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Constitutional Hepatic Dysfunction
CONSTITUTIONAL HEPATIC DYSFUNCTION MANDRED
W.
COMFORT
FROM time to time, cases of mild acholuric jaundice, in which hemolytic, hepatic or biliary tract disease is suspected as the cause, are encountered. The abdomen occasionally has been opened without finding disease of the biliary tract or of the liver, and splenectomy, cholecystectomy, cholecystostomy or even choledochostomy has been performed without relief of the jaundice. Medical measures that are used in treatment of hepatic disease likewise have not relieved the jaundice. More recently, jaundice of this type has been the cause for contemplated dismissal of men from the armed forces of our country. Actually the jaundice in these cases is not due to disease of the blood, liver or biliary tract but apparently is due to an abnormally high threshold for excretion of bilirubin formed at the usual rate. The concentration in the serum reaches 10 to 12 mg. per 100 c.c., and the van den Bergh reaction is indirect. The jaundice is acholuric in type since bilirubin that gives the indirect van den Bergh reaction is not excreted by the kidneys. It is presumably due to an inborn deficiency of the hepatic cells especially with respect to the excretion of bilirubin. The terms "simple familial cholemia," "simple chronic icterus," "familial cholemia" and "familial nonhemolytic jaundice" have been applied to the condition7- 1o , 15 but at the Clinic we prefer to call it "constitutional hepatic dysfunction" because this term indicates the constitutional nature of the condition as well as the organ now believed to be responsible. The jaundice may not be noted before examination or may have been apparent continuously or intermittently for years. It may be~in at anv age and often several members of a family are affected similarly. The patient may be extremely healthy and vigorous but he frequently complains of lack of endurance and symptoms of the functional type. He may give a history suggestive of cholecystic disease, with or without stones. Physical examination usually does not disclose abnormalities other than a slight icteric tint to the scleras. The liver and spleen are not enlarged and, as mentioned previously, the urine is free from bile pigment (acholuria). The level of serum bilirubin is increased and the van den Bergh reaction is indirect. The results of morphologic examination of the cellular elements of the blood are normal, as is the fragility of the erythrocytes to hypotonic salt solution. The excretion of urobilinogen in feces for twenty-four hours is said to be normal or slightly decreased. 5 Other tests of hepatic function have not disclosed dysfunction of the polygonal cells other than that related to excretion of bilirubin. Although roentgenograms of the gallbladder made by the Graham-Cole technic usually disclcse normal function, they may dis-
982
CONSTITUTIONAL HEPATIC VYSFUNCllON
983
close a poorly functioning or nonfunctioning organ with or without stones. However, this incidental finding cannot be held responsible for the increased level of serum bilirubin giving the indirect van den Bergh reaction. HISTORICAL MATERIAL
The jaundice of constitutional hepatic dysfunction has been recognized since 1902, when the first of a series of articles by Gilbert and his associates appeared. They called attention to a group of cases in which the bile pigment in the blood was greater than normal. This finding was not associated with enlargement of the liver or spleen. Icterus of the skin and scleras often was apparent. Bile pigments did not appear in the urine. While Gilbert and associates 7- 10 probably included among their cases patients who had hepatic and hemolytic disease, particularly chronic hemolytic icterus, and even carotinemia, they deserve credit for recognition of a familial type of acholuric jaundice unassociated with enlargement of the liver and spleen. Subsequent refinements of diagnosis permitted differentiation of the various disease processes that produce an increased concentration of serum bilirubin giving an indirect van den Bergh reaction but little attention was given to the jaundice of constitutional hepatic dysfunction. In 1935, Rozendaal, SneH and 12,13 reported the first large series of cases of constitutional hepatic dysfunction. This condition was encountered sixty times at the Clinic during a two year period. In 30 per cent of the sixty cases, cholecystic disease was present. This high percentage suggested that constitutional hepatic dysfunction predisposed to the development of cholecystic disease but the high incidence may have been the result of the method of selection of cases and the greater frequency with which the concentration of serum bilirubin is determined in cases of cholecystic disease than in other cases . Meulengracht in 1939,12 Dameshek and Singer in 1941 5 and Curry, Greenwalt and Tat in 19424 discussed the condition and reported cases. Curry and associates described biopsy in the case of a man, fifty years of age, who had constitutional hepatic dysfunction. The hepatic structure and cells were normal. It is interesting that a similar jaundice exists among a certain strain of rats, as reported by Malloy and Lowenstein. l l In 1944, Hoyne and P reported a series of thirty-five cases collected from the records of the Clinic over an eight year period since the report in 1935. In case 3 of that report features of chronic hemolytic ictt;rus of the acquired type developed. The spleen became palpable and the erythrocytes became microcytic. The fragility of the erythrocytes increased in the four year interval between the first and second examinations. In other cases of constitutional hepatic dysfunction, microcytosis but not spherical microcytosis has been observed. These findings raise the question of relationship between constitutional hepatic dysfunction and chronic hemolytic icterus; that is, whether hepatic
984
MANDRED W. COMFORT
dysfunction of the type seen in constitutional hepatic dysfunction exists in chronic hemolytic icterus. INCIDENCE
