Sanjay Ramrakhiani

Troglitazone-Induced Hepatic Failure Leading to Liver Transplantation: A Case Report

Troglitazone (Rezulin, Parke-Davis, Morris Plains, New Jersey) is a new oral agent approved for treatment of patients with type 2 diabetes mellitus [1]. It inhibits hepatic gluconeogenesis and increases peripheral insulin sensitivity [2], possibly by binding to peroxisomal proliferator-activated receptors and altering insulin-dependent gene expression in the liver [3, 4]. Because troglitazone is the first available agent in a new class of drugs for treatment of a common disease, it has been widely prescribed since its approval by the U.S. Food and Drug Administration on 29 January 1997. In clinical trials, troglitazone-induced hepatotoxicity (alanine aminotransferase level > three times the upper limit of normal) was identified in 1.9% of 2510 patients; these abnormalities resolved with discontinuation of therapy with the drug [5]. In contrast to this experience in clinical trials, postmarketing reports to the U.S. Food and Drug Administration since 15 December 1997 include liver transplantation and death caused by troglitazone hepatotoxicity in 3 of 500 000 patients treated in the United States and 2 deaths out of 150 000 patients treated in Japan [6]. Because of these reports, monthly monitoring of aminotransferase levels in all patients during the first 6 months of therapy and every 2 months for the remainder of the first year is now recommended [7]. The clinical characteristics and histologic correlates of severe troglitazone hepatotoxicity have not been described in detail or published, and physician awareness of troglitazone hepatotoxicity is primarily the result of mailings by the manufacturer. A recent summary of data from troglitazone clinical trials did not identify the possibility of troglitazone-induced hepatic failure [5]. Furthermore, it has been stated that troglitazone-induced changes in liver enzymes are largely mild and reversible [8]. We describe one of the patients reported to the Food and Drug Administration with liver failure apparently caused by troglitazone who ultimately required liver transplantation. Case Report A 59-year-old obese woman had had type 2 diabetes mellitus for 9 years that was complicated by retinopathy, nephropathy and neuropathy. She was prescribed troglitazone, 400 mg/d, because of poor glycemic control despite use of insulin, 150 U/d. She had a history of medullary sponge kidney, surgical removal of kidney stones, and intermittent episodes of hematuria and pyuria Her baseline serum creatinine level was 133 mol/L (1.5 mg/dL). She had no history of autoimmune diseases and had undergone hysterectomy and cholecystectomy. She was taking no other prescription or over-the-counter medications, denied using alcohol or intravenous drugs, and had not received recent blood transfusion. She reported allergy to penicillin and cephalosporins. Troglitazone improved her glycemic control and diminished her insulin requirement. She noted the onset of nausea and vomiting within 2 weeks of starting troglitazone therapy and dark urine after 2 months but did not report these symptoms to her physicians. After 3 months, she presented with nausea, vomiting, malaise, and hematuria. Although trimethoprim-sulfamethoxazole was prescribed for presumed recurrent urinary tract infection and cisapride was prescribed for possible diabetic gastroparesis, neither medication was used for more than 2 days because of nausea and vomiting. After receiving troglitazone for 3.5 months, the patient learned of potential troglitazone hepatotoxicity through the Internet and discontinued therapy with the drug. Over the following 2 weeks, she developed jaundice and was hospitalized. On presentation, she was noted to be icteric but showed no signs of hepatic encephalopathy. Laboratory tests revealed a prothrombin time of 16.5 seconds (international normalized ratio, 1.82), a bilirubin level of 148 mol/L (8.7 mg/dL), an alkaline phosphatase level of 5.7 nkat/L (345 U/L), an aspartate aminotransferase level of 13.3 kat/L (798 U/L), and an alanine aminotransferase level of 6.75 kat/L (405 U/L). Results of tests for anti-hepatitis B core IgM, hepatitis B surface antigen, anti-hepatitis A virus IgM, anti-hepatitis C virus, hepatitis B virus DNA, and hepatitis C virus RNA (the latter by polymerase chain reaction) and results of serology for acute cytomegalovirus and Epstein-Barr virus infection were negative. Her anti-smooth-muscle antibody titer was 1:20, and tests for antinuclear and antimitochondrial antibodies had negative results. Levels of serum ceruloplasmin and 1-antitrypsin and results of iron studies were normal. One year earlier, the patient had had minimal elevations of the alkaline phosphatase level (2.6 nkat/L [156.0 U/L]) and aspartate aminotransferase level (0.67 kat/L [40.0 U/L]). The leukocyte count (4600 cells/mm3) and the peripheral eosinophil count (110 cells/mm3) were normal. Ultrasonography revealed a hyperechoic liver, and computed tomography