Reuben S. Dubois

Immunotherapy with antibody, lymphocytes and transfer factor in chronic hepatitis B

Abstract The efficacy of adoptively transferred humoral and cell-mediated immunity in chronic hepatitis B infection was studied in three patients. The first patient with renal failure and chronic active hepatitis received high titered human antibody to the hepatitis B antigen. The second, an asymptomatic chronic antigen carrier, received “immune” lymphocytes and transfer factor (which was not tested for biologic activity in a normal recipient) prepared from the same collection of cells. In the third patient who had acquired hepatitis B from her mother at birth, transfer factor prepared from maternal leukocytes was given on two occasions. Clinically, there was no change in the first patients liver function despite transient descreases in hepatitis B antigen and increases in antibody titers. Coexistent antigen and antibody persisted for over 4 mo. In the second patient, the immune lymphocytes induced biochemical signs of transient acute hepatitis associated with increased antigen levels, whereas transfer factor did not have an effect. In the third patient, maternal transfer factor caused increased hepatitis B antigen and transaminase levels on two occasions. Subsequently, liver function became normal and the antigen titer was reduced by 95%. Adoptive transfer of humoral immunity does not appear to modify established hepatitis B infection, whereas cell-mediated immunity does. It is postulated that liver cell injury in hepatitis B may be more related to the hosts cell-mediated immune response rather than to a cytopathogenic effect of the putative hepatitis B virus.

Nyctohemeral growth hormone levels in children with growth retardation and inflammatory bowel disease

Short stature is a common complication of inflammatory bowel disease. Recently McCaffery, Nasr, Lawrence, and Kirsner (1970) concluded, from blood growth hormone (GH) levels obtained during insulin-hypoglycaemic provocation, that GH deficiency contributed to the retardation in growth observed in subjects with inflammatory bowel disease. Although it was not possible to eliminate the possibility of partial hypopituitarism, this study does not confirm the existence of GH deficiency in six subjects with short stature complicating inflammatory bowel disease. The nyctohemeral (night and day) serum GH is described, and the insulin and glucose levels in these subjects and normal sleep-related GH rises in all are demonstrated. This finding is not compatible with growth hormone deficiency. In one subject the response to arginine provocation was blunted. Three subjects manifested hyperinsulinism and evidence for `insulin resistance. These findings are unexplained but suggest that insulin resistance may contribute to a blunted GH response to insulin-induced hypoglycaemia. Blunted GH response to both arginine and insulin-induced hypoglycaemia may also result from continuous secretion and reduced pituitary storage of growth hormone. This possibility is suggested by the pattern of raised blood GH levels in one of the subjects.

The varied manifestations of Wilson's disease

Eleven additional cases of Wilsons disease are reported. Delay in diagnosis may stem from the varied modes of presentation of this disease. Hepatic involvement remains the most likely manner for presentation in the pediatric age group, and therefore the diagnosis needs serious consideration in any child with signs and symptoms of liver disease, acute or chronic. Other patients with a predominance of neurologic involvement and one with severe hemolytic crises are also described. Increased awareness of the possibility of Wilsons disease in the pediatric population should lead to earlier diagnosis and improve the prognosis of this serious, but treatable, inborn error of metabolism.

Treatment of chronic active hepatitis in children

Thirty-eight children with chronic active hepatitis are reported. Their mode of presentation was usually indistinguishable from acute viral hepatitis (63%). Extra hepatic manifestations were more common in those patients with an insidious onset. The twenty-eight patients tested for hepatitis B antigen (HB Ag) were all negative and SGOT values were higher (mean 1000 i.u./l) than those reported in adult patients with chronic active hepatitis. Thirty-three patients had marked elevation of serum gammaglobulin (mean 3·78 g/100 ml) and 34% had positive LE cells. All patients had histologic features of ‘aggressive’ hepatitis; in addition five biopsies also showed areas of submassive hepatic necrosis. The initial response to corticosteroid was excellent in all but three patients. To date drug therapy has been suspended in fifteen patients for periods of 3 months to 4 years and 7 months. There have been eight deaths. Three with hepatic insufficiency and two with sepsis. Three others have subsequently died following orthotopic liver transplantation.

Chronic active hepatitis in children

Twenty-eight children with chronic active hepatitis are reported. The majority were diagnosed within the last 5 years. Their mode of presentation was usually indistinguishable from acute viral hepatitis (63%). Extrahepatic manifestations were more common in those patients with an insidious onset. All presented sporadic cases without known exposure or secondary spread. The 19 patients tested for hepatitis-associated antigen (HAA) were all negative and SGOT values were higher (mean, 1080 IU/liter) than those reported in adult patients with chronic active hepatitis. Twenty-seven patients had marked elevation of serum gammaglobulin (mean, 4.04 g/100 ml) and 42% had positive LE cells. All patients had histologic features of “aggressive” hepatitis; in addition, five biopsies also showed areas of submassive lobular necrosis. The initial response to corticosteroid therapy was excellent in all but 3 patients. To date, drug therapy has been suspended in 4 patients for periods of 4 months to 2 years without clinical or biochemical relapse. There have been 4 deaths while on therapy, 2 with hepatic insufficiency and 2 with sepsis. One patient with end-stage liver disease underwent orthotopic liver transplantation and subsequently died.