The true incidence of the disease among patients who register at the Clinic probably is much nearer the average of thirty per yea:, as reported in 1935, than the average of four per year, as reported m. 1944. The incidence in the latter report would have been greater If the records had been examined of all cases in which the concentration of serum bilirubin with an indirect van den Bergh reaction was greater than 2 mg. per 100 c.c.; this was done in preparing the 1935 report. DIFFERENTIAL DIAGNOSIS
The recognition of constitutional hepatic dysfunction as a distinct clinical entity is important, not because it affects the health of the individual but because a correct diagnosis avoids the erroneously serious prognosis of true hepatic disease, prolonged medical treatment and unnecessary surgical treatment. The diagnosis would be made more often if all abnormally high elevations of serum bilirubin with an indirect reaction were examined more critically and if the concentration of bilirubin and the indirect or direct nature of the van den Bergh reaction were determined whenever the patient complains of slight jaundice, biliousness, liverishness and sallowness. The diagnosis of constitutional hepatic dysfunction should be made only after the presence of hemolytic and hepatic disease has been eliminated. Hemolytic disease is excluded by the absence of history of exposure to toxic, infectious and parasitic agents with hemolytic properties, by the absence of anemia and splenomegaly and by normal morphologic examination of erythrocytes, normal fragility of erythrocytes to hypotonic salt solution and normal excretion of urobilinogen in the urine and feces. Occasionally splenomegaly occurs in a case that otherwise conforms to the definition of constitutional hepatic dysfunction but the latter diagnosis should not be made without further observation and study because of the possibility of atypical hemolytic icterus. Most types of jaundice due to hepatic disease are excluded at once by the indirect nature of the van den Bergh reaction. The various hepatic functional tests further serve to exclude other dysfunction of the hepatic cells and, inferentially, disease of the hepatic cells. Only ",:hen th~ serum. bi~irubin responsible for latent jaundice of hepatic dls~ase gives the m~hrect van ~en B:rgh reaction is a differential diagnosl~ n:cessary. Sbght latent jaun.dlce due to serum bilirubin giving the mdlrect van den Bergh reactIOn often precedes the jaundice of ~epatic disease with ~ts more characteristic direct van den Bergh reaction, and may persist for months and even years after recoven' from profound damage to the hepatic polygonal cells and after oth~r
CONSTITUTIONAL REP ATIC DYSFUNCTION
985
hepatic functional tests have become negative. In such cases the history of hepatic damage serves to point to the nature of the disturbance to which the term residual hepatic dysfunction may be applied. In an occasional case of constitutional hepatic dysfunction the retention of dye in the bromsulfalein test of hepatic function has been increased to 6 or 7 per cent at the end of one hour (normal retention 5 per cent), but in no case has the percentage been increased more than might be accounted for by the human factor. Similarly, the van den Bergh reaction occasionally has been delayed direct instead of indirect, just as it is in the occasional case of true hemolytic icterus but this has occurred only when the concentration of bilirubin was relatively high. When the new technic of Sepulveda and Osterberg 14 has been used in such cases the serum bilirubin has been of the indirect variety. The rate of excretion of bilirubin in congenital hepatic dysfunction is said to be decreased, as is to be expected from the nature of the process. The jaundice that results from hepatitis associated with cholecystic disease or from obstruction of the duct due to stone is attributable to an increase in the concentration of bilirubin giving a direct van den Bergh reaction. It is accompanied by other characteristic features of disease of the biliary tract, especially colic, and should not be confused with the jaundice of constitutional hepatic dysfunction. THREE ILLUSTRATIVE CASES
The following abstracts of cases, previously included in the 1944 report by Hoyne and me, illustrate the typical features of constitutional hepatic dysfunction. Jaundice was the sole manifestation of the condition. Disease of the blood, liver, spleen or biliary tract could not be demonstrated. CASE I.-A man, aged sixty years, registered at the Clinic in September, 1938. He was a highly successful, energetic person who had more than the usual amount of endurance. His sole complaint was recurrent attacks of jaundice associated with fatigue, which he thought were precipitated by worry, nervous stresses, anger and constipation. The jaundice was painless and was not associated with chills, fever, nausea or vomiting. The stools remained normal in color during the attacks. There were no general or abdominal symptoms between attacks. The last two episodes of jaundice had followed renal colic. These attacks had occurred since early life and long had been of concern to both the patient and his physicians. The last attack had occurred several months before registration. His mother, one sister and a niece had experienced similar episodes of jaundice. The results of general physical examination were negative with the exception of an icteric tinge to the scleras and skill. The liver and spleen were not palpable. Urinalysis and routine serologic test for syphilis gave negative results. The hemoglobin was 14.8 gm. per 100 c.c. of blood; erythrocytes numbered 4,790,000 and leukocytes 7,000 per cubic millimeter of blood. Morphologic study of the blood did not disclose abnormality of the cells. Fragility of the erythrocytes to hypotonic salt solution was normal. Roentgenograms of the thorax, gallbladder, esophagus and stomach and bromsulfalein and hippuric acid tests for hepatic function
986
MANDRED W. COM.FORT
gave negative results. The concentrations of serum bilirubin were 3.0 and 1.6 mg. per 100 c.c. and the van den Bergh reaction was indirect. The diagnosis was constitutional hepatic dysfunction. The patient recently reported by letter that the episodes of icterus still occurred two or three times a year but that otherwise he had been getting along well.
