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Familial non-hemolytic icterus
Familial WADDY
G.
Non-hemolytic
BAROODY,
M.D. and MAJ.
Florence,
T.
SHUCART,
M.c.?
South Carolina
F
that he had always been entirely well without symptoms of nausea, vomiting, diarrhea, abdominal pain or fever. There had been no significant change in the color of urine or feces during this or any previous episode of observed jaundice. Past history revealed that the patient’s pre-military occupation was assistant funeral embalmer. His military history began October 13, 1953, at Portland, Oregon, thirty miles from his home. He had served only in the Continental United States. The patient stated that he did not smoke or drink alcoholic beverages. No history of chronic drug intake or association with hematopoietic or hepatic toxic agents was obtained. Specific and detailed questioning revealed no evidence of inoculation or injection during the preceding several months with the exception of the previously mentioned blood donation. There had been no known exposure to contaminated food or water sources and no associates had been ill from infectious or contagious diseases. While in the military service the patient had been and is now serving as a surgical technician. (Fig. 1.) Family history revealed that intermittent jaundice had been noted on the maternal side only. The patient’s grandmother, mother, an uncle and an aunt were reputedly involved all of their lives with “yellow skin” at one time or another. The patient’s brother and only sibling was not observed to have jaundice, although an elevated serum bilirubin was obtained. The paternal side of the family had no history of jaundice, liver or blood diseases. Both the maternal and paternal grandparents are living and well. No member of the family mentioned had had serious illnesses that required medical attention. The jaundice observed never stimulated a visit to the family physician. This patient had been hospitalized only once, for “three day measles” in November, 1953. The only operations recorded in the history were a tonsillectomy and adenoidectomy at age five and a lipoma removed from the left hip during hospitalization at Fitzsimons Army Hospital. On physical examination the temperature, pulse, respiration and blood pressure were within normal limits. A slight scleral icterus was noted but there was no evidence of liver palms, spider angiomas, abnormal hair distribution or gynecomastia. Examination of the
AMILIAL non-hemolytic icterus is recognized as a distinct entity.s It does not occur commonly; however, the exact incidence is not determined. ls6 In the past it has been referred to as constitutional hepatic dysfunction. ls2s6In most instances the diagnosis is inadvertently arrived at M.rtul
after analysis of a patient with jaundice has excluded other etiologic factors. This report concerns a patient referred to us for evaluation of jaundice. Study revealed an icteric patient relatively asymptomatic and without evidence of anemia, hemolytic tendency or intrinsic liver disease. Members of three generations of his family were studied because intermittent jaundice had been observed in several individuals on the maternal side. CASE
RICHARD
Icterus*
REPORT
A nineteen year old white male was admitted to Fitzsimons Army Hospital July 26, 1954, because of jaundice. A few days prior to admission the patient was told by friends that he looked yellow and was advised to seek medical attention. He stated that he had been quite well and working every day but noted a mild degree of easy fatigability and some slight loss of appetite. Upon questioning he stated that his family had observed that he had had yellow skin from time to time ever since childhood. He related that on March 3, 1954, after having donated blood, he was told that his blood tests showed jaundice. The patient stated
* From the Department of Medicine, Fitzsimons Army Hospital, Denver, Colorado. t Presently on duty at the 6110th USAF Hospital, A.P.O., San Francisco, Calif. 3’4
AMERICAN
JOURNAL
OF
MEDICINE
Familial
Non-hemolytic
Icterus--&woody,
TABLE LABORATORY
,VuqSnrt
3’ 5
I
DATA OF PATIENTS
WITH JAUNDICE
Normal
/ Negative i Neaativr I I
0
Yes
Kh +
Brother Normal
h4othrr
1Negative ( Negative ~ 0
Yrs
Kh-
Maternal
aunt
Maternal
uncle
Maternal
grandmother
Mattbrnal prandfather
abdomen revealed a liver which could be palpated on deep inspiration but was not believed to be enlarged or tender. The spleen was not enlarged. The remainder of the physical examination was within normal limits. Laboratory data revealed a red blood count of 6.2 million, hemoglobin 17.4 gm., white blood count 6,300 cells with a normal differential, sedimentation rate 3 mm. per hour, hematocrit 54. The blood morphology and urinalysis were within normal limits. The initial reticulocyte count was 1.2 per cent, subsequent counts of 0.7, 0.5 and 0.6 per cent were obtained. Coombs’ test, sickle cell preparation and serologic tests for syphilis gave negative results. Two red cell fragility studies were entirely normal. Serum bilirubin was 3.7 mg. per cent, the direct van den Bergh test 0.5 mg. per cent, indirect 3.3; the total serum cholesterol was 144 mg. per cent, esters 79 per cent; serum alkaline phosphatase was normal, cephalin flocculation and thymol turbidity tests as well as BSP retention test and prothrombin time were within normal limits. A quantitative estimation of urine urobilinogen revealed 0.59 mg. per 24 hours, studies, over a three-day period, of fecal urobilinogen revealed an average excretion of 164.4 mg. per day. A urine test for porphyrins gave negative results. The patient’s blood type was 0 Rh-positive. Bone marrow aspiration from the right iliac crest revealed normal tissue. A radiochromium study of red cell survival time was reported as entirely within normal limits and paper chromatography revealed normal adult hemoglobin. The serum bilirubin remained elevated, only the indirect component being abnormal. Evidence col
. ..’
