Cefdinir-Induced Hepatotoxicity: Potential Hazards of Inappropriate Antibiotic Use

Drug-induced hepatotoxicity is well recognized but can cause some diagnostic problems, particularly if not previously reported. The present case involves a 22-year-old male who presented with jaundice and elevated liver enzymes after a course of cefdinir (Omnicef) for streptococcal pharyngitis. A diagnosis of drug-induced liver injury was suspected but a liver biopsy was required after his jaundice worsened despite cessation of the presumed offending agent. A short course of steroids was initiated and eventually the jaundice resolved. This case highlights the need to suspect medication-induced liver injury in cases of jaundice, even if not previously reported. In addition, it illustrates the potential for adverse outcomes in situations where antibiotics are used inappropriately or where first line antibiotics are not used for routine infections. We report a case of a young male who developed jaundice associated with cefdinir use with pathological confirmation of moderate cholestasis with portal and lobular mixed inflammation and focal bile duct injury consistent with drug-induced liver injury.     

Prolonged cholestasis following successful removal of common bile duct stones： Beware patients on estrogen therapy

There are various well described forms of chronic cholestatic jaundice in adults, such as autoimmune cholangitis, drug-induced cholangitis and intrahepatic cholestasis of pregnancy. We present two cases of prolonged cholestasis following removal of gallstones at endoscopic retrograde cholangiopancreatography （ERCP） and subsequent clear cholangiography. Both patients were taking oral estrogens at the time of presentation, which were subsequently withdrawn. The first case responded rapidly to corticosteroid treatment, and the second case had a much slower resolution with ursodeoxycholic acid. Both cases highlighted the significance of estrogen-induced cholestasis in female patients with protracted jaundice following ERCP and removal of intra-ductal stones. After oral estrogens are discontinued, a short course of steroids needs to be considered.     

Cholestatic jaundice and IgA nephropathy induced by OTC muscle building agent superdrol

Over the counter (OTC) medicines are commonly used in the United States despite a lack of scientific evidence for clinical utility and toxicity associated with their use. A case of jaundice and IgA nephropathy as a consequence of use of a muscle enhancing OTC supplement that was advertised as innocuous with no hormonal activity is described. IgA nephropathy has not been described previously in association with the use of testosterone. The case highlights that, besides adulteration, the misrepresentation of chemicals present in OTC medications and supplements can create confusion and a false sense of security with their use.     

Severe cholestasis due to adalimumab in a Crohn’s disease patient

Elevation of liver biochemistry has been reported with anti-tumor necrosis factor agents, but overt liver failure rarely reported. Autoimmune hepatitis has been more commonly reported with infliximab than adalimumab(ADA). Our case, however, describes the first reported case of ADA-associated severe cholestatic injury. A 39-year-old female with Crohn’s disease developed severe jaundice after initiation of ADA. All serologic tests and imaging studies were normal. Liver biopsy showed prominent pericentral canalicular cholestasis,without features of steatosis or sclerosing cholangitis,consistent with drug-induced cholestasis. The serum total bilirubin peaked at 280 μmol/L, and improvement was seen after 5 wk with eventual normalization of liver enzymes at 10 wk. Our case describes the first reported case of ADA-associated severe cholestatic liver disease and the first histopathologic examination of this adverse drug effect. Clinicians need to be aware of this potential drug-induced liver injury when prescribing this commonly used biologic medication.     

Danazol-Induced Cholestasis

A 39-yr-old female on high-dose Danazol presented with jaundice and pruritus. Danazol-induced cholestasis was suspected, and the drug was discontinued. A liver biopsy revealed panlobular cholestasis with portal and periportal inflammation. The cholestasis resolved completely in 8 wk. This is a rare case of Danazol-induced cholestasis and should be considered in the differential diagnosis of drug-induced liver injury.     

