsible for hepatitis at the genesis of metabolic idiosyncrasy

Isoniazid causes hepatitis in 21 subjects out of 1000 exposed, whose liver injury is not dose-dependent even if the intake of alcohol, rifampicin and pyrazinamide may increase the risk of hepatitis. The damage is more likely in subjects who are carriers of hepatitis B; other drugs are antimycotics, such as ketonazole, terbinafine and fluconazole. Even oral antidiabetic drugs such as troglitazone, not used in Italy or rosiglitazone seem to be associated with drug-induced hepatitis, which is not always dose-dependent. Then follow the hepatitis from farmci used in psychiatry, as the fluoxetina, the venlafaxina, the trazodone, the zolpidem, the alpidem. Dantrolene, a muscle relaxant, causes hepatitis in 1% of subjects.

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