I Galperin, M Sonnenblick.
Department of Geriatrics, Shaare Zedek Medical Center, Jerusalem, Israel.
Correspondence: Dr Ilia Galperin, Dept.Geriatrics, Shaare Zedek Medical Center, P.O.B. 3235, Jerusalem 91031, Israel
Email: son@szmc.org.il
SMJ 2007 52(2): 56
A
78 year-old lady who received nitrofurantoin for two years developed chronic
active hepatitis. In spite of withdrawal of Nitrofurantoin her condition
continued to deteriorate, and a liver biopsy revealed severe chronic active
hepatitis. She was treated by prednisone which resulted in improvement in her
liver function tests and her general condition. However, two months later the
patient developed a relapse of severe hepatitis with hepatic failure and she
died in spite of treatment.
Keywords: nitrofurantoin, chronic hepatitis, treatment, elderly
Nitrofurantoin, a furan derivative, was introduced in the fifties and is widely used as an effective agent for the treatment and prevention of urinary tract infections. Nitrofurantoin-induced hepatic injury was first reported in 1961.1 Since then a spectrum of toxic reactions to nitrofurantoin has been reported, ranging from acute hepatitis, granulomatous reaction, to the very rare adverse effect of chronic active hepatitis that can lead to cirrhosis or death.2 We present here an elderly patient with severe chronic active hepatitis after prolonged exposure to nitrofurantoin.
A 78 year-old woman was admitted with jaundice and slight fever of one week’s duration. Two months prior to admission she began to suffer from general weakness, nausea and diffuse abdominal pain. At that time laboratory tests showed slight elevation in liver enzymes.
Her past medical history included mild asthma, esophagitis, obesity, osteoporosis and recurrent urinary tract infections. There was no history of liver disease; she also denied consumption of alcohol. She had been treated with alendronate, omeprazole, inhalations of salbutamol and with nitrofurantoin 100mg once daily for the last two years because of the recurrent urinary tract infections.
Physical examination on admission revealed deep jaundice and slight tenderness without guarding in the right upper quadrant and epigastrium. Liver span was estimated to be 10 cm and the spleen was not palpable.
Laboratory tests revealed a normal blood count without eosinophilia, total serum bilirubin of 11 mg% with a direct fraction of 10 mg%, AST-1511 IU/L, AST-1201 IU/L, LDH-2026 IU/L, alkaline phosphatase-207 IU/L: total protein-8.0 gm%, albumin-2.9 gm%, polyclonal gamma globulins of 44%, antinuclear Ab >1:400, and anti-smooth muscle antibodies were negative. Serological tests were negative for hepatitis A, B, C, CMV and EBV viruses. Abdominal ultrasonography and computerised tomography were normal and liver isotope scan revealed mild portal hypertension.
A liver biopsy conducted two weeks after admission showed bile duct proliferation with cholestasis, and an inflammatory infiltrate composed of eosinophils, lymphocytes and neutrophils with severe piecemeal necrosis. Nitrofurantoin treatment was discontinued. Over the ensuing three weeks there was a mild decline in liver enzymes, but at the end of the fourth week an increase in serum aminotransferases and alkaline phosphatase was noted. The patient was started on prednisone 60mg daily, following which she felt much better and there was a gradual decrease in serum bilirubin levels and liver enzymes. Two months later the patient had another relapse of severe hepatitis, accompanied by liver failure and sepsis which did not respond to high doses of steroids and antibiotics and she succumbed in spite of treatment.
Nitrofurantoin is a furan derivative, widely used since the fifties in various dosage regimens (100 mg to 400 mg daily) for the treatment and prevention of urinary tract infections.
Adverse effects of nitrofurantoin are well documented, and occur in approximately 10% of patients. The most common adverse effects involve the gastrointestinal tract; serious reactions, including severe liver disease, are extremely rare.
A
report from the Netherlands estimated the incidence of nitrofurantoin-induced
liver injury to be approximately 1:3,000- 5,000,2 however in other
studies the incidence was much lower – of the order of
1:30,000 patients exposed to nitrofurantoin.3
The clinical and histological spectrum of liver injury associated with nitrofurantoin is very broad, ranging from an acute self-limited hepatitis, chronic granulomatous hepatitis, chronic active hepatitis as seen in our patient, to severe hepatic necrosis.2, 4 In one large review that included 52 reported cases of nitrofurantoin-induced liver injury, two main forms were observed – acute hepatic injury and chronic hepatic injury.2 Chronic liver injury was more common in women (82%), while acute injury was observed equally in both sexes. In both forms the clinical signs are non-specific and include nausea, vomiting and malaise. However, in the chronic form jaundice and hepatomegaly are more common and prominent.
The type of injury appears to be related to the period of exposure to nitrofurantoin. In most of the patients with the acute form of injury the exposure is for 1 to 6 weeks, while in chronic hepatitis it is usually more then 6 months.2 Our patient received nitrofurantoin for more than two years before the onset of her illness.
