FAT REPLACEMENT OF THE GLYCOGEN IN THE LIVER AS A CAUSE OF DEATH*
During efforts to produce a cirrhosis of the liver in animals with alcohol, as well as during experiments designed simply to ascertain the effects of alcohol on its structure, an accumulation of the fat in the liver cells has been found so commonly as the main alteration that a relation between alcohol and fatty changes in the liver has long been recognized.
Rosenfeld 1 furnished rather conclusive evidence of this relation by withholding glycogen-forming foods from the diet of animals fed with alcohol and observing fatty changes of the liver as a sequence. In discussions of this subject, it has long been customary to refer to the demonstration of fatty changes by Friedenwald2 as the chief effect in rabbits from long-continued administration of alcohol.
The conclusions of Formad 3 based on postmortem examinations of the bodies of 250 chronic alcoholics, and the presence of large fatty livers in 90 per cent of these has more recently been corroborated by Fahr 4 from an examination of 309 such bodies. Fahr states definitely that a fatty liver is the most constant change with chronic alcoholism, and similar statements by others 5 are not wanting.
Although, as first stated, acceptance of this association of alcohol with marked fatty changes of the liver has in these various ways become general, no such agreement has as yet been arrived at with regard to symptoms enabling an estimate clinically of the degree to which the liver has suffered such alterations, and this notwithstanding the attention this phase of the subject has received since Louis 6 first called attention to marked fatty changes of the liver and especially its association with tuberculosis. That such hepatic disease may be encountered in the bodies of persons who are apparently well has been commented on by Frerichs 7 and Begbie,8 and the absence of symptoms, except those connected with its increased size, has been the subject of comment by many writers9 in considering marked fatty degeneration of the liver.
Some authorities have emphasized the greater ease with which persons with such hepatic disease succumb to infections and infectious diseases. Gilbert and Lereboullet 10 also have pointed out this bearing, but they have gone much further and frankly challenged the laissez faire attitude of clinicians regarding the absence of distinctive symptoms, asserting that competent study should demonstrate impaired function of livers so diseased.
One of us (E. R. L.) has been greatly impressed for many years by encountering huge fatty livers at rare intervals during routine postmortem examinations; these were frequently found in the bodies of small women whose consumption of whisky or similar liquors (brandy) was inordinate.. Little else was found within the bodies to explain death, which was often sudden or unexpected and not the result of delirium tremens. Two examples of such deaths follow.
CASE 1.-J. C., a white woman, aged 45, entered the Cook County Hospital, in the service of Dr. Hassin, March 21, 1924, at 2:00 p. m., and died much to the surprise of those in attendance twelve hours and fifteen minutes later.
The preliminary diagnosis was neurasthenia and the assignment was "neurology." The following was written after death: "This ambulatory patient complained on entrance of vague gastric symptoms, generalized aches and pains, and occipital headache. A superficial examination revealed nothing abnormal. The pulse was strong, the temperature normal and she was resting quietly. At 9:00 p. in., when I visited her, she was apparently in good condition, and death was unexpected." After 1:30 a. in., the nurse noted groaning respirations, a weak pulse and cyanosis of the face, and these continued until death at 2:15 a. in. After death, it was learned that she had been drinking heavily, and was nervous and weak.
Anatomic Diagnosis.-The diagnosis was: marked fatty changes of the liver; moderate edema of the leptomeninges; hyperplasia of the spleen; marked passive hyperemia of the kidneys and bowel lining; sclerosis of the aorta and front mitral leaflet; submucous minute petechial hemorrhages of the pancreatic duct; varicose veins of the lower extremities; slight anasarca (ankles) ; acute catarrhal conjunctivitis; fibrous adhesions between the liver and diaphragm, spleen and diaphragm, and spleen and liver.
The liver weighed 2,900 gm. and presented the well-known alterations of "large fatty liver," grossly and microscopically. Chemical examination of the abdominal viscera and of the gastric and intestinal content failed to disclose the presence of alcohol or any other poison.
CASE 2.-J. D. C., a white man, aged 54, entered the Cook County Hospital in the service of Dr. Hamberger, May 24, 1924, at 9:30 p. m., with a diagnosis of chronic alcoholism and cirrhosis of the liver. He was seen by the resident physician of the ward at 10:35 p. m., and appeared to be in fairly good condition, but he died abruptly about ten minutes later. A brother said the patient had been addicted to alcohol for many years, recently had used "moonshine," and for about a week had complained of weakness, tremor, nausea and epigastric distress.