/.
No
,
lected revealed no hepatic or hemolytic blood disease. A bilirubin tolerance test was done which revealed 83 per cent retention four hours after a test dose of 50 mg. of bilirubin had been administered intravenously, as compared with normal retention of less than 5 per cent. Total evaluation of the data presented led us to the conclusion that this represented a typical case of familial non-hemolytic icterus. Physical examinations and some laboratory studies were made of the patient’s mother and aunt. In addition, relevant laboratory data were obtained on the patient’s brother, uncle and both grandparents. (Table I.) The histories obtained agreed in all details in regard to family illness and the observations regarding intermittent jaundice. Physical examinations on the mother and aunt were entirely normal, no evidence of clinical icterus or enlargement of the spleen or liver being obtained. From the data collected it appeared that there was familial transmission of icterus on the maternal side of the family. COMMENTS Familial recognized
non-hemolytic as an entity
instances
the familial
represented
the
recognized,
‘. lo
considered
in
patient. occurrence I)ilirubin (3)
no
The
many
jaundice
hemolytic and
the
this
reported
had
diagnosis
of jaundice, in of
as to
(2) anemia,
usually
be
an
(1) elevated
indirect (4)
been In past
previously
diagnosis
requires the
has years.
form,
differential
reflected evidence
icterus for
strongly of our familial serum
component, no
apparent
3’6
Familial Non-hemolytic Icterus-Baroody, Shugart
hemolytic blood disease, (5) no liver disease, and (6) a jaundiced yet asymptomatic patient in otherwise good health. The case presented fulfills these criteria. The patient was jaundiced yet essentially asymptomatic. Physical examination revealed jaundice to be the only significant abnormality. Laboratory data revealed an elevated indirect and total serum bilirubin. This suggested the possibility of hemolysis. Study showed no anemia and no evidence of reticulocytosis or sickling, or any increase in excretion of fecal and urinary urobilinogen. Bone marrow aspiration, erythrocyte fragility, red cell survival time, Coombs’ test and paper chromatography were normal. These findings militated against abnormal hemolysis. Liver function studies were performed and no abnormalities discovered. The bilirubin tolerance test revealed delayed clearance. No evidence of acute or chronic disease was apparent. Familial occurrence by history and laboratory data is in accord with previously described cases. The absence of increased serum bilirubin in the maternal grandmother we believe represents the intermittent manifestation of icterus since the family noted “darkening of her skin” from time to time. The most frequently described symptom in previous reports is easy fatigability. ‘v6,’ There is no pain or fever, and the relationship ofjaundice to physical activity has been a point of conjecture; no specific correlation was noted in our patient. Emotional stress has been related to icterus by some observers but this has not been applicable to our patient or to involved members of his family. The mechanism appears to be a physiologic defect resulting in impaired clearance of the This probable defect is serum bilirubin.3s7 illustrated and substantiated by the results of the bilirubin tolerance test recorded in the case report, in addition to all the other data presented.3-5 This defect is probably a dominant mendelian trait which may be carried by either sex.3,8 The prognosis in patients with familial nonhemolytic icterus is excellent.3~6~7 There is no evidence of abnormal red blood cell destruction or primary hepatic damage and no evidence of progression of the disease state as there might be in chronic hepatic disease. The patient reported in this study is age nineteen but his entire family including mother, aunt, uncle and grandparents
are still living a normal life into the seventh decade; therefore age seems not to be a factor except perhaps as an indicator that the prognosis is very good. We are not sure whether the easy fatigability has anything specifically to do with the disease; it may, of course, reflect the personality of the individual involved. Whether or not infection or physical stress have any bearing on the degree of jaundice has yet to be determined. SUMMARY