Comment.-The jaundice in case 1 was familial. It was chronic and latent most of the time but overt at intervals when its depth was increased by nervous and emotional factors. Although the attacks had occurred for forty years, they apparently had not atlected the patient's health or diminished his endurance, and had not led to the development of disease of the blood, liver, spleen or biliary tract. This case emphasizes the effect of nervous and emotional stress on the depth of the jaundice, an effect that long has been recognized. 1 • 5, 6, 1;,1 The jaundice that occurs after renal colic must be explained on a similar basis. CASE 2.-A man, aged thirty-five years, registered at the Clinic in June, 1938. Except for thyroidectomy in 1930 and appendectomy and tonsillectomy in 1937, his health had been good. His endurance was satisfactory and fatigue occurred only aiter long periods of intense work. About six months prior to registration the patient had had a short period of malaise with slight jaundice and some loss of weight. The jaundice had persisted after the malaise disappeared and had fluctuated III intensity. Several doctors had diagnosed the condition as acute hepatitis or catarrhal jaundice. A high carbohydrate diet and various medicines including calcium, vitamin B and dilute hydrochloric acid had been prescribed. The results of general physical examination were essentially negative with the exception of slight scleral icterus. Urinalysis and routine serologic test for syphilis gave negative results. The hemoglobin was 15 gm. per 100 c.c.; erythrocytes numbered 4,900,000 and leukocytes 8,100 in each cubic millimeter of blood. The erythrocytes were normal in size and shape. Fragility of the erythrocytes to hypotonic salt solution was normal. Gastric analysis after a test meal showed free acidity. Roentgenograms of the thorax, gallbladder and stomach were negative. The basal metabolic rate was -3 per cent. The concentration of serum bilirubin was 2.0 mg. per 100 c.c. and the van den Bergh reaction was indirect. Bromsulfalein test of liver function did not disclose retention of dye. The diagnosis was constitutional hepatic dysfunction. The patient was not aware that other members of his family were similarly affected but on inquiry on his return home he found that his brother had a more yellowish tinge to his eyes than the patient. He also learned that his father's family was noted for the yellowish tinge to their complexions, some members of the family having this to a marked degree. His maternal antecedents were fair skinned and there was no history of jaundice among them.
Comment.-Case 2 again illustrates that constitutional hepatic dysfunction is compatible with excellent endurance and health. The jaundice was discovered when the patient was thirty-five years of age, and then only because his physician was a careful examiner. Concern about the jaundice was only natural and treatment for hepatitis was without benefit. The patient's anxiety was dispelled when the nature of the condition was explained and only on inquiry was the familial incidence of the condition established.
