Addition of thioctic acid to a plan for management of hepatic insufficiency

Association

for the Study of Liver Diseases

NH4-N concentrations in fasting jugular bulb blood than arterial or jugular venous blood indicated that brain contributed NH4-N to the circulation in patients with or without cirrhosis. A prompt rise in abdominal collateral venous blood NHd-N concentration occurred in three patients with cirrhosis during infusions of urea. In one instance this effect was prevented by oral neomycin, indicating that the urea yielded NHh-N in the gastrointestinal tract, presumably as a result of bacterial action. Similar rises also occurred after a 50 gm. protein meal and after 10 gm. of oral L-glutamine but were not prevented by neomycin. No rise was observed after oral amino acids (methionine, lysine, glycine, arginine, tyrosine, isoleucine and valine) or after oral NH&l which contained more NH4-N than that in any of the other N substances given. Thus in patients with cirrhosis, these observations suggested that one source (which does not eliminate others) of increased blood NH4-N concentrations after protein ingestion is the amide N of glutamine contained in protein. This NHI-N is absorbed by the small intestine and its formation does not depend on bacterial action. Both in hepatic coma and after diamox administration NHI-N uptake by the extremities was usually observed. (Diamox is a carbonic anhydrase inhibitor which does not liberate its nitrogen in the body and may induce impending hepatic coma associated with increased peripheral venous blood NH4-N concentrations in susceptible patients with cirrhosis.) One hour after the diamox was administered orally increases in brain NHI-N output occurred (increased jugular venous blood NH*-N concentrations). These increases occurred less frequently in nine patients without disease of the liver, were more marked in sixteen with cirrhosis, and were greatest in one with cirrhosis in whom impending coma developed, although two patients with prior signs of impending coma showed rises comparable to those of the group with cirrhosis. Similarly, the brain was thought to contribute NH4-N in two comatose patients without disease of the liver and in five patients in hepatic coma, selected because none had hemorrhage, shock or azotemia. In contrast, a relative uptake of NHI-N by brain followed intravenous NH4 salt, intravenous urea, or oral protein (one patient with cirrhosis) and also frequently occurred in four patients in hepatic coma with hemorrhage, shock JULY,

1956

‘3’

or azotemia. Thus it appeared that in patients in hepatic coma, brain could remove NH4-N added to the circulation in some instances or contribute excess NH4-N as a result of disordered metabolic function in others. METHIONINE

TOXICITY

IN

LIVER

DISEASE

AND

Sheila Sherlock, Elizabeth A. Phear, B. Ruebner and W. H. J. Summerskill. Postgraduate Medical School of London, London, England. PREVENTION

BY CHLORTETRACYCLINE.

Oral methionine caused neurologic deterioration in seven of nine patients with portal cirrhosis and chronic portal systemic encephalopathy. In eight of the nine patients large portalsystemic venous collateral channels were demonstrated. It was without effect in seven patients with cirrhosis of the liver, three of whom had extensive portal systemic circulation and one of whom had extrahepatic portal vein obstruction. These patients had never experienced neurologic complications. Intravenous methionine was without effect in three of those who reacted to the oral amino acid and in one a delayed exacerbation occurred. Neurologic deterioration occurred without significant change in blood ammonium, blood pH or serum bilirubin levels. Blood methionine levels rose equally in those in whom deterioration occurred and in those in whom it did not. Oral chlortetracycline prevented or delayed neurologic deterioration in five sensitive patients blood who received it, despite comparable methionine levels. The fecal flora of patients with disease of the liver and neurologic complications did not differ from that of normal subjects and patients with uncomplicated cirrhosis. Methionine did not change the fecal flora, but in the patients in all groups administration of chlortetracycline resulted in an increase in proteus with elimination of bacteroides and an inconstant fall in Bacterium coli. The streptococcal types changed and lactobacilli increased. In vitro ammonium production by proteus, Bact. coli and bacteroides was small and was unaffected by chlortetracycline. The toxicity of methionine in patients with chronic portal systemic encephalopathy is due to some breakdown product of methionine which is not ammonium. It is suggested that chlortetracycline may be of benefit in spontaneous “hepatic coma.” ADDITION MANAGEMENT

OF

THIOCTIC OF HEPATIC

ACID

TO

A

PLAN

INSUFFICIENCY.