revealed a mildly irregular liver contour. On the second hospital day, the patient developed stage 1 hepatic encephalopathy and was transferred to a liver transplantation center. Transjugular liver biopsy showed severe parenchymal extinction and replacement of 80% of the tissue by loosely organized scar and collapsed parenchyma. Because her encephalopathy worsened from stage I to stage II and her prothrombin time increased to 24 seconds (international normalized ratio, 2.05), the patient underwent orthotopic liver transplantation 3 weeks after stopping troglitazone therapy. During the week before transplantation, her total bilirubin level increased to 279 mol/L (16.3 mg/dL), her serum creatinine concentration increased from 124 mol/L (1.4 mg/dL) to 256 mol/L (2.9 mg/dL), her serum albumin level decreased from 27 g/L to 23 g/L, and her partial thromboplastin time increased from 36 seconds to 49 seconds (high normal, 31 seconds). Her venous ammonia concentration decreased from 77 mol/L (134 g/dL) to 38 mol/L (64 g/dL) with lactulose treatment despite progression of encephalopathy. Other precipitants of hepatic encephalopathy, such as infection or gastrointestinal hemorrhage, were not present. The explanted liver weighed 1950 g and had an irregular nodular surface with marked capsular wrinkling. Histologic examination of the explanted liver confirmed the initial biopsy findings (Figure 1). During 4 months of posttransplantation observation, the transplanted liver functioned well, and the patient regained full cognitive function. Difficulties with persistent hematuria necessitated percutaneous and transurethral removal of renal calculi. Figure 1. Liver histologic findings. Top. Middle. Bottom. Discussion This patient developed nonspecific symptoms during troglitazone treatment that in retrospect were probably caused by drug-induced liver injury. On presentation, she had significant hepatic synthetic dysfunction and elevated aminotransferase levels even though she had stopped taking the drug 1 week earlier. Over the subsequent 2 weeks, her liver function continued to deteriorate, and she ultimately required liver transplantation. This patient had no other known exposure to hepatotoxins, and evaluation did not reveal any evidence of viral, metabolic, or autoimmune liver disease. Liver histologic findings were consistent with drug-induced liver injury. Although other causes of acute liver disease were not identified and biopsy results did not suggest chronic liver disease, the patient had risk factors for chronic liver disease. Nonalcoholic steatohepatitis causes slowly progressive fibrosis in some obese diabetic patients, but histologic examination of the liver did not show steatosis, inflammation, or sinusoidal fibrosis, characteristics that define this syndrome. Medullary sponge kidney is also associated with hepatic fibrosis in rare cases, but our patient did not have the characteristic ductal plate malformations and broad portal fibrosis. Of note, the patient became aware of possible troglitazone-induced hepatotoxicity through information available on the Internet. Patients increasingly obtain information of varying accuracy from the Internet. In this case, the patient identified relevant drug information before her physicians had received new monitoring recommendations from the manufacturer. Unfortunately, it was still too late to affect her outcome. The cause of troglitazone hepatotoxicity remains unknown. Troglitazone is primarily metabolized to sulfate and glucuronide conjugates in the liver. It also induces cytochrome P450 3A4 activity, and a small fraction undergoes cytochrome P450 oxidation to a quinone derivative. The molecular structure of the drug is similar to that of vitamin E; thus, it may be subject to oxidation-reduction reactions. It is thought to have protective properties against oxidant stress [9, 10], but its ability to undergo single-electron reduction could also confer injurious prooxidant reactivity. Examples of toxic quinones include the reactive metabolite of acetaminophen, doxorubicin, and various compounds from tobacco smoke. In this patient, the use of troglitazone seems to have been associated with the development of hepatic failure. The basis for this idiosyncratic reaction is unknown and is therefore unpredictable. Patients treated with troglitazone should have their serum aminotransferase and bilirubin levels monitored in accordance with the manufacturers recommendations: at the start of therapy, monthly during the first 6 months of treatment, every 2 months for the remainder of the first year, and periodically thereafter or if symptoms develop. Therapy with the drug should be discontinued if clinically significant abnormalities are found. From St. Louis University School of Medicine, St. Louis, Missouri; and University of Missouri-Kansas City, Kansas City, Missouri. Drs. Phillips and Brunt: Department of Pathology, St. Louis University School of Medicine, 3635 Vista Avenue, St. Louis, MO 63110. Drs. Quiason, Oki, and Isley: Uni

