William H. J. Summerskill

Bile Acid Secretion and Biliary Bile Acid Composition Altered by Cholecystectomy

After cholecystectomy, bile secretion is continuous and 24-hour bile acid output exceeds that in health. Cholecystokinin-pancreozymin (CCK-PZ) influences neither bile acid secretion nor the bile acid composition of bile after the operation. It is proposed that the absence of the gallbladder causes more rapid enterohepatic recycling of bile acids and therefore increased bile acid secretion. The bile acid composition of bile following cholecystectomy is abnormal for the same reasons. A high proportion of secondary bile acids is present, including several found to be keto bile acids, and this is attributed to increased exposure of the bile acid pool to degradation by intestinal microorganisms.

Australia antigen in chronic active liver disease with cirrhosis.

Abstract Sera from thirty-one patients with chronic active liver disease were examined for the presence of Australia antigen, Au(1). Patients were selected using criteria which include fivefold or greater elevations of serum-glutamic-oxaloacetic-transaminase, hypergammaglobulinaemia, histological changes on biopsy (hepatitis with or without cirrhosis), and liver disease documented for at least 10 weeks. Au(1) was detected in the sera of three of the thirty-one patients. These three patients did not differ biochemically or by liver microscopy from the patients lacking Au(1). The presence of Au(1) did not correlate with activity of disease. Each of the patients with Au(1) had cirrhosis. The patients with Au(1) had not received blood-transfusions or hepatotoxic drugs. Only one of the three patients gave a history suggestive of acute icteric hepatitis at the onset of illness. If Au(1) adequately reflects the presence of hepatitis virus, these findings would suggest that in some patients with chronic active liver disease, a chronic viral infection exists, even in the presence of cirrhosis.

Severe chronic active liver disease

To determine the usefulness of recognizing the different morphologic patterns of chronic active liver disease (CALD), we compared clinical and biochemical features as well as responses to treatment in 32 patients with chronic active hepatitis (CAH); 36 with subacute hepatitis and bridging necrosis (SHB); 30 with subacute hepatitis and multilobular necrosis (SHMN); and 30 with cirrhosis and active hepatitis (Cirrh). The morphological lesions did not correlate with clinical or etiologic features. Patients with CAH had less severe biochemical abnormalities, entered remission more often, and failed to respond to treatment less frequently than those with SHMN or Cirrh. SHB and SHMN resembled each other in many regards and showed greater functional changes than CAH. Cirrhosis developed more often after SHMN than CAH and was associated with a poorer prognosis than CAH. Serial liver biopsies revealed all possible histologic transitions, with reduction of inflammation usually occurring in patients treated with steroids and extension of inflammation being more frequent in those not receiving these drugs. CAH, SHB, SHMN, and Cirrh, therefore, reflect the degree and extent of disease activity at any given time in CALD, rather than representing different conditions. Identification of the initial morphologic lesion is helpful because of differences in prognosis.

Ammonia production in the human colon. Effects of cleansing, neomycin and acetohydroxamic acid.

Abstract In 14 healthy volunteers, studied by colonic perfusion technics, colonic ammonia output during steady-state conditions was 1782 ± 233 μg per hour (S.E.). Colonic outputs and concentrations of ammonia in four patients with cirrhosis and encephalopathy were similar. In these patients, blood ammonia concentrations fell during cleansing by perfusion. Treatment with neomycin reduced colonic ammonia concentration and outputs; the urease inhibitor acetohydroxamic acid reduced colonic ammonia output by a systemic effect but had no effect when perfused through the colon. Outputs of ammonia by the colon studied by perfusion approximated the total produced in the cleansed organ. Accumulation of ammonia in the colon was consistent with simple ionic diffusion and production by bacteria. These data validate the rationale for management of hepatic coma, stress the efficacy of effective cleansing of the colon and describe a human model for assessment of therapy.

Transport of urea and ammonia production in the human colon.

Abstract Perfusion of the cleansed human colon was used to quantify movement of urea between the circulation and lumen, together with the amount of urea hydrolysed to ammonia in the colon. Only 2% of urea delivered to the colon by the circulation was recovered from the lumen at normal or elevated blood-urea concentrations, and only 5% of urea perfused through the colon was absorbed. Urea was not hydrolysed to recoverable ammonia when perfused through the colonic lumen, and only 0·2% of urea reaching the colonic mucosa from the circulation underwent ureolysis, as reflected by the ammonia recoverable from the lumen. Bacterial urease was responsible, because treatment with neomycin prevented accumulation of ammonia in the colonic lumen after urea was given by vein. The increased urinary and colonic outputs of urea found after neomycin was given were equivalent to the 7 g. of urea believed to be hydrolysed each 24 hours by bacterial ureases. It is therefore proposed that (1) the colon is relatively impermeable to urea; (2) urea from the circulation is hydrolysed more readily than that in the lumen; (3) colonic urease activity, although bacterial, has a mucosal or juxtamucosal location; and (4) ammonia generated from ureolysis passes to the circulation rather than the lumen of the colon by nonionic and simple ionic diffusion because of the pH and concentration gradients involved.

