tive serum. Clinical confirmation of this comes from studies demonstrating n, reduction in the incidence of serum hepatitis in cardiac surgery patients who were given gamma globulin prophy- lactically. These studies represent only the tip of the HAA iceberg. The future lies in such directions as the genetics of HAA persistence in normal populations (tropical countries), in immuno-deficient individ- uals (leukemia, transplant patients) and possibly Neutrophils and Host Defense in malignant hepatoma.8 The pathogenicity of HAA for other organs has been hinted at by the THE COMPREHENSIVE ARTICLE by R. I. Lehrer in recent description of HAA-positive periarteritis this issue of CALIFORNIA MEDICINE focuses at- with localization of the virus particles in blood tention on the role of the leukocyte in host de- vessel walls. We are even hearing the first whis- fense against microbial agents. The suggestion pers of a serum hepatitis vaccine. by Mechnikoff that "the essential and primary But what of the semantic chaos with which we element in typical consists in a re- began? Perhaps we can agree for now to broadly action of the phagocyte against a harmful agent" classify the patient with transaminasemia of hepa- remains as valid today as when proposed before tocellular origin as: the turn of the century. The leukocyte is assisted A. Acute Hepatitis in its task by many other factors. The importance of the leukocytes, however, is emphasized by the 1. Viral frequency and severity of in patients (a) iAA-positive with agranulocytosis and by the presence of a (b) HAA-negative group of conditions in which an increased suscep- (c) Subacute hepatic (mAA- tibility to is associated with impaired in- positive or HAA-negative). traleukocytic microbicidal activity. 2. Non-Viral The process of phagocytosis effectively isolates B. Chronic Hepatitis the organism from the extracellular environment 1. Unresolved viral hepatitis in a vacuole lined by the invaginated cell mem- brane. Phagocytosis per se does not appear to be 2. Chronic active hepatitis harmful to the ingested organism; indeed, organ- (a) Viral (HAA-positive) isms sequestered within the phagocytic vacuole (b) Lupoid (HAA-negative; LE posi- but not killed by cellular systems are protected tive or negative; sMA-positive) from extracellular antimicrobial systems and from (c) Idiopathic (muA-negative; LE- certain antibiotics. However, phagocytosis is as- negative; SMA-negative) sociated with a burst of metabolic activity and the (d) Toxic (oxyphenisatin). release of toxic substances from the cytoplasmic 3. Other hepatotoxins and states granules into the phagocytic vacuole. Death and with secondary liver involvement. degradation of the ingested organisms follow. The MARTIN BROTMAN, M.D. microbicidal systems oDnsist of products of leu- San Francisco kocytic metabolic activity such as acid and H202, granular components with no known enzyme REFERENCES activity, such as certain cationic proteins (phago- 1. Boyer JL, Klatskin G: Pattern of necrosis in acute viral hepatitis. cytin, leukin) and granular components with New Eng J Med 283:1063-71, 1970 enzyme activity, such as lysozyme and myeloper- 2. Mistilis SP, Blackburn CRB: Active chronic hepatitis. Amer J Med 48:484-95, 1970 oxidase. Myelopero'xidase is a component of a 3. Gitnick GL, Shorter RG, Schoenfield LJ: Experimental acute and chronic viral hepatitis. Gastroenterology 58:516-23, 1970 complex microbicidal system which also requires 4. Krugman S: Viral hepatitis: New clinical, epidemiological and immunological concepts. Calif Med 113:58-9, 1970 H202 and an appropriate oxidizable cofactor such 5. Krugman S, Giles JP: Viral hepatitis, new light on an old dis- as iodide, bromide, chloride or thioeyanate ions ease. JAMA 212:1019-29,1970 6. Sutnick Al, London WT, Blumberg BS: Australia antigen: A and is facilitated by the acid pH which is believed genetic basis for chronic liver disease and hepatoma? Ann Intern Med 74:442-4, 1971 to exist in the vacuole. The ingested organisms