Orlistat in the Treatment of NASH: A Case Series

Nonalcoholic steatohepatitis is now recognized as a common chronic liver disorder. Up to 16% of affected patients may progress to cirrhosis. The incidence and prevalence of this disease are noted to be increasing, in parallel with the nationwide increase in obesity and diabetes. Treatment options for these patients remain quite limited, however. Weight reduction has been advocated, but there are little data to support this practice, as most patients are unable to comply with the proper dietary modifications. We report three obese patients with biopsy-proven nonalcoholic steatohepatitis treated for 6–12 months with a weight reduction medication, orlistat, who lost between 22–42 lb, and had significant clinical and histopathological improvement on follow-up.

Biliary-Venous Fistula Complicating Transjugular Intrahepatic Portosystemic Shunt Presenting With Recurrent Bacteremia, Jaundice, Anemia and Fever

A 50‐year‐old White man with noncirrhotic portal hypertension presented with bleeding from gastric varices. Bleeding was initially managed with band ligation and subsequent transjugular intrahepatic portosystemic shunt (TIPS). Over the next few months, the patient had recurrent episodes of anemia, jaundice, fever and polymicrobial bacteremia. Computed tomography (CT) of the abdomen and chest, upper and lower endoscopy, endoscopic retrograde cholangiopancreatography (ERCP), and echocardiography failed to explain the bacteremia and anemia. Follow‐up CT scan and Doppler sonography 9 months after placement showed TIPS was occluded. Repeat ERCP showed a bile leak with free run‐off of contrast from the left hepatic duct into a vascular structure. The patients status was upgraded for liver transplantation with Regional Review Board agreement and subsequently received a liver transplant. Gross examination of the native liver demonstrated a fistula between the left bile duct and the middle hepatic vein. Pathologic evaluation confirmed focal necrosis of the left hepatic duct communicating with an occluded TIPS and nodular regenerative hyperplasia consistent with noncirrhotic portal hypertension. Infection is rarely reported in a totally occluded TIPS. Biliary fistulas in patent TIPS have been treated by endoluminal stent graft and endoscopic sphincterotomy with biliary stent placement. Liver transplantation may be the preferred treatment if TIPS becomes infected following its complete occlusion.

Possible cholestatic injury from ranitidine with a review of the literature

Although one of the histamine-2 (H2) receptor antagonists, oxmetidine, has been shown to be intrinsically hepatotoxic, overt liver injury attributable to the commonly used analogues such as ranitidine is rare, given the millions of patients who have received this medication. However, isolated cases of hepatitis associated with ranitidine have been reported in the literature since the early 1980s when this drug was first introduced. We report a case of cholestatic hepatitis associated with ranitidine use. Liver biopsy showed diffuse panacinar canalicular cholestasis and cholestatic rosettes in zone 3. The clinical syndrome and the laboratory abnormalities resolved completely after discontinuation of the drug. There have been a few other published reports of ranitidine associated acute cholestatic hepatitis, and in this case ranitidine was temporally related to the onset of symptoms and liver enzyme abnormalities. With recent over-the-counter (OTC) availability of the H2 receptor antagonists and the increasing use of these drugs in the general population, physicians need to be aware of this rare but potentially serious side effect of ranitidine.

Is hepatitis G/GB virus-C virus hepatotropic? Detection of hepatitis G/GB virus-C viral RNA in liver and serum.

The recently identified hepatitis G virus (HGV, also named GB virus‐C, GBV‐C) appears to have similarities to hepatitis C virus and other flaviviridae. To better understand its clinical significance and hepatotropism, we collected liver tissue and matched serum samples from 56 patients undergoing liver transplantation. HGV/GBV‐C RNA was detected by reverse transcription–nested PCR, using primers from the relatively conserved 5′ noncoding region of the genome to detect HGV/GBV‐C RNA and the amount was semiquantitatively estimated by serial 10‐fold endpoint dilution. The presence and amount of HCV RNA was estimated by the same methodology. Seventeen patients (30%) had HGV/GBV‐C RNA detectable either in liver or in serum, including two of three with cryptogenic liver disease. Interestingly, 5 of 17 (29%) patients had HGV/GBV‐C RNA in serum but not liver, even with repeated testing of hepatic RNA from different portions of the liver. Furthermore, the titer of HGV/GBV‐C RNA was significantly lower in liver than in serum in most samples (mean log titer, 1.33 vs. 2.56, P < 0.05). In contrast, all 21 patients with HCV RNA in serum also had the virus detectable in liver. In five patients coinfected with HCV and HGV/GBV‐C, the mean titer of HCV RNA in liver was higher than that in serum (log titer, 2.8 vs. 3.0, P > 0.05). Thus, our results suggest that HGV/GBV‐C is probably not hepatotropic and may replicate predominantly in sites other than the liver. These findings brings into question the role of HGV in causing significant liver disease. J. Med. Virol. 58:160–164, 1999.

