This enzyme, which converts lactose or "milk sugar" into its simple sugar components, glucose and galactose, is essential to digestion and subsequent absorption of lactose. Subsequently, increasing evidence has been found that intolerance to milk is a relatively common syndrome in adults.

Last year Institute grantees at Johns Hopkins University School of Medicine, Baltimore, demonstrated that milk intolerance based on lactase deficiency is much more common in Negro adults (70 percent in Baltimore and 72 percent in Uganda) than in the adult white population (5-10 percent), suggesting that intestinal lactase activity may be genetically controlled. It was also found that lactose-induced symptoms in Negro children and adults increased in frequency with advancing age, suggesting a gradual decrease in lactase activity after weaning. This was not as common in the white subjects studied.

Similar studies also have been carried out by Institute grantees at the University of Oklahoma Medical Center, Norman, Oklahoma. Both the Johns Hopkins and the Oklahoma studies indicate that there is a distinct racial difference in lactase activity, and that a genetically determined intestinal lactase deficiency is responsible for the majority of instances of milk intolerance found in adults.

The same Johns Hopkins investigators now have shown that milk intolerance, presumably due to a lactase deficiency, is also very common among adults of Oriental ancestry. Thus, a large part of the world's non-white population may have a genetically determined intolerance to milk, a situation which would require re-evaluation of the importance of milk as a source of nutrition and protein among non-white adult populations.

These studies have considerable diagnostic and therapeutic significance, particularly for Negro and Oriental patients presenting a variety of gastrointestinal symptoms, such as diarrhea, nausea, and abdominal pains, which do not appear to be related to any specifically manifest pathologic lesion. In view of these findings, it becomes necessary to rule out, in such patients, the presence of milk intolerance or lactase deficiency (a presently uncommon diagnosis in adults). Once this diagnosis is confirmed, dietary restriction of milk, milk products, and foods containing milk sugar (lactose) usually leads to cessation of the distressing symptoms.

LIVER DISEASES

The liver performs a multitude of complex chemical tasks without which life cannot exist. The liver functions, for example, as a filter and clearing station for purification and detoxification of blood, as a chemical factory

for interconversion of carbohydrates, fats, and proteins, as a storage house for certain nutrients (particularly sugars and certain vitamins), as a site of production of blood proteins and of antibodies, and as a secretory gland which aids both digestion and the removal of wastes.

It is not surprising, then, that an organ of such complexity is also subject to a broad range of injuries and diseases, including disorders of infectious, parasitic, nutritional, metabolic, obstructive, toxic, and malignant origin. Prominent among liver diseases is cirrhosis, the endstage of a progressive destructive process often resulting from chronic alcoholism or infection.

Fatty Livers

Institute-supported studies have indicated in the past that excessive consumption of alcohol can lead to development of fatty liver forerunner of cirrhosis - in man despite a concurrent, well-balanced dietary intake, a finding contrary to the conventional hypothesis that a poor diet is the cause of alcoholic liver damage in alcoholic individuals. Institute grantees at Mt. Sinai School of Medicine and at Cornell Medical Division of Bellevue Hospital in New York City now find that, in persons who drink only occasionall acute exposure to alcohol may lead rapidly (after only two days) to fat accumulation in the liver and intracellular microscopic structural changes, regardless of nutritional factors. After two days this damage is reversible, but it becomes permanent and cumulative after more prolonged exposures.

According to the investigators, it is clear that alcohol can rapidly produce liver injury when taken in amounts equivalent to those consumed not only by recognized alcoholic persons but by many "social" drinkers as well. The blood alcohol level determinations during the experiments showed that a person need never have been intoxicated to sustain alcoholinduced liver injury.

These findings are significant because they provide insight into the pathogenesis of the alcoholic fatty liver and indicate that, regardless of the high quality of the concurrent diet, alcohol per se in even moderate amounts can lead to the production of a fatty liver.

Liver Enzyme Detects Bile Blockage

Determination of the changes in concentration of different liver enzymes in the serum has been an accepted practice in diagnosing hepatobiliary disease This method is imperfect, however, for specific diagnosis of liver disease in individual patients because none of the indices used to date differentiate between intrahepatic and extrahepatic biliary obstruction.

At St. Luke's Hospital Center, New York, Institute grantees have evaluate: the potential clinical application of determining serum alcohol dehydrogenase levels in the diagnosis of liver disease. Alcohol dehydrogenase is an enzyme found principally in hepatic tissue cells. They determined that elevated ser levels of alcohol dehydrogenase reflect in the serum the extent of necrosis

of liver cells and may serve to differentiate between extrahepatic biliary obstruction and intrahepatic cholestasis (suppression of bile excretion). Measurement of the levels of this enzyme in the serum will probably be of greatest clinical value in the diagnosis of patients with prolonged obstructive jaundice of unknown cause.

Estrogens and Altered Liver Functions

Another grantee at Cornell University Medical College has duplicated the symptoms of itching, jaundice, and cholestasis which complicate some pregnancies by administering a synthetic estrogen to patients post-partum. In each instance clinical and biochemical abnormalities associated with impaired hepatic excretory function, similar to those recorded during pregnancy, were exhibited.

Although several investigations have pointed to a hormonal basis for this disorder, no direct evidence of such a relationship had been demonstrated heretofore. Estrogens, it is now suggested, may play an important role in the pathogenesis of these symptoms and, perhaps, in that of the associated alterations in liver function. These findings are of particular interest in view of recent reports that estrogen-containing hormones given to suppress ovulation may occasionally cause hepatic dysfunction.

