Resistance can emerge from mutations in ethA, which is needed to activate the drug, or ethR, which can be overexpressed to repress ethA. Mutations in inhA or the promoter of inhA can also lead to resistance through changing the binding site or overexpression.The FDA has placed it in pregnancy category C, because it has caused birth defects in animal studies. It is not known whether ethionamide is excreted into breast milk. Adverse effects
Ethionamide frequently causes gastrointestinal distress with nausea and vomiting which can lead patients to stop taking it. This can sometimes be improved by taking it with food.Ethionamide can cause hepatocellular toxicity and is contraindicated in patients with severe liver impairment. Patients on ethionamide should have regular monitoring of their liver function tests. Liver toxicity occurs in up to 5% of patients and follows a pattern similar to isoniazid, usually arising in the first 1 to 3 months of therapy, but can occur even after more than 6 months of therapy. The pattern of liver function test derangement is often a rise in the ALT and AST.Both central neurological side effects such as psychiatric disturbances and encephalopathy, along with peripheral neuropathy have been reported. Administering pyridoxine along with ethionamide may reduce these effects and is recommended.Ethionamide is structurally similar to methimazole, which is used to inhibit thyroid hormone synthesis, and has been linked to hypothyroidism in several TB patients. Periodic monitoring of thyroid function while on ethionamide is recommended. Interactions
Ethionamide may worsen the adverse effects of other antituberculous drugs being taken at the same time.
Differential diagnosis
The differential diagnosis of HLH includes secondary HLH and macrophage-activation syndrome or other primary immunodeficiencies that present with hemophagocytic lymphohistiocytosis, such as X-linked lymphoproliferative disease.Other conditions that may be confused with this condition include autoimmune lymphoproliferative syndrome. As a syndrome of intense inflammation it needs to be differentiated from sepsis, which may be extremely challenging.The diagnosis of acquired, or secondary, HLH is usually made in association with infection by viruses, bacteria, fungi, or parasites or in association with lymphoma, autoimmune disease, or metabolic disease. Acquired HLH may have decreased, normal, or increased NK cell activity. Griscelli syndrome
A major differential diagnosis of HLH is Griscelli syndrome (type 2). This is a rare autosomal recessive disorder characterized by partial albinism, hepatosplenomegaly, pancytopenia, hepatitis, immunologic abnormalities, and lymphohistiocytosis. Most cases have been diagnosed between 4 months and 7 years of age, with a mean age of about 17 months.Three types of Griscelli syndrome are recognised: type 1 has neurologic symptoms and mutations in MYO5A. Prognosis depends on the severity of neurologic manifestations. Type 2 has mutations in RAB27A and haemophagocytic syndrome, with abnormal T-cell and macrophage activation. This type has a grave prognosis if untreated. Type 3 has mutations in melanophilin and is characterized by partial albinism. This type does not pose a threat to those so affected. Treatment
In secondary cases, treatment of the cause, where possible, is indicated. Additionally, treatment for HLH itself is usually required.While optimal treatment of HLH is still being debated, current treatment regimes usually involve high dose corticosteroids, etoposide and cyclosporin.