Jaundice and Hepatocellular Damage

8/13/01 (Franz)

Question: How long does jaundice linger after acute hepatocellular damage or injury?

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Unique Identifier: 21039878 / PubMed Identifier: 11197248

Authors: Kim HJ. Kim BH. Han YS. Yang I. Kim KJ. Dong SH. Kim HJ. Chang YW. Lee JI. Chang R.

Institution: Department of Internal Medicine, Kyung Hee University College of Medicine, Seoul, Korea.

Abstract: OBJECTIVES: Although symptomatic propylthiouracil (PTU)-induced hepatic injury is known to be rare, there have been few reports about its exact incidence in patients with hyperthyroidism. We tried to evaluate its incidence in a single center and its clinical course. METHODS: Medical records of 912 hyperthyroid patients who had been diagnosed between March 1990 and December 1998 were reviewed about clinical characteristics, management, and laboratory findings. Symptomatic PTU-induced hepatic injury was defined as the development of jaundice or hepatitis symptoms with at least a 3-times elevation of liver function tests (LFT) without other causes. RESULTS: Four hundred ninety-seven patients (age 42.6 +/- 10.7 yr, male/female 140/357) were included. Clinically overt hepatitis developed in six patients (1.2%; age, 43.7 +/- 14.8 yr; male:female ratio, 3:3) between 12 and 49 days after PTU administration. Jaundice and itching developed in five patients, fever in two, rash in two, and arthralgia in one. Bilirubin, ALT, and ALP increased in five, four, and six patients, respectively (293 +/- 288 micromol/L, 143 +/- 111 U/L, and 265 +/- 81 U/L; normal, < 117 U/L). The type of hepatic injury was cholestatic in three, hepatocellular in one, and mixed in two patients. None resulted from viral hepatitis. There were no statistical differences in age, sex, PTU dose, or T4 and T3 levels at initial diagnosis between patients with and without hepatic injury. LFT normalized in all patients between 16 and 145 (72.8 +/- 46.4) days after the PTU withdrawal. CONCLUSIONS: Symptomatic hepatic injury develops usually within the first few months of PTU administration with rare frequency, but its clinical course is relatively benign once the drug is withdrawn. However, it may be difficult to predict its development, so all patients should be monitored for rise in LFTs at regular intervals, especially during the early period.

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Unique Identifier: 99028701 / PubMed Identifier: 9812167

Authors: Romagnuolo J. Sadowski DC. Lalor E. Jewell L. Thomson AB.

Institution: Department of Gastroenterology, University of Alberta, Edmonton. jr5@gpu.srv.ualberta.ca

Abstract: Azathioprine is a drug commonly used for the treatment of inflammatory bowel disease, organ transplantation and various autoimmune diseases. Hepatotoxicity is a rare, but important complication of this drug. The cases reported to date can be grouped into three syndromes: hypersensitivity; idiosyncratic cholestatic reaction; and presumed endothelial cell injury with resultant raised portal pressures, venoocclusive disease or peliosis hepatis. The components of azathioprine, 6-mercaptopurine and the imidazole group, may play different roles in the pathogenesis of hepatotoxicity. The strong association with male sex, and perhaps with human leukocyte antigen type, suggests a genetic predisposition of unknown type. Many of the symptoms of hepatotoxicity, such as nausea, abdominal pain and diarrhea, can be nonspecific and can be confused with a flare-up of inflammatory bowel disease. As well, the subtype resulting in portal hypertension can occur without biochemical abnormalities. A 63-year-old man with Crohn's disease who is presented developed the rare idiosyncratic form of azathioprine hepatotoxicity, but also had a severe disabling steroid myopathy, peripheral neuropathy, resultant deep venous thrombosis and pulmonary embolism related to immobility, and a nosocomial pneumonia. His jaundice and liver enzyme levels improved markedly on withdrawal of the drug, returning to almost normal in five weeks. Treating inflammatory bowel disease effectively while trying to limit iatrogenic disease is a continuous struggle. Understanding the risks of treatment is the first important step. There must be a low threshold for obtaining liver function tests, especially in men, and alertness to the need to discontinue the drug or perform a liver biopsy should patients on azathioprine develop liver biochemical abnormalities, unexplained hepatomegaly or signs of portal hypertension. [References: 24]

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Unique Identifier: 98359691 / PubMed Identifier: 9696502

Authors: Van Steenbergen W. Peeters P. De Bondt J. Staessen D. Buscher H. Laporta T. Roskams T. Desmet V.