CALIFORNIA MEDICINE 47 The Western Journal of Medicine vary in their susceptibility to the intravacuolar granulomatous disease, familial lipochrome his- microbicidal systems; some organisms (pneumo- tiocytosis,' absent leukocyte glucose-6-phosphate cocci, for example) are rapidly killed by acid dehydrogenase2) attests the heterogencity of this whereas others (such as lactobacilli) are aci- group. A microbicidal defect could not be demon- dophilic; some are readily lysed by lysozyme strated in the leukocytes of the two original pa- whereas most organisms resist the action of this tients with Job's syndrome,3 which suggests that enzyme unless previously damaged, as, for ex- this condition may not be a variant of chronic ample, by antibody - complement; some organ- granulomatous disease as suggested by Banna- isms (such as streptococci, pneumococci, lactoba- tyne et al.4 cilli) secrete H1202 into the intravacuolar space Another leukocytic lesion associated with im- and thus contribute to their own destruction by paired microbicidal activity is myelopLroxidase H202-dependent systems whereas others (certain deficiency. Myeloperoxidase deficiency may be Gram-negative pathogens, gonococci, staphylo- hereditary or acquired. Patients with hereditary cocci) contain catalase which brea4s down H202. myeloperoxidase deficiency have leukocytes with As a result of this highly complex interrelation- decreased fungicidal and bactericidal activity al- ship, certain organisms are killed more readily bv though the microbicidal defect is not as severe as leukocytes than otheirs and the effective antimi- in chronic granulomatous disease. These patients crobial system may vary with the type of organ- are relatively free of infection. Of five patients ism and with the functional state of the leukocyte. with hereditary myeloperoxidase deficiency, one In a typical in vitro experiment 99 to 99.9 percent had systemic candidiasis while the remainder of streptococci or pneumococci are killed in one were in good health. A second patient with can- hour by isolated leukocytes under conditions in dida infection and an absence of myeloperoxidase which approximately 90 percent of staphylococci from the majority of peripheral neutrophils was and 30 to 50 percent of Candida albicans are reported in the article by Lehrer in this issue; killed. however, it is not clear whether the lesion in this Defects in the intraleukocytic microbicidal sys- instance was hereditary or acquired. A reversible tems exist which result in the prolonged intra- decrease or loss of myeloperoxidase from some or cellular survival of ingested organisms. A begin- all leukocytes has been reported by Sato5 in epi- ning in the classification of these conditions demic encephalitis Economo, and by Graham6 in according to the molecular lesion can be made. severe bacterial infection. Graham, in the pre- The leukocytes of patients with chronic granulo- antibiotic era, followed the decline in neutrophil matous disease have impaired microbicidal activ- peroxidase in a patient with pneumococcal pneu- ity and decreased phagocytosis-induced glucose monia; 96 percent of neutrophils contained no carbon 1 oxidation, H202 formation, nitroblue peroxidase by histochemical staining at the time tetrazolium reduction and iodination. The im- of death. These findings suggest that myeloper- portance of the decreased H202 formation to the oxidase deficiency may be a consequence of, as defect in microbicidal activity has been empha- well as a cause of, infection. Certain agents which sized by the partial reversal of the lesion by the inhibit peroxidase-catalyzed reactions inhibit the introduction of a H202 generating system into the microbicidal activity of normal leukocytes but cell. A degranulation defect also has been sug- have no effect on peroxidase-negative leukocytes.7 gested. Although degranulation does occur in This, and the decreased microbicidal activity of these cells, it is possible that the rate of degranu- peroxidase-negative leukocytes, suggests the in- lation may be abnormal under certain conditions. volvement of peroxidase in the microbicidal ac- The result is repeated and severe infections. The tivity of normal cells. The relative freedom from H202 deficiency syndrome, if this is the basic de- infection in hereditary deficiency may be due to fect, may arise from a variety of primary enzyme an overkill capacity of the leukocytes for most lesions affecting the formation of H1202 and its organisms, which allows them to function ade- availability for the microbicidal act. The demon, quately under most circumstances even when the stration of a leukocyte functional defect compa- total microbicidal potential is decreased. Further, rable to that of the classical x-linked variety of an increase in the activity of the non-peroxidase chronic granulomatous disease in patients with antimicrobial systems may compensate for the de- atypical histories (non x-linked variety of chronic crease in peroxidase-mediated systems.7

48 JUNE 1971 * 14 * 6 The complexity of the intraneutrophilic micro- REFERENCES 1. Rodey GE, Park BH, Ford DK, et al: Defective bactericidal ac- bicidal systems and their importance in the host tivity of peripheral blood leukocytes in lipochrome histiocytosis. Amer defense is emphasized by the studies of rare in- J Med 49:322-327, 1970 2. Cooper MR, DeChatelet LR, McCall CE, et al: Leucocyte G.-6- born errors of metabolism such as chronic granu- P.D. deficiency. Lancet II: 110, 1970 lomatous disease and hereditary myeloperoxidase 3. White LR, lannetta A, Kaplan EL, et al: Leukocytes in Job's deficiency. Certainly it might be expected that syndrome. Lancet I:630, 1969 4. Bannatyne RM, Skowron PN, Weber JL: Job's syndrome-A more subtle changes in leukocyte function intro- variant of chronic granulomatous disease. J Pediat 75:236-242, 1969 5. Sato A, Yoshimatsu S: The peroxidase reaction in epidemic en- duced by therapy, diet or coexisting disease also cephalitis-A new diagnostic and prognostic method. Amer J Dis may influence the course of infection. Child 29:301-311, 1925 6. Graham GS: Ihe neutrophilic of the circulating blood SEYMOUR J. KLEBANOFF, M.D., PH.D. in health and in disease-A preliminarygranulesreport. NY State J Med USPHS Hospital, and Department of Medicine, 20:46-55,'1920 University of Washington School of Medicine, 7. Klebanoff SJ: Myeloperoxidase: Contribution to the microbicidal Seattle activity of intact leukocytes. Science 169:1095-1097, 1970

ABDOMINAL ANGINA "The onset of symptoms [in patients with intestinal due to mesenteric arterial disease] is a late phenomenon and indicates rather far advanced vas- cular disease. Many patients with such limitation of their mesenteric blood supply are asymptomatic and when there is abdominal angina, weight loss, etc., it usually heralds impending catastrophe and constitutes a fairly urgent indica- tion to proceed with diagnosis and therapy. Of the 17 patients we saw with abdominal angina, none had had symptoms for longer than two years and 12 of the 17 had either acute infarction -or definitive surgery within six months of onset of their abdominal angina. "In conclusion, I think some patients inay survive acute intestinal ischemia with successful embolectomy and arterial reconstruction. But when arterial occlusive disease exists, the occurrence of symptoms is a very late phenomenon, and the best hope for improved results lies in prompt recognition of chronic ischemic symptoms and elective revascularization before acute ischemia devel- ops. -GARLAND D. PERDUE, JR., M.D., Atlanta Extracted from Audio-Digest Surgery, Vol. 16, No. 17, in the Audio-Digest Foundation's sub- scription series of tape-recorded programs. For subscription information: 619 S. Westlake Ave., Los Angeles, Ca. 90057.

CALIFORNIA MEDICINE 49 The Western Journal of Medicine