A study was made of three generations of a family each presenting a history of jaundice, substantiated by laboratory data. The family members were active and in good health. No evidence of hemolysis was unearthed even though indirect-reacting bilirubin of the serum was the abnormal component in all affected members. No evidence of hepatocellular damage was obtained. These findings support the diagnosis of non-hemolytic icterus exhibiting familial transmission, in this instance on the maternal side of the family. The importance of recognition of this established entity is stressed. The prognosis is excellent and confusion with congenital hemolytic anemia or chronic liver disease could well be the source of iatrogenic illness. REFERENCES 1. COMFORT, M. W. Constitutional hepatic dysfunction. Proc. Staff Meet. Mayo Clin., 10: 57, 1935. 2. ROZENDAAL, H. M., COMFORT, M. W. and SNELL, A. M. Slight and latent jaundice. J. A. M. A., 104: 374, 1935. 3. DAMESHEK, W. and SINGER, K. Familial nonhemolytic jaundice. Arch. Znt. Med., 67: 259-285, 1941. 4. SOPFER, L. J. and PAULSON, M. Comparative advantages and further modification of the bilirubin excretion test for hepatic function. Am. J. M. SC., 192: 535, 1936. 5. WEECH, A. A., VANN, D. and GRILLO, R. A. The clearance of bilirubin from the plasma. A measure of the excreting power of the liver. J. Clin. Znuestigation, 20: 326, 1941. 6. COMFORT,M. W. and HOYNE, R. M. Constitutional hepatic dysfunction: clinical study of thirty-five cases. Gastroenterology, 3: 155, 1944. 7. COMFORT, M. W. Constitutional hepatic dysfunction. M. Clin. North America, 29: 982, 1945. 8. CRIGLER, J. F. and NAJJER, V. A. Congenital familial non-hemolytic jaundice with kernicterus. Pediatrics, 10: 169, 1952. 9. CURRY, J. J. et al. Familial non-hemolytic jaundice. NEW England J. Med., 226: 909, 1942. 10. CARITHERS, H. A. Non-hemolytic familial jaundice. J. Pediat., 19: 817-821, 1941. AMERICAN
JOURNAL
OF
MEDICINE
G.
Non-hemolytic
BAROODY,
M.D. and MAJ.
Florence,
T.
SHUCART,
M.c.?
South Carolina
F
that he had always been entirely well without symptoms of nausea, vomiting, diarrhea, abdominal pain or fever. There had been no significant change in the color of urine or feces during this or any previous episode of observed jaundice. Past history revealed that the patient’s pre-military occupation was assistant funeral embalmer. His military history began October 13, 1953, at Portland, Oregon, thirty miles from his home. He had served only in the Continental United States. The patient stated that he did not smoke or drink alcoholic beverages. No history of chronic drug intake or association with hematopoietic or hepatic toxic agents was obtained. Specific and detailed questioning revealed no evidence of inoculation or injection during the preceding several months with the exception of the previously mentioned blood donation. There had been no known exposure to contaminated food or water sources and no associates had been ill from infectious or contagious diseases. While in the military service the patient had been and is now serving as a surgical technician. (Fig. 1.) Family history revealed that intermittent jaundice had been noted on the maternal side only. The patient’s grandmother, mother, an uncle and an aunt were reputedly involved all of their lives with “yellow skin” at one time or another. The patient’s brother and only sibling was not observed to have jaundice, although an elevated serum bilirubin was obtained. The paternal side of the family had no history of jaundice, liver or blood diseases. Both the maternal and paternal grandparents are living and well. No member of the family mentioned had had serious illnesses that required medical attention. The jaundice observed never stimulated a visit to the family physician. This patient had been hospitalized only once, for “three day measles” in November, 1953. The only operations recorded in the history were a tonsillectomy and adenoidectomy at age five and a lipoma removed from the left hip during hospitalization at Fitzsimons Army Hospital. On physical examination the temperature, pulse, respiration and blood pressure were within normal limits. A slight scleral icterus was noted but there was no evidence of liver palms, spider angiomas, abnormal hair distribution or gynecomastia. Examination of the
AMILIAL non-hemolytic icterus is recognized as a distinct entity.s It does not occur commonly; however, the exact incidence is not determined. ls6 In the past it has been referred to as constitutional hepatic dysfunction. ls2s6In most instances the diagnosis is inadvertently arrived at M.rtul