Hemochromatosis: Advances in Molecular Genetics and Clinical Diagnosis

Hereditary hemochromatosis (HH) is a human leukocyte antigen-linked inherited disease that is characterized by inappropriately high absorption of iron by the gastrointestinal mucosa. The spectrum of disease presentation is changing with more and more patients now being identified before they are symptomatic with complications of iron overload. A candidate gene for HH, called HFE, was identified in 1996, and a test for the gene is commercially available. A review of the recent identification of the gene and its implications for clinical diagnosis and therapy is presented. We also propose an algorithm for evaluation of patients for HH. Early diagnosis and appropriate therapy can prevent significant morbidity and mortality associated with the development of end-organ complications of HH. The understanding of the C282Y and H63D mutations is still evolving, and the algorithm and the contribution of various heterozygous mutations to the diagnosis and management of iron overload need to be confirmed by further clinical and genetic studies.

Hepatology in the new millennium. Advances in viral hepatitis, hepatic disorders, and liver transplantation.

The 1990s have been an exciting time for the field of hepatology. There has been a rapid expansion of knowledge, and new discoveries have revolutionized the field. It is now possible to characterize and treat many more liver diseases. Newer medications in the form of interferon alfa and nucleoside analogues have been added to the armamentarium for treatment of chronic viral hepatitis. Liver transplantation has been established as an effective therapy for patients with end-stage liver disease.

751c Effectiveness of the Third Eye Retroscope for Detecting Polyps in the Right Colon

Background & Aims: Lysophosphatidic acid (LPA), a naturally produced phospholipid, mediates multiple effects that are vital to disease process, including cancer and inflammation. The expression of LPA receptor 2 (LPA2) is up-regulated in several types of cancer, including ovary and colon cancer (CC), but the importance of LPA and LPA2 in the development and progression of CC is unclear. Chronic inflammation is also a risk factor for CC. In this study, we sought to determine whether LPA and LPA2 regulate the progression of CC using animal models of CC. Methods: We examined the potential effects of LPA in CC progression by administering LPA to ApcMin/+ mice. We determined the role of LPA2 in colon tumorigenesis by examining the loss of LPA2 function. We treated LPA2-/mice with azoxymethane (AOM) and dextran sulfate sodium (DSS). Furthermore, we examined the role of LPA2 in modulating intestinal adenoma formation by crossing LPA2-/mice with ApcMin/+ mice. Results: We found that LPA treatment by gavage increased the number of adenomas in small intestine in Apcmin/+ mice. The difference in body weight and mortality suggested that the absence of LPA2 protected animals from the AOM/DSS treatment. LPA2-/mice treated with AOM/DSS showed significantly fewer and smaller tumors in the colon than wild-type (WT) mice. There was no difference in number and size of tumors between LPA2+/and WT mice. We observed reduced epithelial cell proliferation and decreases in β-catenin, Kruppel-like factor 5 (KLF5), and cyclooxygenase-2 (COX-2) expression in LPA2-/mice compared to WT. Compared to WT mice, induction of monocyte chemoattractant protein-1 (MCP-1) and macrophage migration inhibitory factor (MIF) was significantly abrogated in LPA2-/mice with reduced infiltration by macrophages. The absence of LPA2 expression in ApcMin/ + mice resulted in a significant decrease in adenomas. At 5 month, ApcMin/+/LPA2-/mice developed an average of 22 adenomas in the small intestine compared with 38 in ApcMin/ +/LPA2+/+ and 43 in ApcMin/+/LPA2+/mice. Consistently, the average number of adenomas in the colon was 2.67, 1.75, and 0.64 for ApcMin/+/LPA2+/+, ApcMin/+/LPA2+/-, and ApcMin/ +/LPA2-/respectively. Adenomas larger than 2 mm accounted for 18% for ApcMin/+/LPA2-/mice in contrast to 38% for ApcMin/+/LPA2+/+. Conclusion: The absence of LPA2 attenuates several effects that may contribute to tumorigenesis In Vivo. Hence, our studies identify LPA2 as a modulator of intestinal tumorigenesis.