CONSTITUTIONAL HEPATIC DYSFUNCTION
987
CASE 3.-A woman, aged forty years, registered at the Clinic in December, 1934. 111 health develope
Comment.-The patient in this case complained, as do so many patients who have constitutional hepatic dysfunction, of a multitude of symptoms of the functional type. The jaundice was intensified and became overt under stimulation of increased fatigue and emotional and nervous stress but scarcely could be blamed for the patient's disability. The attacks of jaundice continued in spite of the institution of numerous medical and surgical procedures. The jaundice was not familial, whi,ch is true in certain cases of constitutional hepatic dysfunction. PROGNOSIS
The general health of the patient who has constitutional hepatic dysfunction may remain excellent, Some patients may have no complaints and may be curiuos only about the jaundice (cases 1 and 2). In most cases the patient may, and probably does, have other complaints
988
MANDRED W. COMFORT
since otherwise he would not consult a physician. Such complaints are usually functional but may be of some other type. It is not certain that the fatigue and lack of vitality so frequently complained of are due to the condition. As prevIOusly mentioned, the liver was normal in the one case in which biopsy has been performed. TREATMENT
Whether treatment of constitutional hepatic dysfunction is indicated is questionable since it apparently does not affect the general health. Treatment such as is given in disease of the liver is disappointing and is not indicated. Cholecystectomy, choledochostomy and splenectomy have no influence on the course of the jaundice or on the functional complaints of the patient. Operations on the biliary tract are indicated only when bona fide disease of the gallbladder or calculous disease of gallbladder or ducts exists. Avoidance of precepitating stresses such as overwork, fatigue and emotional and nervous stress may lessen the depth and the frequency with which increases in depth of jaundice occur. COMMENT AND SUMMARY
Attention is again called to constitutional hepatic dysfunction, a condition in which jaundice is due to an inborn inadequacy of the hepatic cells, particularly with regard to excretion of bilirubin. Its sole clinical manifestation is acholuric jaundice. The jaundice may be latent or overt. The essential pathologic finding is an increase in serum bilirubin giving an indirect van den Bergh reaction. It is not due to hemQlytic or true hepatic disease or dIsease of the biliary tract. The prognosis is excellent. Its recognition is important to prevent an erroneously serious prognosis and unwarranted medical and surgical treatment. REFERENCES
1. Chrometzka, Friedrich: "Ober die Norm des Bilirubinspiegels des Menschen und die hyperbilirubinamie; 1. Mitteilnng. zur Kritik der quantitativen Bilirubinbestimmung im Serum des gesunden und kranken Menschen. Ztschr. f. d. ges. exper. Med. 67:475-481, 1929. 2. Comfort, M. W.: Constitutional hepatic dysfunction. Proc. Staff Meet., Mayo Clin. 10:57-61 (Jan. 23) 1935. 3. Comfort, M. W. and Hoyne, R. M.: Constitutional hepatic dysfunction: clinical study of thirty-five cases. Gastroenterology. 3:155-162 (Sept.) 1944. 4. Curry, J. J., Greenwalt, T. J. and Tat, R. J.: Familial nonhemolytic jaundice; report of a case with liver biopsy. New England J. Med. 226:909-912 (June 4) 1942. • 5. Dameshek, William and Singer, Karl: Familial nonhemolytic jaundice; constitutional hepatic dysfunction with indirect van den Bergh reaction. Arch. Int. Med. 67:259-285 (Feb.) 1941. 6. Eppinger, Hans and Hess, Leo: Vagotonia; a clinical study in vegetative neurology. In: Nervous and Mental Disease Monograph Series No. 20. (Trans-
CONSTITUTIONAL HEPArIC DYSFUNCTION
7. 8. 9. 10. 11. 12. 13. 14. 15.
989
lated by W. M. Kraus and S. E. JelIiffe.) New York, The Nervous and Mental Disease Publishing Company, 1915, 93 pp. Gilbert, A. and Lereboullet, P.: La cholemie simple familiale. Gaz. hebd. de med. 49:889-897, 1902. Gilbert, A. and Lereboullet, P.: Sur la teneur en bilirubine du serum sanguin dans la cholcmie simple familiale. Compt. rend. Soc. de bioI. 58:937-940 (June 3) 1905. Gilbert, A. and Lereboullet, P.: La cholemie simple familiale son importance en pathologie. J. med. franc. 4:110-119, 1910. Gilbert, A .• Lereboullet, P. and Herscher, M.: Les trois cholcmies congcnitales. Bull. et memo Soc. med. d. hop. de Paris. 24:1203-1211 (Nov. 15) 1907. Malloy, Helga T. and Lowenstein, Louis: Hereditary jaundice in the rat. Can ad. 1\1. A. J. 42:122-125 (Feb.) 1940. Meulengracht, E.: Icterus intermittens jllvenilis. (Chronischer intermittierender juveniler Subikterus.) Klin. vVchnschr. 18:118-121 (Jan. 28) 1939. Rozendaal, H. M., Comfort, M. W. and Snell, A. M.: Slight and latent jaundice; the significance of elevated concentrations of bilirubin giving an indirect van den Bergh reaction. J.A.M.A. 104:374-379 (Feb. 2) 1935. Sepulveda, Bernardo and Osterberg, A. E.: Serum bilirubin: a procedure for the determination of indirect and direct values. J. Lab. & Clin. Med. 28: 1359-1368 (Aug.) 1943. Tecon. R. M.: Lcs hyperbilirubinenmies hercditaires: la cholemie familiale et l'ictcre hcmolytiquc. Arch. d. mal. de l'app. digestif. 28:567-589 (June) 1938.
