Carroll M. Leevy

Lymphocyte Cytotoxicity in Alcoholic Hepatitis

Studies were undertaken to evaluate the cytotoxicity of peripheral lymphocytes obtained from patients with alcoholic hepatitis. Lymphocyte cytotoxicity to Chang liver cells was investigated by a microcytotoxicity test, and that to autologous liver cells obtained by percutaneous liver biopsy was studied using a 51Cr release assay. Lymphocytes from patients with alcoholic hepatitis were found to be highly cytotoxic to Chang liver cells and autologous liver cells when compared to those of healthy subjects (P is less than 0.001). Cell-free supernatant fluid of lymphocytes from patients with alcoholic hepatitis incubated with purified alcoholic hyalin for 5 days was significantly cytotoxic to Chang liver cells (P is less than 0.01), indicating that a cytotoxic factor is elaborated by sensitized lymphocytes. A significant reduction in cytotoxicity was noted with disappearance of clinical features or direct addition of a purified isolate of alcoholic hyalin or its preincubation with lymphocytes. Preincubation of sensitized lymphocytes with acetaldehyde increased cytotoxicity for autologous liver beyond that obtained by the combined effects of lymphocytes alone and acetaldehyde alone (P is less than 0.001), interpreted as evidence that ethanol toxicity and hyperactivity of lymphocytes independently and collectively contribute to development of cirrhosis in patients with alcoholic hepatitis who continue to imbibe alcohol.

Alcoholic Hepatitis: Cell-mediated immunological response to alcoholic hyalin

Immunological reactivity in alcoholic hepatitis has bben attributed to alcoholic hyalin, the histological hallmark of this disease. A purified isolate of alcoholic hyalin with electron microscopic, biochemical, and serological characteristics documented previously was added to lymphocytes from healthy subjects and patients with alcoholic hepatitis or other hepatic disorders. Production of migration inhibition factor (MIF) in response to this material was used as an index to lymphocyte reactivity. MIF was significantly increased in lymphocytes obtained from patients with alcoholic hepatis, as compared to the healthy controls (P less than 0.001), and persons with other liver diseases (P less than 0.005). These observations indicate that immunological hyperreactivity to alcoholic hyalin occurs in patients with alcoholic hepatitis; such activity may be of key importance in the pathogenesis or sequelae (or both) of this disease.

ALCOHOLIC HEPATITIS, CIRRHOSIS, AND IMMUNOLOGIC REACTIVITY

Serial observations in over 40 alcoholics reveal there is a marked variation in the time required for transformation of alcoholic hepatitis t o cirrhosis. Some exhibited morphologic evidence of cirrhosis in less than a year, while others took as long as 12 years before its appearance. N o relationship could be established between the amount and type of alcoholic beverages and the dietary intake in patients who developed cirrhosis.’ These findings have led t o the consideration that altered immunologic reactivity might be responsible for the conversion of alcoholic hepatitis t o cirrhosis (FIGURE 1). This thesis is supported by the progressive shortening of the interval required for recurrence of alcoholic hepatitis with healing and subsequent resumption of alcoholism. An immunologic role in pathogenesis is also suggested by occasional hypersensitivity reactions following ingestion of alcoholic beverages; the ability of acetaldehyde t o depolymerize protein, which could then serve as an antigen; and the morphologic findings in alcoholic hepatitis, which simulate an Arthus-like reaction and/or delayed hypersensitivity reaction.

Protection of Pyridoxal 5′-Phosphate against Toxicity of Acetaldehyde to Hepatocytes

Abstract Methods were evaluated for annulling the cytotoxicity of acetaldehyde (AcH) for isolated autologous liver cells, obtained by percutaneous liver biopsy, from cases of alcoholic hepatitis. Hepatocytes so obtained were more susceptible to the cytotoxicity of AcH than hepatocytes from normal liver, viral hepatitis, alcoholic fatty liver, and stable alcoholic cirrhosis. Benzylamine (an aldehyde buffer) and pyridoxal 5′-phosphate (PLP) counteracted the cytotoxicity of AcH in vitro; pyridoxol did not. AcH cytotoxicity was seen in liver cells from vitamin B6deficient alcoholics with alcoholic hepatitis but was reversed when the B6 deficiency was corrected by intramuscular administration of flushing doses of pyridoxol (150 mg daily). We suggest that in vitro, benzylamine neutralizes AcH toxicity through a Schiff-base condensation with AcH, whereas pyridoxal 5′-phosphate protects against AcH toxicity in vitro and in vivo by probably forming a Schiff base with cellular amino acids, blocking further condensation of these amino groups with AcH.

Studies of nucleic acid and collagen synthesis: current status in assessing liver repair.

Much progress has been made in delineating biochemical, physiologic and morpholigic events in liver regeneration and collagen synthesis. Pharmacologic agents have been purported to be helpful in facilitating repair and preventing fibrosis. Objective indices are now available to monitor their effectiveness in man.

Immunologic Aspects of Liver Disease of the Alcoholic

The immune system identifies native, altered, and foreign macromolecules; it attempts to eliminate the latter two groups, which include neoantigens, toxins, and infectious agents. This process is carried out by (1) specific immune reactions such as antibodies produced by bone-marrow-derived B cells, cell-mediated activity resulting from thymus-derived T cells, and macrophages; (2) immune augmenters—nonspecific complement proteins, polymorphonuclear leukocytes, and phagocytic cells. The thymic-dependent arm fosters cells clonally committed to individual antigens; production of cytotoxic, memory, helper, and suppressor lymphocytes subsets; recruitment of mononuclear phagocytes and interaction with surface constituents of other cells to induce inflammation; and promotion of vascular permeability and blood coagulation (Cerottini, 1977).