after analysis of a patient with jaundice has excluded other etiologic factors. This report concerns a patient referred to us for evaluation of jaundice. Study revealed an icteric patient relatively asymptomatic and without evidence of anemia, hemolytic tendency or intrinsic liver disease. Members of three generations of his family were studied because intermittent jaundice had been observed in several individuals on the maternal side. CASE
RICHARD
Icterus*
REPORT
A nineteen year old white male was admitted to Fitzsimons Army Hospital July 26, 1954, because of jaundice. A few days prior to admission the patient was told by friends that he looked yellow and was advised to seek medical attention. He stated that he had been quite well and working every day but noted a mild degree of easy fatigability and some slight loss of appetite. Upon questioning he stated that his family had observed that he had had yellow skin from time to time ever since childhood. He related that on March 3, 1954, after having donated blood, he was told that his blood tests showed jaundice. The patient stated
* From the Department of Medicine, Fitzsimons Army Hospital, Denver, Colorado. t Presently on duty at the 6110th USAF Hospital, A.P.O., San Francisco, Calif. 3’4
AMERICAN
JOURNAL
OF
MEDICINE
Familial
Non-hemolytic
Icterus--&woody,
TABLE LABORATORY
,VuqSnrt
3’ 5
I
DATA OF PATIENTS
WITH JAUNDICE
Normal
/ Negative i Neaativr I I
0
Yes
Kh +
Brother Normal
h4othrr
1Negative ( Negative ~ 0
Yrs
Kh-
Maternal
aunt
Maternal
uncle
Maternal
grandmother
Mattbrnal prandfather
abdomen revealed a liver which could be palpated on deep inspiration but was not believed to be enlarged or tender. The spleen was not enlarged. The remainder of the physical examination was within normal limits. Laboratory data revealed a red blood count of 6.2 million, hemoglobin 17.4 gm., white blood count 6,300 cells with a normal differential, sedimentation rate 3 mm. per hour, hematocrit 54. The blood morphology and urinalysis were within normal limits. The initial reticulocyte count was 1.2 per cent, subsequent counts of 0.7, 0.5 and 0.6 per cent were obtained. Coombs’ test, sickle cell preparation and serologic tests for syphilis gave negative results. Two red cell fragility studies were entirely normal. Serum bilirubin was 3.7 mg. per cent, the direct van den Bergh test 0.5 mg. per cent, indirect 3.3; the total serum cholesterol was 144 mg. per cent, esters 79 per cent; serum alkaline phosphatase was normal, cephalin flocculation and thymol turbidity tests as well as BSP retention test and prothrombin time were within normal limits. A quantitative estimation of urine urobilinogen revealed 0.59 mg. per 24 hours, studies, over a three-day period, of fecal urobilinogen revealed an average excretion of 164.4 mg. per day. A urine test for porphyrins gave negative results. The patient’s blood type was 0 Rh-positive. Bone marrow aspiration from the right iliac crest revealed normal tissue. A radiochromium study of red cell survival time was reported as entirely within normal limits and paper chromatography revealed normal adult hemoglobin. The serum bilirubin remained elevated, only the indirect component being abnormal. Evidence col
. ..’
/.
No
,
lected revealed no hepatic or hemolytic blood disease. A bilirubin tolerance test was done which revealed 83 per cent retention four hours after a test dose of 50 mg. of bilirubin had been administered intravenously, as compared with normal retention of less than 5 per cent. Total evaluation of the data presented led us to the conclusion that this represented a typical case of familial non-hemolytic icterus. Physical examinations and some laboratory studies were made of the patient’s mother and aunt. In addition, relevant laboratory data were obtained on the patient’s brother, uncle and both grandparents. (Table I.) The histories obtained agreed in all details in regard to family illness and the observations regarding intermittent jaundice. Physical examinations on the mother and aunt were entirely normal, no evidence of clinical icterus or enlargement of the spleen or liver being obtained. From the data collected it appeared that there was familial transmission of icterus on the maternal side of the family. COMMENTS Familial recognized
non-hemolytic as an entity
instances
the familial
represented
the
recognized,
‘. lo
considered
in
patient. occurrence I)ilirubin (3)
no
The
many
jaundice
hemolytic and
the
this
reported
had
diagnosis
of jaundice, in of
as to
(2) anemia,
usually
be
an
(1) elevated
indirect (4)
been In past
previously
diagnosis
requires the
has years.
