Erythromycin Jaundice: Diagnosis by an In Vitro Challenge Test

Summary: Erythromycin jaundice: diagnosis by an in vitro challenge test. A 53‐year‐old housewife who had developed. severe cholestatic hepatitis following the administration of erythromycin estolate therapy two‐and‐a‐half years previously, was studied by an in vitro “challenge” test in which peripheral venous lymphocytes were cultured in the presence of erythromycin estolate, erythromycin stearate and erythromycin base. Evidence of histogenesis was observed in response to erythromycin estolate, but not to erythromycin stearate or erythromycin base. This test thus provided evidence that the patient was “sensitized” to erythromycin estolate without exposing her to the risk of in vivo challenge. Furthermore, in contrast to previous studies, the findings provide evidence that erythromycin estolate jaundice is mediated by immunological mechanisms. Copyrigh

Cell-mediated immunity to liver antigen in toxic liver injury. I. Occurrence and specificity

To investigate the possible role of cell-mediated immunity in the pathogenesis of liver disease lymphocyte function was studied in CBA mice in which predictable sublethal liver necrosis had been included by the administration of the hepatotoxin carbon tetrachloride (CCl). Non-specific lymphocyte function, as assessed by the response to the mitogen phytohaemagglutinin (PHA) was normal in over 90% of the animals. Forty-three per cent of the treated mice demonstrated specific lymphocytes sensitivity to liver antigen preparations. Such specific sensitivity was transient and apparent in only one case for more than 2 weeks after the CCl treatment. The lymphocyte sensitization was not reproduced by the addition of CCl to the lymphocyte cultures. There was no correlation between the severity of the liver disease and the detection of sensitized lymphocytes. Although these data may not be extrapolated directly to human liver disease, they demonstrate that cell-mediated immune reactivity to liver-derived antigens can occur as a result of non-immunological toxic liver injury

Immunological abnormalities associated with liver disease: Cause or effect?

Summary: Immunological abnormalities are demonstrable in patients with various types of liver damage. These may be (a) non‐specific and unrelated to Pathogenesis, e.g. auto‐antibodies such as anti‐nuclear factor; (6) specifically directed against liver antigens but not pathogenetic, e.g. cell mediated immune (CMI) reactions to liver antigen as seen in experimental carbon tetrachloride poisoning; (c) of such a nature as to modify the pathology produced by hepatotoxic agents, e.g. hepatitis B virus or alcohol; (d) primarily responsible for hepatic pathology, e.g. in idiopathic chronic active hepatitis. The latter two possibilities remain unproven although there is growing evidence that immune responses do play some role in the pathogenesis of acute and chronic hepatitis B and possibly also in the pathogenesis of alcoholic liver disease. It seems much less likely that primary abnormalities of the immune systems are responsible for any type of liver disease. In summary, therefore, the available evidence suggests that immune reactions could develop as a consequence of liver damage and only in certain circumstances do these reactions play a role in the development and continuation of hepatic pathology. Copyrigh

A comparison of cobalamin binding by liver and kidney in rat and man

Binding of cobalamin (Cbl) was compared in liver and kidney plasma membranes prepared from rat and human tissues. Single, high-affinity, saturable (200 pmol/l), binding sites for TC II-Cbl were found in all tissues; by contrast no receptors were present for free cobalamin, for which only non-specific adsorption occurred. Binding constants for TC II-CNCbl determined for liver and kidney plasma membranes were of a similar magnitude. Mean values for K(a) (litre/nmol) were 16.7 (rat liver), 18.8 (rat kidney), 8.0 (human liver) and 7.5 (human kidney). Results for binding TC II-OHCbl instead of TC II-CNCbl showed no difference in K(a) and B(max) values, although the non-specific adsorption was decreased to a third. Competitive inhibition results showed that the receptors are specific for the TC II molecule and that binding is unaffected either by the cobalamin moiety or by the presence of free cobalamin. Degradation of the receptor protein molecules by trypsin (10 μg/ml) resulted in 90% inhibition of binding. It is concluded that differences between liver and kidney in cobalamin uptake and accumulation cannot be attributed to differences in their TC II receptors

Reticuloendothelial phagocytic function in human liver disease and its relationship to haemolysis

Summary. This study was undertaken to examine the hypothesis that enhanced reticuloendothelial (RE) phagocytosis and splenic sequestration of red blood cells are important aetiological factors in the haemolysis accompanying liver disease. RE phagocytic capacity (REPC) was measured by the rate of plasma disappearance of radio‐iodinated microaggregated human serum albumin (I‐MAA) in 57 patients with acute or chronic liver disease, and its relationship to splenic size, RBC survival and splenic sequestration of RBC was analysed. In addition, RE perfusion was measured using a tracer dose of I‐MAA, and the RE phagocytic index (REPI), an index of the individual cellular RE activity, independent of perfusion, was calculated. An increased REPI was found in all forms of liver disease, largely independent of aetiology or severity. REPC was normal in most forms of cirrhosis but was decreased in patients with alcoholic cirrhosis, many of whom had diminished RE perfusion, associated with clinical or radiographic evidence of portal systemic shunting. This decreased REPC was due to decreased RE perfusion since a close correlation between REPC and RE perfusion was demonstrated. The relationship between spleen size and REPC in patients with cirrhosis depended on the aetiology of the disease, since in alcoholic cirrhosis splenomegaly was usually indicative of portal hypertension, whereas in patients with active chronic hepatitis splenomegaly was often an integral part of the disease. A shortened RBC survival was demonstrated in 24 of 30 patients studied, but the degree of haemolysis did not correlate with REPC, REPI or splenic size. Furthermore, splenic sequestration of RBC could be demonstrated in only two patients. It would appear that in hepatic cirrhosis, the RE system, whether its phagocytic capacity is increased or decreased, removes effete RBC presented to it, but is not primarily responsible for the mild haemolytic process. Copyrigh