W.
COMFORT
FROM time to time, cases of mild acholuric jaundice, in which hemolytic, hepatic or biliary tract disease is suspected as the cause, are encountered. The abdomen occasionally has been opened without finding disease of the biliary tract or of the liver, and splenectomy, cholecystectomy, cholecystostomy or even choledochostomy has been performed without relief of the jaundice. Medical measures that are used in treatment of hepatic disease likewise have not relieved the jaundice. More recently, jaundice of this type has been the cause for contemplated dismissal of men from the armed forces of our country. Actually the jaundice in these cases is not due to disease of the blood, liver or biliary tract but apparently is due to an abnormally high threshold for excretion of bilirubin formed at the usual rate. The concentration in the serum reaches 10 to 12 mg. per 100 c.c., and the van den Bergh reaction is indirect. The jaundice is acholuric in type since bilirubin that gives the indirect van den Bergh reaction is not excreted by the kidneys. It is presumably due to an inborn deficiency of the hepatic cells especially with respect to the excretion of bilirubin. The terms "simple familial cholemia," "simple chronic icterus," "familial cholemia" and "familial nonhemolytic jaundice" have been applied to the condition7- 1o , 15 but at the Clinic we prefer to call it "constitutional hepatic dysfunction" because this term indicates the constitutional nature of the condition as well as the organ now believed to be responsible. The jaundice may not be noted before examination or may have been apparent continuously or intermittently for years. It may be~in at anv age and often several members of a family are affected similarly. The patient may be extremely healthy and vigorous but he frequently complains of lack of endurance and symptoms of the functional type. He may give a history suggestive of cholecystic disease, with or without stones. Physical examination usually does not disclose abnormalities other than a slight icteric tint to the scleras. The liver and spleen are not enlarged and, as mentioned previously, the urine is free from bile pigment (acholuria). The level of serum bilirubin is increased and the van den Bergh reaction is indirect. The results of morphologic examination of the cellular elements of the blood are normal, as is the fragility of the erythrocytes to hypotonic salt solution. The excretion of urobilinogen in feces for twenty-four hours is said to be normal or slightly decreased. 5 Other tests of hepatic function have not disclosed dysfunction of the polygonal cells other than that related to excretion of bilirubin. Although roentgenograms of the gallbladder made by the Graham-Cole technic usually disclcse normal function, they may dis-
982
CONSTITUTIONAL HEPATIC VYSFUNCllON
983
close a poorly functioning or nonfunctioning organ with or without stones. However, this incidental finding cannot be held responsible for the increased level of serum bilirubin giving the indirect van den Bergh reaction. HISTORICAL MATERIAL
The jaundice of constitutional hepatic dysfunction has been recognized since 1902, when the first of a series of articles by Gilbert and his associates appeared. They called attention to a group of cases in which the bile pigment in the blood was greater than normal. This finding was not associated with enlargement of the liver or spleen. Icterus of the skin and scleras often was apparent. Bile pigments did not appear in the urine. While Gilbert and associates 7- 10 probably included among their cases patients who had hepatic and hemolytic disease, particularly chronic hemolytic icterus, and even carotinemia, they deserve credit for recognition of a familial type of acholuric jaundice unassociated with enlargement of the liver and spleen. Subsequent refinements of diagnosis permitted differentiation of the various disease processes that produce an increased concentration of serum bilirubin giving an indirect van den Bergh reaction but little attention was given to the jaundice of constitutional hepatic dysfunction. In 1935, Rozendaal, SneH and 12,13 reported the first large series of cases of constitutional hepatic dysfunction. This condition was encountered sixty times at the Clinic during a two year period. In 30 per cent of the sixty cases, cholecystic disease was present. This high percentage suggested that constitutional hepatic dysfunction predisposed to the development of cholecystic disease but the high incidence may have been the result of the method of selection of cases and the greater frequency with which the concentration of serum bilirubin is determined in cases of cholecystic disease than in other cases . Meulengracht in 1939,12 Dameshek and Singer in 1941 5 and Curry, Greenwalt and Tat in 19424 discussed the condition and reported cases. Curry and associates described biopsy in the case of a man, fifty years of age, who had constitutional hepatic dysfunction. The hepatic structure and cells were normal. It is interesting that a similar jaundice exists among a certain strain of rats, as reported by Malloy and Lowenstein. l l In 1944, Hoyne and P reported a series of thirty-five cases collected from the records of the Clinic over an eight year period since the report in 1935. In case 3 of that report features of chronic hemolytic ictt;rus of the acquired type developed. The spleen became palpable and the erythrocytes became microcytic. The fragility of the erythrocytes increased in the four year interval between the first and second examinations. In other cases of constitutional hepatic dysfunction, microcytosis but not spherical microcytosis has been observed. These findings raise the question of relationship between constitutional hepatic dysfunction and chronic hemolytic icterus; that is, whether hepatic
984
MANDRED W. COMFORT
dysfunction of the type seen in constitutional hepatic dysfunction exists in chronic hemolytic icterus. INCIDENCE