Abnormalities of Chemical Tests for Copper Metabolism in Chronic Active Liver Disease: Differentiation from Wilson's Disease

Because identical clinical findings, alterations of hepatic function, and changes in hepatic morphology can occur in Wilsons disease (WD) and chronic active liver disease (CALD), chemical tests that reflect copper metabolism are important in the differential diagnosis of these conditions. The authors therefore measured 24-hr urinary copper excretion, hepatic copper concentration, and serum ceruloplasmin concentration in 54 patients with CALD. Twenty-four hour urinary copper excretion was increased in about 50% of patients, was significantly higher during active disease compared to remission, and was in the WD range in approximately 10% of patients. Hepatic copper concentration was also increased in the majority of patients, generally during active disease, and it sometimes overlapped with values reported in WD. By contrast, serum ceruloplasmin levels were elevated in nearly one-half the Cald patients and were never below normal. It is concluded that the chemical tests routinely used to assess copper metabolism in WD are frequently abnormal in CALD. Because the serum ceruloplasmin concentration never fell in the WD range and often was elevated, it is the most reliable routine chemical screening test to differentiate between CALD and WD.

Hepatic cirrhosis secondary to obstruction of the biliary system

A CAUSAL relationship between unrelieved extrahepatic biliary obstruction and the ultimate development of cirrhosis of the liver has long been accepted. 5, 9, 10 Features relevant to mechanical biliary obstruction prior to the onset of cirrhosis, as well as the technical aspects and therapeutic results of surgical treatment, have been well documented. 4, 2o By contrast, little information is available with regard to the course of the patient once cirrhosis has become established. In particular, impairment of hepatic function and portal hypertension, with their characteristic features and responses to treatment are ill-defined. The purpose of this paper is to report these and other aspects of the disease in a representative series of patients with secondary biliary cirrhosis.

Body and Serum Potassium in Liver Disease: I. Relationship to hepatic function and associated factors

Summary Serial determinations of exchangeable potassium and ratios derived from it in the same patient or comparisons of total exchangeable potassium to total body water (K E : TBW ) with anticipated normal values for the groups studied appeared the most valid methods of assessing body potassium stores in patients with viral hepatitis or cirrhosis. Reductions of body exchangeable potassium approximating 500 mEq were found in a high proportion of patients with hepatitis or cirrhosis. Low values are present particularly in patients with severely impaired hepatic function, and repletion with potassium supplements can rarely be achieved in this group. Changes in body exchangeable potassium are unrelated to those in serum potassium concentrations during the course of hepatitis or cirrhosis.

Malabsorption syndrome associated with anicteric liver disease.

Summary Studies are reported on 7 patients with a malabsorption syndrome and anicteric liver disease. Disorders of absorption usually dominated the clinical course, but evidence of liver disease antedated or coincided with that of malabsorption, and prognosis seemed to be most closely related to liver function. The majority of patients had liver disease, usually cirrhosis, of uncertain etiology. Abnormalities of absorption involved fat, carotene, vitamin B 12 and other substances; roentgenologic changes were present in the small intestine, but the appearance of jejunal biopsies was normal. Simultaneous fluctuations in hepatic and absorptive function and failure to identify an alternative cause for the malabsorption support the presence of a causal relationship between primary liver disease and malabsorption. Special studies, including therapeutic trials with broad spectrum antibiotics, human bile, pancreatic exocrine replacement therapy and prednisone given by mouth, failed to indicate a specific metabolic cause for the malabsorption. Treatment with a diet high in protein and calories but low in fat, together with replacement therapy for specific deficiencies, seemed to be most satisfactory. The effect of prednisone therapy requires a trial in some patients.

Identification of the Gastroesophageal Mucosal Junction by Transmucosal Potential in Healthy Subjects and Patients with Hiatal Hernia

Summary The purpose of this investigation was to determine whether the contrasting transmucosal potentials of the stomach and the esophagus can be used to identify the gastroesophageal mucosal junction. To relate changes in the potential difference (PD) to other characteristics of the junctional zone, pressure and pH determinations were made simultaneously with those of PD. Observations were made during fasting on 18 healthy persons, 5 dogs, and 12 patients with hiatal hernia. A zone of elevated pressure was found at the junctional region in the healthy persons and the dogs. The PD changed within the region of elevated pressure. The greatest change was at the physiologic hiatus (site of respiratory reversal) or just distal to it. The pH in the healthy persons and the dogs usually changed within the zone of elevated pressure, and, as with PD, the greatest change usually occurred just distal to the point of respiratory reversal. In some tests, an acid pH extended into the esophagus. When the gastroesophageal junction was visualized in an anesthetized dog with the exploring electrode previously fixed at the site of maximal change in PD, the electrode was found within 5 mm of the mucosal junction. Pressure characteristics indicative of hiatal hernia were detected in the 12 patients known to have hiatal hernia. In these patients, the site of greatest change in PD was shifted to the proximal region of the zone, indicating displacement of the mucosal junction into the chest. An acid pH in the esophagus was common in the patients with hiatal hernia.