A case of severe cholestatic jaundice with hyperthyroidism successfully treated with methimazole

Liver dysfunction is a common complication observed in patients with hyperthyroidism, however the dysfunction is always mild and obvious jaundice is rarely observed. We present the case of a 43-year-old man who suffered from hyperthyroidism complicated by severe jaundice. The jaundice likely occurred as a secondary consequence of cholestasis due to hyperthyroidism, since other causes such as drug-induced or autoimmune liver dysfunction were ruled out. Treatment with methimazole improved severe cholestatic jaundice in parallel with normalization of thyroid function. The mechanism of cholestasis as a secondary complication of hyperthyroidism has not been uncovered and there is no specific biochemical marker for cholestasis due to this hormonal disease at present. This case serves as a reminder that severe jaundice can be a manifestation of simple hyperthyroidism, and that administration of antithyroid drugs is an effective treatment for severe cholestatic jaundice in such cases.     

Benign familial recurrent intrahepatic cholestasis

Three new cases of benign familial recurrent intrahepatic cholestasis in a brother, sister, and mother are reported. These cases emphasize the familial nature of the disorder and the characteristic clinical findings of recurrent attacks, cholestatic jaundice, pruritus with increases in the serum bilirubin, and increased alkaline phosphatase. A normal extrahepatic biliary tree was shown by dye studies, and liver biopsy showed central lobular cholestasis without any inflammation or necrosis. Liver function tests were normal between attacks. This condition must be differentiated from extrahepatic obstruction, parenchymal liver disease, drug-induced cholestatic disease, and other familial types of jaundice.     

Drug-induced jaundice

A large number of drugs may be associated with impaired bile flow. Drug-associated cholestasis presents like other forms of cholestasis with pale stools, dark urine, pruritus and jaundice. Abdominal pain may be present in some instances and can be so severe as to lead to a false diagnosis of acute cholecystitis. Biochemically, drug-associated cholestasis resembles other forms of cholestasis although the presence of eosinophilia may suggest drug involvement. Many types of drug-induced cholestasis run a benign course with resolution of signs and symptoms within 3 months but occasionally the jaundice can take a year or more to resolve. Progression to cirrhosis is uncommon. Some patients may develop a syndrome resembling primary biliary cirrhosis. The mechanisms of drug-associated cholestasis are uncertain but may arise from alteration of bile formation within the hepatocyte or bile excretion at the level of the canaliculus or the extrahepatic ducts. Histological examination of the liver may be helpful in classifying the types of jaundice but the diagnosis of drug-induced cholestasis is usually one of temporal association and exclusion of other causes.     

Protracted cholestasis probably induced by oral contraceptive.

The case of a patient with intrahepatic cholestasis, probably induced by an oral contraceptive agent, is reported. Initially, early primary biliary cirrhosis was suspected, but this diagnosis could not be verified either clinically or by immunological tests. Re-examination and re-evaluation of the liver biopsy revealed some eosinophilia and sinusoidal dilatation, changes indicative of drug-induced liver injury. The cholestasis gradually disappeared as indicated both biochemically and histologically, but the elevation of serum alkaline phosphatase levels persisted for some 10 years after termination of drug therapy. Oral contraceptive agent-induced jaundice or cholestasis is generally reported to disappear when the drug is stopped, and we are unaware of similar cases in the literature with a protracted course such as that described here. Still, the circumstances of this patient suggest that a correlation between the oral contraceptive agent and the hepatic reaction is most likely, and we consider it important that colleagues pay attention to this possibility.     

Steroids for the treatment of methimazole-induced severe cholestatic jaundice in a 74-year-old woman with type 2 diabetes

Methimazole is a widely used antithyroid agent. Although methimazole is generally well tolerated, rare but severe cholestatic jaundice may occur. We described a 74-year-old woman who had a 10-year history of type 2 diabetes had developed severe jaundice and itching 1 month after receiving methimazole (10 mg tid) and propranolol (10 mg tid) for the treatment of hyperthyroidism. Clinical investigations revealed no evidence of any mechanical obstruction in the common bile duct or other obvious causes of hepatic injury, and the diagnosis methimazole-induced cholestasis was made on the basis of the temporal relationship between initiation of methimazole and onset of cholestasis. Methimazole was hence discontinued. However, the patient experienced a progressive worsening in cholestasis after receiving 2 weeks of ursodeoxycholic acid (UDCA) therapy. Prednisone therapy was then attempted. Liver function tests eventually improved with combination of glucocorticoids and ursodeoxycholic acid therapy. This case clearly showed that glucocorticoids could be a possible additional way of treatment for some cases of drug-induced cholestatic jaundice even in diabetic patients.     