The true incidence of the disease among patients who register at the Clinic probably is much nearer the average of thirty per yea:, as reported in 1935, than the average of four per year, as reported m. 1944. The incidence in the latter report would have been greater If the records had been examined of all cases in which the concentration of serum bilirubin with an indirect van den Bergh reaction was greater than 2 mg. per 100 c.c.; this was done in preparing the 1935 report. DIFFERENTIAL DIAGNOSIS
The recognition of constitutional hepatic dysfunction as a distinct clinical entity is important, not because it affects the health of the individual but because a correct diagnosis avoids the erroneously serious prognosis of true hepatic disease, prolonged medical treatment and unnecessary surgical treatment. The diagnosis would be made more often if all abnormally high elevations of serum bilirubin with an indirect reaction were examined more critically and if the concentration of bilirubin and the indirect or direct nature of the van den Bergh reaction were determined whenever the patient complains of slight jaundice, biliousness, liverishness and sallowness. The diagnosis of constitutional hepatic dysfunction should be made only after the presence of hemolytic and hepatic disease has been eliminated. Hemolytic disease is excluded by the absence of history of exposure to toxic, infectious and parasitic agents with hemolytic properties, by the absence of anemia and splenomegaly and by normal morphologic examination of erythrocytes, normal fragility of erythrocytes to hypotonic salt solution and normal excretion of urobilinogen in the urine and feces. Occasionally splenomegaly occurs in a case that otherwise conforms to the definition of constitutional hepatic dysfunction but the latter diagnosis should not be made without further observation and study because of the possibility of atypical hemolytic icterus. Most types of jaundice due to hepatic disease are excluded at once by the indirect nature of the van den Bergh reaction. The various hepatic functional tests further serve to exclude other dysfunction of the hepatic cells and, inferentially, disease of the hepatic cells. Only ",:hen th~ serum. bi~irubin responsible for latent jaundice of hepatic dls~ase gives the m~hrect van ~en B:rgh reaction is a differential diagnosl~ n:cessary. Sbght latent jaun.dlce due to serum bilirubin giving the mdlrect van den Bergh reactIOn often precedes the jaundice of ~epatic disease with ~ts more characteristic direct van den Bergh reaction, and may persist for months and even years after recoven' from profound damage to the hepatic polygonal cells and after oth~r
CONSTITUTIONAL REP ATIC DYSFUNCTION
985
hepatic functional tests have become negative. In such cases the history of hepatic damage serves to point to the nature of the disturbance to which the term residual hepatic dysfunction may be applied. In an occasional case of constitutional hepatic dysfunction the retention of dye in the bromsulfalein test of hepatic function has been increased to 6 or 7 per cent at the end of one hour (normal retention 5 per cent), but in no case has the percentage been increased more than might be accounted for by the human factor. Similarly, the van den Bergh reaction occasionally has been delayed direct instead of indirect, just as it is in the occasional case of true hemolytic icterus but this has occurred only when the concentration of bilirubin was relatively high. When the new technic of Sepulveda and Osterberg 14 has been used in such cases the serum bilirubin has been of the indirect variety. The rate of excretion of bilirubin in congenital hepatic dysfunction is said to be decreased, as is to be expected from the nature of the process. The jaundice that results from hepatitis associated with cholecystic disease or from obstruction of the duct due to stone is attributable to an increase in the concentration of bilirubin giving a direct van den Bergh reaction. It is accompanied by other characteristic features of disease of the biliary tract, especially colic, and should not be confused with the jaundice of constitutional hepatic dysfunction. THREE ILLUSTRATIVE CASES
The following abstracts of cases, previously included in the 1944 report by Hoyne and me, illustrate the typical features of constitutional hepatic dysfunction. Jaundice was the sole manifestation of the condition. Disease of the blood, liver, spleen or biliary tract could not be demonstrated. CASE I.-A man, aged sixty years, registered at the Clinic in September, 1938. He was a highly successful, energetic person who had more than the usual amount of endurance. His sole complaint was recurrent attacks of jaundice associated with fatigue, which he thought were precipitated by worry, nervous stresses, anger and constipation. The jaundice was painless and was not associated with chills, fever, nausea or vomiting. The stools remained normal in color during the attacks. There were no general or abdominal symptoms between attacks. The last two episodes of jaundice had followed renal colic. These attacks had occurred since early life and long had been of concern to both the patient and his physicians. The last attack had occurred several months before registration. His mother, one sister and a niece had experienced similar episodes of jaundice. The results of general physical examination were negative with the exception of an icteric tinge to the scleras and skill. The liver and spleen were not palpable. Urinalysis and routine serologic test for syphilis gave negative results. The hemoglobin was 14.8 gm. per 100 c.c. of blood; erythrocytes numbered 4,790,000 and leukocytes 7,000 per cubic millimeter of blood. Morphologic study of the blood did not disclose abnormality of the cells. Fragility of the erythrocytes to hypotonic salt solution was normal. Roentgenograms of the thorax, gallbladder, esophagus and stomach and bromsulfalein and hippuric acid tests for hepatic function
986
MANDRED W. COM.FORT
gave negative results. The concentrations of serum bilirubin were 3.0 and 1.6 mg. per 100 c.c. and the van den Bergh reaction was indirect. The diagnosis was constitutional hepatic dysfunction. The patient recently reported by letter that the episodes of icterus still occurred two or three times a year but that otherwise he had been getting along well.