Anatomic Diagnosis.-The diagnosis was: marked fatty changes of the liver; edema of the leptomeninges; moderately lessened "lipoid" of the suprarenal cortices; cholesterol deposits in the liver and kidneys; almost empty bowel; hypertrophy of the heart; passive hyperemia of the spleen, kidneys, liver and bowel; calcified tracheobronchial lymph glands; retention cysts of the left kidney; left focal fibrous pleuritis; fibrous localized perihepatitis; lessened colloid (atrophy) of the thyroid gland.
Chemical examination of 254 Gm. of stomach and content yielded 0.34 cc. of alcohol, but no other poison.
In the table, the age, sex, and ratio of the liver to body weight are given.11 A much larger series could easily be tabulated by using more necropsy records, but it is believed that these few from recent necropsies answer the purpose. It is of special significance that of the eleven, five were women.
About one-half hour before the death of one patient, a convulsion occurred with frothing at the mouth and cyanosis; another was subject to "fits," but had none during the three days he was in the hospital.12
For one of these patients, the clinical diagnosis was delirium tremens, but when death occurred this had largely cleared up; for six, the diagnosis was chronic, and for two acute, alcoholism; for two cirrhosis of the liver. The enlargement of the liver was usually noted clinically, once thought to be due to secondary growths from a rodent ulcer of the face, once regarded as hypertrophic cirrhosis. In six patients there was jaundice-marked in only one.
Some bronchopneumonia developing during the last days in the hospital, due to poor pulmonary ventilation and infection of dependent parts of the lungs, was present in a number of bodies.
In considering the way in which death is brought about in cases such as these, acute poisoning from alcohol is excluded by the absence of coma, for alcohol causes death in an acute condition as does ether and similar anesthetics. Drinking of a large amount of alcohol, as occurs at times on a wager, is followed by stupor, then coma and death. Delirium tremens may also be excluded, although, as stated, one of the patients had delirium tremens shortly before death. It is of some significance that the lining of the stomach in deaths such as these has no hemorrhages characteristic of delirium tremens,13 nor are such large fatty livers common with delirium tremens, nor is cirrhosis of the liver, as Fahr 4 has also emphasized.
Fahr, in discussing the cause of death from alcohol, mentions the possibility of alterations in the vagus and sympathetic nerves and ganglions within the heart, but his comments do not especially concern the type of disease we are dealing with in which the ratio of liver weight to that of the body is so large, nor does he present evidence of such changes in nerves or ganglions. That alcohol is concerned with changes in the peripheral and central nervous system is generally accepted in connection with both alcoholic neuritis and the Korsakoff syndrome. In another place,14 one of us (E. R. L.) has an account of gross alterations of the brain with delirium tremens, changes not encountered in the bodies of persons whose deaths are accompanied by the circumstances under discussion.
In these the most conspicuous features are the huge size of the liver and the difficulty in finding liver cells microscopically which from their number and size seem to possess any evidence of glycogen storage consistent with life. This.marked fatty infiltration has played a part so important in the classroom work of teaching pathology and has been the subject of so much illustration and description ever since instruction in such details of disease has been practiced, that the alteration may be regarded as familiar to all physicians.
It will be recalled that large globules of fat replace the cytoplasm of the liver cells, and that the nucleus and remaining cytopi. sm form a thin crescent ("signet ring") about a part of the periphery of the fat. It is obvious that in such cells there is no considerable store of glycogen. Such livers as these are so loaded with fat that thin slices float in water. A cirrhosis may be present, but is usually not marked. The little present may not be noted grossly, the irregularities otherwise denoting it being smoothed out by the accumulation of fat.
It seems to us that any attempt to explain unexpected deaths such as these must include absence of an adequate store of glycogen to meet the requirements of the body for glucose. In only one of these ten patients was chemical examination of the blood made, but in that instance, the sugar, 67 mg. per one hundred cubic millimeters, was significantly low.
Sheep becoming carnivorous when kept in abattoirs and developing an aversion for herbivorous foods, waste and die with fatty livers twice their normal size,15 and Williams16 has reported the death of a diabetic patient who had received no insulin, the death, "due to inanition," being accompanied by hypoglycemia and convulsions.