Determination of serum cholestatic factor level by ELISA in drug-induced allergic hepatitis

We have shown that intrahepatic cholestasis often observed in drug-induced allergic hepatitis may be induced by a kind of lymphokine, the cholestatic factor (CF). In this study, we measured the CF level in the serum of patients with jaundice by ELISA using anti-CF monoclonal antibody. As a result, CF was detected in the serum of most of the patients at the peak of jaundice, but it was not detected when the patients were recovering from jaundice. When the changes in the serum CF level were followed during the clinical course of a patient, it reached its maximum level before that of the serum total bilirubin level and quickly decreased thereafter. These results also suggest that intrahepatic cholestasis in drug-induced allergic hepatitis may be induced by CF.     

Determination of serum cholestatic factor level by ELISA in drug-induced allergic hepatitis

We have shown that intrahepatic cholestasis often observed in drug-induced allergic hepatitis may be induced by a kind of lymphokine, the cholestatic factor (CF). In this study, we measured the CF level in the serum of patients with jaundice by ELISA using anti-CF monoclonal antibody. As a result, CF was detected in the serum of most of the patients at the peak of jaundice, but it was not detected when the patients were recovering from jaundice. When the changes in the serum CF level were followed during the clinical course of a patient, it reached its maximum level before that of the serum total bilirubin level and quickly decreased thereafter. These results also suggest that intrahepatic cholestasis in drug-induced allergic hepatitis may be induced by CF.     

Paraneoplastic cholestasis associated with prostate carcinoma.

Paraneoplastic syndromes associated with prostate carcinoma are very rare. We report a patient with prostate carcinoma and cholestatic jaundice without biliary obstruction, hepatic involvement or infectious etiology. In the literature, only one case of idiopathic cholestatic jaundice with prostate carcinoma has been reported and a paraneoplastic etiology was suggested. In our case, cholestasis rapidly regressed with chemotherapy and the patient is well at six months of follow-up. Paraneoplastic cholestasis should be kept in mind in the absence of biliary tract obstruction, hepatic involvement or infectious etiology.     

Treatment of primary biliary cirrhosis

Primary biliary cirrhosis is a chronic liver disease of unknown etiology, characterized by inflammation and destruction of the intrahepatic biliary ducts, resulting in chronic cholestasis and eventually cirrhosis. The main clinical manifestations consists of pruritus, jaundice, xanthomas, and the consequences of intestinal malabsorption, including vitamin deficiencies and osteodystrophy. Treatment of PBC is addressed at preventing or relieving the symptoms and clinical consequences of chronic cholestasis, and also at correcting the bile duct abnormalities by specific treatments. Pruritus is treated with cholestyramine, but in some cases other drugs, such as rifampicin or opioid antagonists are needed. Bisphosphanates are effective for increasing bone mass in osteopenic patients. Vitamin D and cAlcium supplements are also recommended, particularly in patients with severe cholestasis. Ursodeoxycholic acid (UDCA) has become the standard treatment (13-15 mg/kg/day), resulting in marked relieving of cholestasis. UDCA also prevents the histological progression of the disease, although the effects on survival are less apparent. Small trials of combination therapy using UDCA with methotrexate, colchicine, or prednisone, have been reported but have not shown any increased efficacy over UDCA therapy. Liver transplantation is the only treatment available when cholestasis progresses, with very good survival rates.     