FOR

Charles

132

Association for the Study of Liver Diseases

M. Thompson, Joseph M. Gambescia, Philip Lisan and Morton Fuchs. Hahnemann Medical College, Philadelphia, Pa. In hepatic coma elevated blood ammonia levels have been repeatedly observed. High blood and spinal fluid levels of glutamine, methionine sulfoxide and amino aciduria indirectly suggest marked alteration in the metabolism of nitrogenous compounds. Evidence also exists of an interruption in intermediate carbohydrate metabolism. This is indicated by elevations of blood lactic acid, pyruvic acid and alpha-ketoglutaric acid. It could be postulated that failure of an enzyme system or systems could account for the elevated blood levels of these metabolites. The failure of an enzyme system to facilitate the aerobic oxidative decarboxylation of alpha-keto acids and the transference of decarboxylated pyruvic acid into the Krebs cycle could be one result of hepatic insufficiency. Thioctic acid (Iipoic acid, pyruvate oxidation factor, protogen, and the like) is one of the more recently recognized biocatalysts, and has now been synthetized in pure form. The nutritionally effective form of thioctic acid is a complex of thioctic acid and thiamin. This molecular conjugate appears to have an essential role in the oxidation of aIpha-keto -acids and in the transference of pyruvic acid into the Krebs cycle. First, a group of patients who showed no evidence of disease of the liver were studied, and diurnal variations in the blood pyruvic acid and lactic acid levels in relationship to time of day, diet or exercise were recorded. No effect of thioctic acid on normal blood pyruvic and lactic acid levels was noted. A group of patients who showed evidence of hepatic insufficiency marked by torpor or coma and normal or elevated blood pyruvic acid and lactic acid IeveIs were then followed and an aggressive plan for management instituted. No change in the IeveI of blood metabolites in the majority of these cases was noted. A group of patients in whom gross evidence of hepatic insufficiency and coma were noted were followed after institution of the hepatic regimen with the addition of intramuscular thioctic acid. In the majority of these a decrease in the elevations was noted and this decrease most often coincided with improvement in sensorium. It is suggested that thioctic acid be added to

the usual aggressive plan for the management of hepatic insufficiency and that further studies be planned to determine its essential role in the utilization of alpha-keto acids. THE

MECHANISM

LIVER

IN

OF COPPER

DEPOSITION

HEPATOLENTICULAR

IN

THE

DEGENERATION.

L. Lahut Uzman, Frank L. Iber, Marjorie Knowlton and Thomas C. Chalmers. Walter Reed Army Medical Center, Washington, D. C. Liver tissue was obtained surgically from a twelve year old asymptomatic boy who had hepatolenticular degeneration (HLD). The liver showed severe cirrhosis. A homogenate of the liver from this boy and one from the liver of a normaI person were placed in cellophane tubing and dialyzed against buffered copper sulfate solution. Portions of the outside bath were removed for analysis, additional copper was added and the dialysis continued. The results revealed that the liver showing hepatoIenticular degeneration bound from two to seven times as much copper with increasing copper concentrations as that of the liver from the normal person. An additional portion of the HLD liver homogenate and portions of two Iivers from norma persons were subjected to paper electrophoresis. The patterns were dried and stained for protein (ninhydrin) and copper (diethyldithiocarbamate). The HLD liver showed a high protein peak migrating slowly toward the anode that was entirely absent in the liver from the normal subject. This was called the X peak. Copper stains did not stain material in the liver from the normal subject but showed intense staining in the region of the X peak in the HLD liver. If the homogenates were treated with excess copper and then subjected to electrophoresis and stained for copper, marked activity was found in exactly the site of the X peak in the HLD liver. The studies thus demonstrate an increased affinity of the liver for ionic copper in Wilson’s disease and that this increased affinity seems to be due to the high copper binding properties of an electrophoretically distinct protein present in the liver in Wilson’s disease. AMMONIA

METABOLISM

IN

PATIENTS

WITH

CIR-

William W. Faloon, J. Howland Auchincloss, Robert Eich and Robert Gilbert. State Univ. of New York, Upstate Medical Center, Syracuse, N. Y.

RHOSIS

WHO

HAD

PORTACAVAL

SHUNTS.

The association of portacaval shunt surgery with the occurrence of episodic stupor has