form,
differential
reflected evidence
icterus for
strongly of our familial serum
component, no
apparent
3’6
Familial Non-hemolytic Icterus-Baroody, Shugart
hemolytic blood disease, (5) no liver disease, and (6) a jaundiced yet asymptomatic patient in otherwise good health. The case presented fulfills these criteria. The patient was jaundiced yet essentially asymptomatic. Physical examination revealed jaundice to be the only significant abnormality. Laboratory data revealed an elevated indirect and total serum bilirubin. This suggested the possibility of hemolysis. Study showed no anemia and no evidence of reticulocytosis or sickling, or any increase in excretion of fecal and urinary urobilinogen. Bone marrow aspiration, erythrocyte fragility, red cell survival time, Coombs’ test and paper chromatography were normal. These findings militated against abnormal hemolysis. Liver function studies were performed and no abnormalities discovered. The bilirubin tolerance test revealed delayed clearance. No evidence of acute or chronic disease was apparent. Familial occurrence by history and laboratory data is in accord with previously described cases. The absence of increased serum bilirubin in the maternal grandmother we believe represents the intermittent manifestation of icterus since the family noted “darkening of her skin” from time to time. The most frequently described symptom in previous reports is easy fatigability. ‘v6,’ There is no pain or fever, and the relationship ofjaundice to physical activity has been a point of conjecture; no specific correlation was noted in our patient. Emotional stress has been related to icterus by some observers but this has not been applicable to our patient or to involved members of his family. The mechanism appears to be a physiologic defect resulting in impaired clearance of the This probable defect is serum bilirubin.3s7 illustrated and substantiated by the results of the bilirubin tolerance test recorded in the case report, in addition to all the other data presented.3-5 This defect is probably a dominant mendelian trait which may be carried by either sex.3,8 The prognosis in patients with familial nonhemolytic icterus is excellent.3~6~7 There is no evidence of abnormal red blood cell destruction or primary hepatic damage and no evidence of progression of the disease state as there might be in chronic hepatic disease. The patient reported in this study is age nineteen but his entire family including mother, aunt, uncle and grandparents
are still living a normal life into the seventh decade; therefore age seems not to be a factor except perhaps as an indicator that the prognosis is very good. We are not sure whether the easy fatigability has anything specifically to do with the disease; it may, of course, reflect the personality of the individual involved. Whether or not infection or physical stress have any bearing on the degree of jaundice has yet to be determined. SUMMARY
A study was made of three generations of a family each presenting a history of jaundice, substantiated by laboratory data. The family members were active and in good health. No evidence of hemolysis was unearthed even though indirect-reacting bilirubin of the serum was the abnormal component in all affected members. No evidence of hepatocellular damage was obtained. These findings support the diagnosis of non-hemolytic icterus exhibiting familial transmission, in this instance on the maternal side of the family. The importance of recognition of this established entity is stressed. The prognosis is excellent and confusion with congenital hemolytic anemia or chronic liver disease could well be the source of iatrogenic illness. REFERENCES 1. COMFORT, M. W. Constitutional hepatic dysfunction. Proc. Staff Meet. Mayo Clin., 10: 57, 1935. 2. ROZENDAAL, H. M., COMFORT, M. W. and SNELL, A. M. Slight and latent jaundice. J. A. M. A., 104: 374, 1935. 3. DAMESHEK, W. and SINGER, K. Familial nonhemolytic jaundice. Arch. Znt. Med., 67: 259-285, 1941. 4. SOPFER, L. J. and PAULSON, M. Comparative advantages and further modification of the bilirubin excretion test for hepatic function. Am. J. M. SC., 192: 535, 1936. 5. WEECH, A. A., VANN, D. and GRILLO, R. A. The clearance of bilirubin from the plasma. A measure of the excreting power of the liver. J. Clin. Znuestigation, 20: 326, 1941. 6. COMFORT,M. W. and HOYNE, R. M. Constitutional hepatic dysfunction: clinical study of thirty-five cases. Gastroenterology, 3: 155, 1944. 7. COMFORT, M. W. Constitutional hepatic dysfunction. M. Clin. North America, 29: 982, 1945. 8. CRIGLER, J. F. and NAJJER, V. A. Congenital familial non-hemolytic jaundice with kernicterus. Pediatrics, 10: 169, 1952. 9. CURRY, J. J. et al. Familial non-hemolytic jaundice. NEW England J. Med., 226: 909, 1942. 10. CARITHERS, H. A. Non-hemolytic familial jaundice. J. Pediat., 19: 817-821, 1941. AMERICAN
JOURNAL
OF
MEDICINE