The
pathogenesis of nitrofurantoin-induced hepatic injury is not fully understood,
but seems to be idiosyncratic, based on an immune reaction rather than a direct
toxic effect. In support of that mechanism are the findings of hepatic injury
even after the consumption of only 100mg of the agent during rechallenge, the
presence of long-term hepatic memory for hypersensitivity to nitrofurantoin that
may last for many years,5 and the presence of autoantibodies such as
ANA and anti-smooth muscle in 70%-90% of the patients.4, 6
Autoantibodies are present in both the acute and the chronic types of hepatic
injury although much more frequent in the chronic. Furthermore, in patients with
chronic hepatitis the histopathologic findings are very similar to those seen in
autoimmune hepatitis6 and therefore support an immune pathogenesis.
In addition, in some of the patients with hepatitis other adverse reactions of
an autoimmune nature, such as pneumonitis, peripheral neuropathy and lupus-like
syndrome have been described.7
The diagnosis of nitrofurantoin-induced hepatitis could be made by a re-challenge test, however, since re-challenge with even a low dose of the drug may cause severe hepatitis, hepatic failure or death, it is not recommended.
One of the main difficulties is the differentiation of nitrofurnation induced chronic hepatitis from immune hepatitis. A history of nitrofurantoin consumption and clinical and biochemical improvement after the discontinuance of the offending agent is in supporting the diagnosis of nitrofurnation induced hepatitis. On the other hand the presence of HLA-DR-3 serotype and HLA-DR-4 have been recognised as independent risk factors for autoimmune hepatitis.8, 9 In one study 90% of the patients with autoimmune hepatitis who were DR-typed had either DR-3 or DR-4 compared with 53% of controls.10
The prognosis of nitrofurantoin-induced chronic active hepatitis is generally good. Withdrawal of the offending drug usually leads to improvement, but in some cases hepatic injury may continue to inexorably worsen and lead to liver failure and death, especially in the elderly. Hence, since withdrawal of the drug does not always resolve the situation, the question is whether one should administer steroids in every such patient without deferral. On the other hand, it has been suggested that treatment with steroids should be limited to those patients who do not improve after withdrawal of the nitrofurantoin.11 This dilemma remains unresolved. Other unresolved questions relate to the dosage of steroids, and the duration of treatment.
The clinical presentation of our patient was unusual, in that the hepatic injury developed after at least two years of exposure to nitrofurantoin in a very old woman. Nitrofurantoin is a drug that is frequently prescribed for elderly patients on a long term basis for the prevention of recurrent urinary tract infection. Therefore, the possibility of hepatic injury has to be considered, even after prolonged exposure to drug. As a significant percentage of patients with hepatic injury will develop cirrhosis, and some of them will die from the injury, it is suggested that liver function be monitored in those patients on long-term treatment with nitrofurantoin. In patients with persistent hepatitis, in addition to withdrawal of the offending drug, treatment with steroids should be carefully considered, especially in the elderly.
Ernaelsteen D, Williams R. Jaundice due to nitrofurantoin. Gastroenterology 1961; 41: 590-593.
Stricker BH, Blok AP, Claas FH, Van Parys GE, Desmet VJ. Hepatic injury associated with the use of nitrofurans: a clinicopathological study of 52 reported cases. Hepatology 1988 May-Jun;8(3):599-606.
D’Arcy PF. Nitrofurantoin. Drug Intell Clin Pharm 1985; 19: 540-547.
Sharp JR, Ishak KG, Zimmerman HJ. Chronic active hepatitis and severe hepatic necrosis associated with nitrofurantoin. Ann Intern Med 1980 Jan;92(1):14-19.
Paiva LA, Wright PJ, Koff RS. Long-term hepatic memory for hypersensitivity to nitrofurantoin. Am J Gastroenterol 1992 Jul;87(7):891-893.
Czaja AJ. Autoimmune hepatitis. Evolving concepts and treatment strategies. Dig Dis Sci 1995 Feb;40(2):435-456.
Lundgren R, Back O, Wiman LG. Pulmonary lesions and autoimmune reactions after long-term nitrofurantoin treatment. Scand J Respir Dis 1975;56(4):208-216.
Czaja AJ, Carpenter HA, Santrach PJ, Moore SB. Significance of HLA DR4 in type 1 autoimmune hepatitis. Gastroenterology 1993 Nov;105(5):1502-7.
Czaja AJ, Strettell MD, Thomson LJ, Santrach PJ, Moore SB, Donaldson PT, Williams R. Associations between alleles of the major histocompatibility complex and type 1 autoimmune hepatitis. Hepatology 1997 Feb;25(2): 317-323.
Donaldson PT, Doherty DG, Hayllar KM, McFarlane IG, Johnson PJ, Williams R. Susceptibility to autoimmune chronic active hepatitis: human leukocyte antigens DR 4 and A1-B8-DR-3 are independent risk factors. Hepatology 1991; 13: 701-706.
Iwarson S, Lindberg J, Lundin P. Nitrofurantoin-induced chronic liver disease. Clinical course and outcome of five cases. Scand J Gastroenterol 1979;14(4):497-502.