Insulin Stimulated Transport of 3-O- Methyl Glucose Across the Rat Jejunum

Summary The transport of 3-O-methyl-D-glucose was studied in 20-cm segments of upper jejunum removed with an intact circulation from the animal and perfused extracorporeally. Intestinal preparations from alloxanized animals had a significantly higher percentage minute absorption of the substrate. Insulin failed to modify the transport rate in both the control and the alloxantreated animals. However, insulin stimulation of transport was observed in experiments carried out in a group of rats where diabetes was induced by anti-insulin serum.

Intestinal nodular lymphoid hyperplasia, hypogammaglobulinemia, and hematologic abnormalities in a child with a ring 18 chromosome

The previously unreported combination of ring 18 chromosome, intestinal nodularlymphoid hyperplasia, severe hypogammaglobulinemia, and bone marrow hypoplasia was found in a deaf and mentally retarded 12-year-old girl. In addition to a quantitative deficiency of platelets, lymphocytes, and neutrophils, functional abnormalities of neutrophils were demonstrated by various recently developed in vitro tests. Defective stem cell maturation and the presence of faulty “bursal-equivalent” tissue are postulated as the basis for the hematologic and immunologic abnormalities.

Monosaccharide Induction of 3-0-Methyl Glucose Transport Through the Rat Jejunum

Summary The effects of a 48-hr intraduodenal perfusion of electrolyte solution, 50 mM 3-0-methyl glucose (3-0-MG), glucose, or fructose, 1.39 M glucose or fructose on the subsequent absorption of 3-0-MG were studied in 20-cm segments of rat jejenum perfused extracorporeally through the superior mesenteric artery. The feeding of glucose or fructose enhanced the transport of 3-0-MG while 3-0-MG itself had no effect. This adaptive change was independent of substrate concentration, calories fed, weight loss, bowel wall glucose content, and hexokinase activity of mucosal scrapings. The authors thank Doctor M. Strobel of the University of Montreal for assistance with the statistical analyses.

LACK OF DIETARY REGULATION OF JEJUNAL GLYCOLYTIC ENZYMES AND DISACCHARIDASES IN OBESITY: THE ROLE OF INSULIN

Dietary regulation of jejunal glycolytic regulatory enzymes and disaccharidases were studied in 9 obese subjects, aged 9 to 18 years. These subjects were divided into two groups on the basis of altered carbohydrate metabolism as measured by circadian insulin levels and flux of glucose, inorganic phosphorus, and insulin measured during a 5-hr oral glucose tolerance test. Those patients with nocturnal hyperinsulinemia and abnormal carbohydrate flux showed no adaptation of jejunal enzymes. These data suggest that both glycolytic regulatory enzymes and disaccharidases are susceptible to insulin regulation.

Studies on the dietary regulation of jejunal pyruvate kinase and sucrase activities

The dietary regulation of jejunal glycolytic and disaccharidase enzyme activities is well documented, however failure of adaptation has been described (Gastroenterology 58:990 1970). The mechanism of these adaptive changes is not known. This report describes 2 females aged 9 and 11 years with exogenous obesity. Both had 5 hour oral glucose tolerance tests (OGTT) with serial measurement of blood glucose, insulin and serum inorganic phosphorous (SIP). There was an inappropriate insulin-glucose ratio (I/G), mean 1.4, range 0.6 to 1.8 (normal controls, mean 0.4 range 0.2 to 0.7) and a lack of fall in SIP during the OGTT, suggesting that the insulin was biologically abnormal (Clin. Res. 19:201 1971). Jejunal biopsies were performed after 48 hours of fasting and again after 96 hours of a high carbohydrate (CHO) diet. The activities of jejunal pyruvate kinase (PK) lactase and sucrase(S) were assayed. The PK activities (U/g wet wt. and the sucrase-lactase ratio (S/L) with fasting were 34.6 and 1.81 in one and 39.6 and 2.54 in the other subject, while with feeding were 36.2, 1.63, 40.4 and 2.38 respectively. Both patients were re-studied 2 months after the institution of a low simple CHO diet. At this time I/G and SIP fall during the OGTT were normal . The PK activities with fasting and feeding were 27.2 and 51.8 in one and 42.2 and 53.1 in the other, while the S/L with fasting and feeding were 1.73, 2.79, and 1.88, 2.41 respectively. These data suggest that the dietary regulation of PK and S is mediated through insulin and the lack of adaptation in obesity may be due to the presence of biologically abnormal insulin.