Institution: Department of Internal Medicine, University Hospital Gasthuisberg-St Rafa&#x00EB;l, Catholic University of Leuven, Belgium.

Abstract: BACKGROUND/AIMS: A number of nonsteroidal anti-inflammatory drugs have been reported to provoke hepatic injury. Nimesulide is a new agent of the sulfonanilide class, and is a more selective inhibitor of cyclooxygenase type 2 than of type 1. Well-documented cases of acute hepatitis have not yet been reported with this drug. We report on six patients who developed acute liver damage after initiation of nimesulide. METHODS: Between April 1996 and January 1997, six patients with apparent nimesulide-induced liver injury were admitted. Clinical, laboratory, serologic, radiological, and histologic data of all six cases were extensively analyzed. The causal relationship between nimesulide and liver injury was assessed, using a scoring system elaborated by the French and International consensus meeting group. RESULTS: Four women developed a centrilobular (three) or panlobular (one) bridging necrosis, whereas two men showed a bland intrahepatic cholestasis. Jaundice was the presenting symptom in five of the six cases. One patient with hepatocellular necrosis and one with cholestasis had hallmarks of hypersensitivity with an increased blood and tissue eosinophilia. The causal relationship could be designated as "highly probable" in one, "probable" in four, and "possible" in one patient. One patient died from a pancreatic tumor 5 months after the diagnosis of toxic liver injury. In all other patients, liver tests returned to completely normal values within a late follow-up period of 6 to 17 months. CONCLUSIONS: Nimesulide-induced liver injury can present with hepatocellular necrosis or with pure cholestasis. From clinical and histologic data, it appears that both immunologic and metabolic idiosyncratic reactions can be invoked as the pathogenic mechanisms of nimesulide-induced liver disease.

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Unique Identifier: 96319106 / PubMed Identifier: 8747106

Authors: Pan CG. Leichter HE. Werlin SL.

Institution: Department of Pediatrics, Medical College of Wisconsin, Children's Hospital of Wisconsin, Milwaukee 53226-0509, USA.

Abstract: Streptococcus pneumoniae is an uncommon etiological organism in hemolytic uremic syndrome (HUS). Production of neuraminidase by S. pneumoniae results in exposure of red blood cell T-antigen, resulting in hemolysis, thrombocytopenia, and acute renal failure. Hepatic involvement in this form of HUS has not been described in the literature. We report in three children with S. pneumoniae-associated HUS the presence of severely elevated transaminases and conjugated hyperbilirubinemia. Increases in asparagine transaminase ranged from 11 to 46 times normal values and an increase in alanine transaminase ranged from 1.6 to 8 times normal. In all patients the rise in total bilirubin was 7-15 times normal. Biliary tree obstruction and viral causes for liver dysfunction were absent. Hepatocellular injury in S. pneumoniae-associated HUS likely results from mechanisms involved in sepsis and pneumonia-induced jaundice, combined with severely increased bilirubin production following massive hemolysis. The hepatic injury in all three patients resolved within 9, 5, and 10 days. Our experience suggests that an extensive evaluation including liver biopsy is not indicated.

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Unique Identifier: 95119556 / PubMed Identifier: 7819719

Authors: Habior A. Walewska-Zielecka B. Butruk E.

Institution: Department of Gastroenterology, Medical Center for Postgraduate Education, Warsaw, Poland.

Abstract: Two cases (first cases from Poland and Eastern Europe) with liver injury due to amoxycillin-clavulanic acid (augmentin) are reported. Pruritus and jaundice were the main symptoms. Liver biopsy revealed mixed hepatocellular-cholestatic liver injury in both cases. In addition, in one case the microgranulomalike aggregate of inflammatory cells was found. Clinical and laboratory abnormalities returned to normal within 13 weeks.

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Unique Identifier: 90171482 / PubMed Identifier: 2307831

Authors: Iveson TJ. Ryley NG. Kelly PM. Trowell JM. McGee JO. Chapman RW.

Institution: Department of Gastroenterology, John Radcliffe Hospital, Headington, Oxford, U.K.