When death is contributed to by hypoglycemia following the use of insulin, convulsions have also been observed; they were not noted, except as mentioned, in the illnesses of the ten patients with these large livers.
It is well known that during heavy drinking of alcoholic beverages, food consumption is frequently reduced to a minimum, and that vomiting may also lessen the value of that taken. The alcohol drunk is oxidized, and the question naturally arises: Is the oxygen available from respiration inadequate to burn both the alcohol and the fat brought to the liver, or is the lessened destruction of fat due wholly or in part to a lowered supply of carbohydrates necessary for the metabolism of the fats?
Such questions are beyond the scope of this article, obviously maters for experimentation. Removal of the liver from animals causes their death, and certainly its replacement by fat to the end that little normal liver tissue remains places such persons in jeopardy, and apparently may either alone cause death or constitute the main contributory factor.
The weight of the liver, when diseased, as well as the weight of other organs, has special significance when considered with regard to the weight of the body. With an extensive replacement of the liver by fat in persons who drink heavily of alcoholic beverages, death may be entirely unexpected and abrupt and with few symptoms of illness.
In postmortem examinations of such persons, little else than a large fatty liver may be found to explain death.
*From the Pathological Laboratories of Rush Medical College. University of Chicago, and the Cook County Hospital.
1. Rosenfeld. G.: Fettbildung, Ergeb. d. Physiol. 2:50-94, 1903: Beitr:ige zur pathologie des Alkohols, Zentralbl. f. Med. 21:1049-1060, 1900.
2. Friedenwald, J.: The Pathologic effects of Alcohol on Rabbits. J. A. -11. A. 45:780-784, 1905.
3. Formal, H. F.: The "Pig-Backed" or Alcoholic Kidney of Drunkards, Tr. Am. Assn. Physicians 1:225-230, 188.
4. Fahr, T.: Zur Frage des chronischen Alkoholismus, Verhandl. d. dentsch. pa);th. Gesellsch. 13:163-169, 1909.
5. Moebius, E.: Die Fettleber, Deutsch. Min. 2:240-241, 1850. Schulppel, O.: Fettleber, Hepar Adiposum, Handl. d. Spec. Path. (Ziemssen), Leipzig 8:389-419. 1878. Weichselbaum, A.: Discussion. Verhandl. d. deutsch. path. Gesellsch. 13: 169, 1909. Mcjunkin, F. A.: The Human and Animal Liver After Alcohol. Arch. Int. Med. 19:786-800, 1917.
6. Louis, P. C. A.: Recherches anatomiques, pathlogiques, et therapeutiques sur la phthisie, trans. by Charles Cowan, Washington, D. C., 1836.
7. Frerichs, F. T.: Diseases of the Liver, trans. by Charles Murchison, New York 1:196-219, 1879.
8. Begbie, J. W.: Fatty Liver, in Reynolds: A System of Medicine, London 3:360-370, 1871.
9. Addison, T.: Observations on Fatty Degeneration of the Liver, Guy's Hosp. Rep. 1:476-483, 1836. Bamberger, H.: Die Fettleber; Schmidt's Jahrb. d. ges. Med. 79:298-300, 1853. Murchison, C.: Clinical Lectures on Diseases of the Liver, New York, 1868, pp. 43-52. Rolleston, H. D.: Diseases of the Liver, Gallbladder and Bile Ducts, London, pp. 426-433, 1912.
10. Gilbert, A., and Lereboullet, F.: La steatose latent des alcoholiques, Bull. et mem Soc. med. d. hop. de Paris 19:577-585, 1902.
11. The normal ratio of the liver to the body weight is from 1 : 31 to 1: 36. Vierordt, H.: Daten and Tabellen fur Mediziner, Ed. 3, Jena, 1906.
12. The term "whisky fits" has long been in common use by policemen.
13. Hirsch, E. F.: The Gastric Mucosa in Delirium Tremens, Arch. Int. Med. 63:354, 1914.
14. Sceleth, C. E., and Beifeld, A. F.: Cerebral Edema (Wet Brain) in Chronic Alcoholism, Am. J. led. Sc. 149:886, 1915.
15. Pages, H.: Hsitorie d'un monton nugnard; enseignement qu'on tirer, Compt. rend. Soc. de biol. 4:654-55, 1902.
16. Cited by Woodyatt, R.T.: The Clinical Use of Insulin, J. Metab. Res. 2:800, 1922.
Copyright College of American Pathologists Jan 2001
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