Bile Acid Absorption

In absorption studies on bile acids, grant-supported investigators at Long Island Jewish Hospital-Queens Hospital Center Affiliation, Jamaica, New York; The Long Island Jewish Hospital; and the Public Health Research Institute of New York City have established the previously unproved concept that significant absorption of bile acids takes place from the large bowel of man. The cecum, ascending colon, hepatic flexure, and transverse colon may all be reabsorption sites. Their data suggested that 5-20 percent of the bile acid pool is exposed daily to the effects of bacteria in the large bowel before being reabsorbed into the circulation and eventually, reexcreted into the gallbladder. The presence of bacterial transformation products of primary bile acids in the human gallbladder can be explained on the basis of these data.

MALABSORPTION STUDIES

Bile Salt Malabsorption

In studies relating to bile salt malabsorption, investigators at the University of Colorado Medical Center, Denver, examined this phenomenon in regional ileitis, ileal resection, and in mannitol-induced diarrhea, concluding that ileal resection and ileal disease are major factors, with rapid

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intestinal transit a minor factor, in causing excessive fecal bile salt loss. It is therefore clear that the amount of healthy ileal mucosa present is the single most important factor in bile salt absorption.

Malabsorption Management

Dietary supplementation with a semisynthetic fat preparation, medium chain triglycerides, or MCT, has proved its value in managing fat malabsorpti disorders of various origins, according to researchers at St. Luke's Hospital Center, New York. MCT has been used to provide additional nutrition both in disorders for which specific therapy exists and in those disorders for which no specific therapy is currently available.

Among the former are included gluten induced sprue, an intestinal sensitivity to the protein fraction gluten (found in wheat, rye, oats and barley), pancreatic and biliary insufficiency, and Whipple's disease; among the latter are included malabsorption following gastrectomy (removal of part of the stomach) and massive resection of the small bowel.

The efficient absorption of MCT in fat malabsorption states has been explained by the finding that medium chain triglycerides are more rapidly hydrolyzed to fatty acids than are most dietary fats, which are composed of long chain triglycerides. In addition, the studies demonstrated that the presence of bile and pancreatic lipase in the intestine is not necessary for the normal absorption of MCT, explaining its importance in hepatobiliary diseases and in pancreatic insufficiency. Further, MCT may be of particular value in therapeutic diet in infancy and childhood, when malabsorptive disorders take more severe forms and tend to impair normal growth.

Hirschsprung's disease is a disorder of the nerve centers (ganglions) that control contractile movements of the colon. Because of the derangement of nervous control in the lower rectum peristaltic action is impaired, defecation is infrequent and incomplete and the upper rectum fills and dilates massively and the abdomen may become quite enlarged.

Presently the only method of diagnosing this disorder is by surgery a deep-muscle biopsy of the lower rectum to prove the absence of ganglion cells. Because this procedure carries some risk, grantees at Baltimore City Hospitals and at Johns Hopkins University School of Medicine have devised a nonsurgical technique for diagnosing Hirschsprung's disease. The new technique utilizes a manometric device, with separate pressure recordings obtained from internal and external anal sphincters by a double balloon device, and from the rectum by a third balloon.

In addition, since the pathophysiology is incompletely defined, and since the therapy of Hirschsprung's disease is surgical and thus its differentiation from other forms of colonic dilatation is important, these investigators also described more accurately the relexes of the various intestinal sphincters in this disorder. These relexes were contrasted with those found in idiopathic megacolon, a condition in which there is massive dilatation of the lower colon, but normal ganglion cells are present throughout the bowel.

They found that in patients with Hirschsprung's disease the external sphincter responses were normal (contracted), but there was contraction instead of relaxation of the internal sphincter. In this disorder there was also a consistent rectal contraction that was both delayed and longerlasting than normal. In contrast, in 31 patients with idiopathic megacolon, both internal and external sphincter responses were normal, indicating that the abnormal contractile response found in Hirschsprung's disease is characteristic of this disorder, and further, that this response probably contributes to obstructive symptoms in the disease.

Celiac Disease

Celiac disease (nontropical sprue) is characterized by fatty diarrhea, intestinal malabsorption, and dietary deficiency symptoms, all caused by an intestinal sensitivity to a polypeptide fraction (gliadin) of the wheat protein, gluten, in the diet.

Antibodies to gluten fractions are frequently found in the blood of celiac disease patients. Recently, grant-supported scientists at Yale University School of Medicine and the Yale-New Haven Hospital, Connecticut, have suggested that inadequately digested polypeptides of gluten elicit production of antibodies with immunologically competent cells in the intestinal mucosa and that the intestine continues to secrete these antibodies for extended periods even in the absence of foods with a high gluten content, such as wheat, rye, barley and oats.

The investigators succeeded in demonstrating intestinal antibodies to a specific gluten fraction in the stools of three patients with celiac disease, In two patients coproantibodies were present when the disease was diagnosed; in the third, they were found after the patient had been receiving a glutenfree diet for six months and had become asymptomatic. No such antibodies were found in fourteen patients with other, non-celiac diarrheal diseases or in six normal control subjects. The demonstration of these antibodies to a fraction of wheat, the scientists feel, may be a clue to the nature of gluten sensitivity and, with further evaluation, may provide a specific means for diagnosing celiac disease.