Drug- and chemical-induced cholestasis

Cholestasis caused by medicinal and chemical agents is an increasingly well-recognized cause of liver disease. Clinical drug-induced cholestatic syndromes producing jaundice and bile duct injury can mimic extrahepatic biliary obstruction, primary biliary cirrhosis, and sclerosing cholangitis, among others. This article updates the various forms of drug-induced cholestasis, focusing on the clinicopathologic features of this form of hepatic injury and on the known or putative mechanisms by which drugs and chemicals lead to cholestasis.     

Prochlorperazine-induced cholestasis in a patient with alpha-1 antitrypsin deficiency

A case of a 58-year-old woman with history of bilateral lung transplant secondary to alpha-1 antitrypsin deficiency (PIZZ), who presented with a severe drug-induced cholestasis secondary to prochlorperazine is reported. After 27 months of prochlorperazine use, she developed liver failure consisting of jaundice with ascites. Computed tomography of the abdomen, abdominal ultrasonography as well as an endoscopic retrograde cholangiopancreatography showed no evidence for biliary obstruction. Liver biopsy demonstrated diffuse ongoing advanced chronic cholestasis, moderate portal and periportal inflammation as well as bridging fibrosis. During her hospitalization, her total bilirubin increased to 38.6 mg/dL; alkaline phosphatase to 362 IU/L, alanine aminotransferase to 71 IU/L and aspartate aminotransferase to 88 IU/L. After several weeks of ursodiol therapy without clinical improvement the prochlorperazine was discontinued and was followed by a rapid improvement in her measures of liver injury. An immediate decline of her serum total bilirubin and alkaline phosphatase to 21.4 mg/dL and 258 IU/L, respectively, occurred strongly suggesting the idea of a prochlorperazine-induced injury.     

Fosinopril-induced prolonged cholestatic jaundice and pruritus: first case report

We report a case of fosinopril-induced prolonged cholestatic jaundice and pruritus in a 61-year-old man, with no previous hepatobiliary disease, who presented with asthenia, jaundice and itching 3 weeks after starting fosinopril therapy. Other drugs taken by the patient were not considered probable causes. The diagnostic evaluation showed no biliary obstruction and other possible causes of intra-hepatic cholestasis were excluded. Liver biopsy showed cholestasis without bile duct damage. The disease ran a severe course during the 2 months of hospitalization, with prolonged itching for 6 months, eventually controlled with oral naltrexone. Jaundice subsided after 4 months, with anicteric cholestasis persisting for more than 18 months. Similar occurrences have been reported with other inhibitors of angiotensin-converting enzyme (mostly captopril), but this is the first case of an important adverse reaction to fosinopril.     

A case of Venoplant-induced hepatic injury

The first case of hepatic injury induced by Venoplant, extracts of Aesculus Hippocastanum, having antiinflammatory activities, was described. A 37 yr-old man was admitted for treatment of pathological fracture of the left brachial bone. He had been received 65 mg Venoplant at another hospital several hours before admission. 17 days later, a liver function test showed mild abnormality and 60 days after injection, he complained of pruritus and jaundice. Laboratory studies revealed moderate elevation of total bilirubin, ALP, gamma-GTP and mild eosinophilia. CT studies and ERC showed no signs of extrahepatic obstructive jaundice. The lymphocyte stimulation test was positive. The liver biopsy demonstrated marked cholestasis with zonal necrosis in the centrilobular areas but showed little or no changes in the portal tracts. These features are consistent with drug-induced hepatic injury.     

Drug- and chemical-induced cholestasis

Cholestasis resulting from drugs is an increasingly recognized cause of liver disease. It produces a broad clinical-pathologic spectrum of injury that includes simple jaundice, cholestatic hepatitis, and bile duct injury that can mimic extrahepatic biliary obstruction, primary biliary cirrhosis, and sclerosing cholangitis. Although the risk of drug-induced cholestasis leading to a fatal outcome is quite rare, knowledge and recognition of the various forms of cholestatic injury assumes an importance whenever clinicians are confronted with jaundice or other manifestations of liver disease in patients receiving medicinal or chemical agents.