Abstract: Diclofenac is a widely used non-steroidal anti-inflammatory drug, being the most commonly prescribed of its kind in the world. This paper describes five cases of hepatitis with clinical features indicating a direct link with diclofenac. All the patients presented with an acute hepatitis, three being jaundiced. They gave a history of taking diclofenac up to the time of presentation, four of the five having started the drug within the previous 3 months. There were no other features in the histories to suggest alternative causes for the liver dysfunction. Liver function tests were grossly abnormal in all cases, showing a hepatitic picture. A liver biopsy was performed in 4 cases, and showed features of an acute hepatitis with inflammation and hepatocyte damage dominating. The liver dysfunction returned to normal on drug withdrawal in four of the five cases, with full recovery by 3 months. One patient developed steroid-responsive chronic active hepatitis. Hepatotoxicity associated with diclofenac is documented, but previously only a few isolated cases have been described. The occurrence of five cases in one gastroenterology unit over a 12-month period suggests that hepatitis associated with diclofenac may be commoner than previously supposed.

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Unique Identifier: 87129626 / PubMed Identifier: 3101906

Authors: Lake-Bakaar G. Scheuer PJ. Sherlock S.

Abstract: Ketoconazole was introduced in the United Kingdom in 1981. By November 1984 the Committee on Safety of Medicines had received 82 reports of possible hepatotoxicity associated with the drug, including five deaths. An analysis of the 75 cases that had been adequately followed up suggested that 16, including three deaths, were probably related to treatment with the drug. Of the remainder, 48 were possibly related to treatment, five were unlikely to be so, and six were unclassifiable. The mean age of patients in the 16 probable cases was 57.9, with hepatotoxicity being more common in women. The average duration of treatment before the onset of jaundice was 61 days. None of these well validated cases occurred within the first 10 days after treatment. The results of serum liver function tests suggested hepatocellular injury in 10 (63%); the rest showed a mixed pattern. In contrast, the results of histological examination of the liver often showed evidence of cholestasis. The characteristics of the 48 patients in the possible cases were similar. Allergic manifestations such as rash and eosinophilia were rare. Hepatitis was usually reversible when treatment was stopped, with the results of liver function tests returning to normal after an average of 3.1 months. In two of the three deaths probably associated with ketoconazole treatment the drug had been continued after the onset of jaundice and other symptoms of hepatitis. Clinical and biochemical monitoring at regular intervals for evidence of hepatitis is advised during long term treatment with ketoconazole to prevent possible serious hepatic injury.

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Unique Identifier: 77194499 / PubMed Identifier: 866571

Authors: Tugwell P. Williams AO.

Abstract: Twenty-eight patients with jaundice associated with lobar pneumonia have been studied. The epidemiological and clinical features were compared with 70 patients with lobar pneumonia without jaundice. Jaundice was associated with a predominance of males, a high incidence of right lower lobe consolidation and hepatic tenderness. Although the jaundiced patients remained pyrexial for longer it was not associated with a poor prognosis. There was no evidence of immunological deficiency although pneumococcal polysaccharide antigenaemia was commoner in jaundiced patients. Laboratory investigations showed evidence of haemolysis in the majority of jaundiced patients and the cause of this was found to be G6PD deficiency. Starch-yel electrophoresis demonstrated that the phenotype was A- in deficient patients. Hepatic function tests were unhelpful. Light and electron microscopical changes consistent with haemolysis were present in liver biopsies from G6PD deficient patients although hepatocellular damage and cholestasis were also present.

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Unique Identifier: 76178400 / PubMed Identifier: 1265605

Authors: Champion HR. Jones RT. Trump BF. Decker R. Wilson S. Miginski M. Gill W.

Abstract: Nineteen patients who had profound hypotensive shock were studied to correlate the light and electron microscopic appearances of the liver with the clinical and biochemical evidence of hepatic dysfunction. Despite the multiple etiologic factors that can result in jaundice in these patients, a fluctuating pattern occurs which enables the correlation of a bilirubin peak with the predominating etiologic factor. Immediately after shock, there was enzymatic and light and electron microscopic evidence of hepatocellular damage, resulting in a jaundice peak on the eighth to tenth day after the shock episode. This was followed by repair and regeneration of the liver as well as an increase in cholestatic enzyme levels. Later, bilirubin peaks occurred when hepatocellular function was further decreased or overloaded against this background of dysfunction related to the episode of shock. Recovery of hepatic function could continue or be delayed by intercurrent disease, particularly systemic infection. Support of hepatic function, similar to that available for pulmonary and renal failure may, in the future, be used to effect the prognosis of these patients.