Leonard B. Seeff

Histopathologic analysis of suspected amiodarone hepatotoxicity

This analysis of the morphology of suspected amiodarone (AD) liver disease is based on a study of liver specimens from 17 individuals. Changes similar to alcoholic liver injury were commonly seen. Steatosis, both macrovesicular and microvesicular, was the most frequent histopathologic feature. Ballooning of hepatocytes, Mallory bodies, and fibrosis were also common. Other changes included nuclear unrest, acidophilic bodies, foam cells, glycogenated nuclei, and portal inflammation. Characteristic lamellar lysosomal inclusion bodies representing phospholipidosis were found in two of 14 specimens studied ultrastructurally. These changes of pseudoalcoholic hepatitis and/or phospholipidosis were present in liver specimens from asymptomatic, anicteric patients with mild elevations in serum aminotransferase or alkaline phosphatase values with or without hepatomegaly, as well as in patients with clinically overt symptoms of hepatotoxicity. Phospholipidosis appears to be a generalized systemic effect of cationic amphophilic compounds, such as AD. The cytotoxic pseudoalcoholic changes appear to be an independent phenomenon in susceptible patients, whom we speculate may have been unable or less able to metabolize AD through normal pathways. The true incidence of hepatic injury from AD remains to be determined from prospective evaluations of pretreatment and follow-up liver biopsies.

Significance of megamitochondria in alcoholic liver disease

The significance of megamitochondria in the alcoholic liver injury of humans was investigated as part of a large Veterans Administration cooperative study of the natural history of alcoholic hepatitis. Two hundred twenty patients were clinically stratified into the following three groups according to disease severity using serum bilirubin and prothrombin time as indicators: Group 1 (mild disease), serum bilirubin levels less than 5 mg/dl and prothrombin time prolonged for less than 4 s; group 2 (moderate disease), serum bilirubin levels greater than 5 mg/dl but prothrombin time prolonged for less than 4 s; and group 3 (severe disease), serum bilirubin levels greater than 5 mg/dl and prothrombin time prolonged for greater than 4 s. Megamitochondria were observed in 20% of the patients (45 of 220). Of these, 43 patients were in groups 1 and 2 of severity and only 1 patient belonged in group 3. The association of megamitochondria with cirrhosis was infrequent (33%, 15 of 45 patients). The differences in severity correlated with the differences in mortality: in patients with megamitochondria, only 1 had died at 6 mo compared with 40 deaths in patients without megamitochondria. By 12 mo, there were two deaths in patients with megamitochondria versus 51 deaths in those patients without. No complications were present in 72% of patients with megamitochondria versus 39% for those without. Infection, gastrointestinal bleeding, pancreatitis, hyperglycemia, azotemia, delirium tremens, seizures, and hepatic encephalopathy were all more common in patients without megamitochondria. The patients with megamitochondria appear to represent a subcategory of alcoholic hepatitis with a milder degree of clinical severity, lower incidence of cirrhosis, fewer complications, and good long-term survival.

Hepatitis C from a Needlestick Injury

To the Editors: Transfusion-associated non-A, non-B hepatitis has recently been shown to result usually from infection with the hepatitis C virus (HCV) (1). Although we recognize that non-A, non-B ...

Azathioprine induced hepatic veno-occlusive disease in rheumatoid arthritis.

A patient with rheumatoid arthritis developed hepatic veno-occlusive disease following the use of azathioprine. Although azathioprine induced veno-occlusive disease is suspected to occur more frequently in patients with autoimmune dysfunction, it has not previously been reported as a complication of treatment in rheumatoid arthritis. The mechanism responsible for this condition remains unknown.

‘How Frequent is Posttransfusion Hepatitis after the Introduction of 3rd Generation Donor Screening for Hepatitis B? What is its Probable Nature?’

Third generation donor screening for hepatitis B is not generally efficacious in reducing PTH B except under certain epidemiological conditions. The nature of the remaining cases of PTH varies from region to region and depends on actual epidemiological circumstances. Cases of HB, transmitted by HBsAg-negative but nevertheless HBV-infectious blood, should be considered as well as cases of HB, transmitted by vehicles other than transfusion-blood, but confusingly also classified as PTH. Hepatitis A and hepatitis due to agents not yet identified occurring in blood recipients need further investigation. In such cases it remains an open question too, whether the disease is mainly transmitted with the transfusion-blood or by other vehicles, associated with large and long-lasting wounds or hospital environments as closely as blood transfusions are.

Preliminary assessment of glycine conjugation of para-aminobenzoic acid as a quantitative test of liver function.

OBJECTIVESnOur hypothesis is that because of its hepatic metabolism paraaminobenzoic acid (PABA) could be a test of liver function.nnnDESIGN AND METHODSnPABA is well absorbed by the gastrointestinal tract and acetylated and conjugated in the liver to glycine before being excreted. Its three major metabolites include para-acetoamidobenzoic acid (PAABA), paraaminohippuric acid (PAHA), and paraacetamidohippuric acid (PAAHA). In this study, we measured the metabolism of lidocaine to monoethylglycinexylidide (MEGX) and PABA to PAHA+PAAHA/PABA+PAABA+PAHA+PAAHA (hippurate ratio) in 14 patients with liver disease and 12 control subjects.nnnRESULTSnComparison of the total bilirubin with the hippurate ratio (at 30 min) and the conventional MEGX test (at 15 min) was assessed. The 30 min hippurate ratio correlated well with the 15 min MEGX results (r = 0.69).nnnCONCLUSIONSnWhile these results are preliminary the PABA test appears to be equally sensitive to MEGX and has the distinct advantage over the MEGX test of being administered orally versus the intravenous administration of lidocaine which is often associated with unwanted side-effects such as hypotension, drowsiness and paresthesias.

In vitro immune responses to hepatitis B surface antigen (pre-S2 and S) following remote infection by hepatitis B virus in humans

In this report we evaluate the human immune response to hepatitis B surface antigen (HBsAg) following remote infection with hepatitis B virus (HBV). HBsAg-reactive lymphocytes can be readily demonstrated in the peripheral blood of individuals with established immunity following infection with HBV.In vitro stimulation with small doses of plasma-derived HBsAg, yeast-derived HBsAg (S region) or pre-S2 peptide will induce specific IgG to HBsAg (anti-HBs) in the absence of a polyclonal increase in total IgG. The pre-S2 peptide will stimulate, in a T cell-dependent fashion, thein vitro production of anti-HBs with specificity for the S domain. This anti-HBs production is mediated by pre-S2-stimulated soluble T-cell factors. Peripheral blood mononuclear cells from individuals with established immunity proliferate to the yeast-derived HBsAg but not to the plasma-derived HBsAg or pre-S2 peptide. The chronic HBsAg carriers do not produce anti-HBs following stimulation with HBsAg regardless of the source or component of antigen used. Different study protocols failed to demonstrate HBsAg-specific responses in the peripheral blood mononuclear cells of chronic carriers.

Jaundice of Systemic Infection

A variety of infectious diseases may produce jaundice or other biochemical abnormalities, even though the liver is not the primary site of infection.1–3 Despite the often serious nature of the infection or underlying disease process, the hepatic aspects are generally not life-threatening. However, the assorted liver aspects can mimic extrahepatic obstructive jaundice, making it important to identify the source of the hepatic dysfunction using such imaging techniques as ultrasonography or computed tomography (CT) or performing the appropriate Cholangiographic procedures.4