Comment.-The jaundice in case 1 was familial. It was chronic and latent most of the time but overt at intervals when its depth was increased by nervous and emotional factors. Although the attacks had occurred for forty years, they apparently had not atlected the patient's health or diminished his endurance, and had not led to the development of disease of the blood, liver, spleen or biliary tract. This case emphasizes the effect of nervous and emotional stress on the depth of the jaundice, an effect that long has been recognized. 1 • 5, 6, 1;,1 The jaundice that occurs after renal colic must be explained on a similar basis. CASE 2.-A man, aged thirty-five years, registered at the Clinic in June, 1938. Except for thyroidectomy in 1930 and appendectomy and tonsillectomy in 1937, his health had been good. His endurance was satisfactory and fatigue occurred only aiter long periods of intense work. About six months prior to registration the patient had had a short period of malaise with slight jaundice and some loss of weight. The jaundice had persisted after the malaise disappeared and had fluctuated III intensity. Several doctors had diagnosed the condition as acute hepatitis or catarrhal jaundice. A high carbohydrate diet and various medicines including calcium, vitamin B and dilute hydrochloric acid had been prescribed. The results of general physical examination were essentially negative with the exception of slight scleral icterus. Urinalysis and routine serologic test for syphilis gave negative results. The hemoglobin was 15 gm. per 100 c.c.; erythrocytes numbered 4,900,000 and leukocytes 8,100 in each cubic millimeter of blood. The erythrocytes were normal in size and shape. Fragility of the erythrocytes to hypotonic salt solution was normal. Gastric analysis after a test meal showed free acidity. Roentgenograms of the thorax, gallbladder and stomach were negative. The basal metabolic rate was -3 per cent. The concentration of serum bilirubin was 2.0 mg. per 100 c.c. and the van den Bergh reaction was indirect. Bromsulfalein test of liver function did not disclose retention of dye. The diagnosis was constitutional hepatic dysfunction. The patient was not aware that other members of his family were similarly affected but on inquiry on his return home he found that his brother had a more yellowish tinge to his eyes than the patient. He also learned that his father's family was noted for the yellowish tinge to their complexions, some members of the family having this to a marked degree. His maternal antecedents were fair skinned and there was no history of jaundice among them.
Comment.-Case 2 again illustrates that constitutional hepatic dysfunction is compatible with excellent endurance and health. The jaundice was discovered when the patient was thirty-five years of age, and then only because his physician was a careful examiner. Concern about the jaundice was only natural and treatment for hepatitis was without benefit. The patient's anxiety was dispelled when the nature of the condition was explained and only on inquiry was the familial incidence of the condition established.
CONSTITUTIONAL HEPATIC DYSFUNCTION
987
CASE 3.-A woman, aged forty years, registered at the Clinic in December, 1934. 111 health develope
Comment.-The patient in this case complained, as do so many patients who have constitutional hepatic dysfunction, of a multitude of symptoms of the functional type. The jaundice was intensified and became overt under stimulation of increased fatigue and emotional and nervous stress but scarcely could be blamed for the patient's disability. The attacks of jaundice continued in spite of the institution of numerous medical and surgical procedures. The jaundice was not familial, whi,ch is true in certain cases of constitutional hepatic dysfunction. PROGNOSIS
The general health of the patient who has constitutional hepatic dysfunction may remain excellent, Some patients may have no complaints and may be curiuos only about the jaundice (cases 1 and 2). In most cases the patient may, and probably does, have other complaints
988
MANDRED W. COMFORT
since otherwise he would not consult a physician. Such complaints are usually functional but may be of some other type. It is not certain that the fatigue and lack of vitality so frequently complained of are due to the condition. As prevIOusly mentioned, the liver was normal in the one case in which biopsy has been performed. TREATMENT
Whether treatment of constitutional hepatic dysfunction is indicated is questionable since it apparently does not affect the general health. Treatment such as is given in disease of the liver is disappointing and is not indicated. Cholecystectomy, choledochostomy and splenectomy have no influence on the course of the jaundice or on the functional complaints of the patient. Operations on the biliary tract are indicated only when bona fide disease of the gallbladder or calculous disease of gallbladder or ducts exists. Avoidance of precepitating stresses such as overwork, fatigue and emotional and nervous stress may lessen the depth and the frequency with which increases in depth of jaundice occur. COMMENT AND SUMMARY
Attention is again called to constitutional hepatic dysfunction, a condition in which jaundice is due to an inborn inadequacy of the hepatic cells, particularly with regard to excretion of bilirubin. Its sole clinical manifestation is acholuric jaundice. The jaundice may be latent or overt. The essential pathologic finding is an increase in serum bilirubin giving an indirect van den Bergh reaction. It is not due to hemQlytic or true hepatic disease or dIsease of the biliary tract. The prognosis is excellent. Its recognition is important to prevent an erroneously serious prognosis and unwarranted medical and surgical treatment. REFERENCES
1. Chrometzka, Friedrich: "Ober die Norm des Bilirubinspiegels des Menschen und die hyperbilirubinamie; 1. Mitteilnng. zur Kritik der quantitativen Bilirubinbestimmung im Serum des gesunden und kranken Menschen. Ztschr. f. d. ges. exper. Med. 67:475-481, 1929. 2. Comfort, M. W.: Constitutional hepatic dysfunction. Proc. Staff Meet., Mayo Clin. 10:57-61 (Jan. 23) 1935. 3. Comfort, M. W. and Hoyne, R. M.: Constitutional hepatic dysfunction: clinical study of thirty-five cases. Gastroenterology. 3:155-162 (Sept.) 1944. 4. Curry, J. J., Greenwalt, T. J. and Tat, R. J.: Familial nonhemolytic jaundice; report of a case with liver biopsy. New England J. Med. 226:909-912 (June 4) 1942. • 5. Dameshek, William and Singer, Karl: Familial nonhemolytic jaundice; constitutional hepatic dysfunction with indirect van den Bergh reaction. Arch. Int. Med. 67:259-285 (Feb.) 1941. 6. Eppinger, Hans and Hess, Leo: Vagotonia; a clinical study in vegetative neurology. In: Nervous and Mental Disease Monograph Series No. 20. (Trans-
CONSTITUTIONAL HEPArIC DYSFUNCTION
7. 8. 9. 10. 11. 12. 13. 14. 15.
989
lated by W. M. Kraus and S. E. JelIiffe.) New York, The Nervous and Mental Disease Publishing Company, 1915, 93 pp. Gilbert, A. and Lereboullet, P.: La cholemie simple familiale. Gaz. hebd. de med. 49:889-897, 1902. Gilbert, A. and Lereboullet, P.: Sur la teneur en bilirubine du serum sanguin dans la cholcmie simple familiale. Compt. rend. Soc. de bioI. 58:937-940 (June 3) 1905. Gilbert, A. and Lereboullet, P.: La cholemie simple familiale son importance en pathologie. J. med. franc. 4:110-119, 1910. Gilbert, A .• Lereboullet, P. and Herscher, M.: Les trois cholcmies congcnitales. Bull. et memo Soc. med. d. hop. de Paris. 24:1203-1211 (Nov. 15) 1907. Malloy, Helga T. and Lowenstein, Louis: Hereditary jaundice in the rat. Can ad. 1\1. A. J. 42:122-125 (Feb.) 1940. Meulengracht, E.: Icterus intermittens jllvenilis. (Chronischer intermittierender juveniler Subikterus.) Klin. vVchnschr. 18:118-121 (Jan. 28) 1939. Rozendaal, H. M., Comfort, M. W. and Snell, A. M.: Slight and latent jaundice; the significance of elevated concentrations of bilirubin giving an indirect van den Bergh reaction. J.A.M.A. 104:374-379 (Feb. 2) 1935. Sepulveda, Bernardo and Osterberg, A. E.: Serum bilirubin: a procedure for the determination of indirect and direct values. J. Lab. & Clin. Med. 28: 1359-1368 (Aug.) 1943. Tecon. R. M.: Lcs hyperbilirubinenmies hercditaires: la cholemie familiale et l'ictcre hcmolytiquc. Arch. d. mal. de l'app. digestif. 28:567-589 (June) 1938.