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Hemochromatosis
Hemochromatosis* Cardiac Failure Associated with Extensive Hemosiderosis
of the
Myocardium HOWARD
L.
Minneapolis, LTHOUGH the
occurrence of extensive hemosiderosis of the myocardium in cases of hemochromatosis is a frequent autopsy finding, associated disturbances of cardiac function have rarely been noted. For this reason the present case is of- interest.
A
CASE REPORT The patient, a fifty-four year old male, entered the University of Minnesota Hospital on the otolaryngology service February 10, 1945, with complaints of bilateral hearing loss and leftsided facial paralysis of eight months’ duration. He had had chronic otitis media since the age of two following scarlet fever, and in June, 1944 he had suffered acute bilateral ear infections followed by complete hearing loss. Two weeks later complete left facial paralysis suddenly appeared. In July of the same year an increase in thirst, appetite and urine output was noted and at the same time a brownish pigmentation of the hands, arms and groins was observed for the first time. The diabetes was controlled with 35 to 40 units of protamine insulin daily. Three years before admission the patient had a series of attacks of transient, severe precordial pain radiating into the neck. The attacks were not related to exertion and were untreated; after a few weeks they ceased and did not recur. However, during the succeeding months he noted mild exertional dyspnea and orthopnea requiring two pillows for comfortable slumber. For one month prior to admission slight ankle edema which disappeared with rest was present. The past history was otherwise non-contributory. By occupation he had been a farmer and day laborer. His alcohol consumption was limited to an occasional glass of beer. There were no other * From the Department of Internal Medicine, University Minneapolis,
272
HORNS,
M.D.
Minnesota instances of diabetes or of excessive pigmentation in members of his family. He was married and had two children. Upon physical examination the patient was found to be a well developed, middle-aged male in no acute distress. The skin was diffusely pigmented with a grayish brown color marked on the face, hands, forearms, linea alba, intercrural regions and scrotum. Except for ectropion of the left lower lid the eyes were normal. There was paralysis of both upper and lower facial muscles on the left side and the tympanic membranes of both ears were completely destroyed. No other abnormalities of the head and neck were noted. The chest was of normal contour and the lung fields were clear. The heart was slightly enlarged, a soft systolic murmur was audible over the entire precordium but was not transmitted to the axilla. The pulse rate was 80 with a regular rhythm; blood pressure ranged from 106/60 to 120/70 on a series of determinations. The liver was found to extend 9 cm. below the costal margin in the right mid-clavicular line and the spleen was palpable 3 cm. below the costal margin. Both were described as being smooth, firm and non-tender. Except for the scar of an old hernial repair the remainder of the abdomen was normal. There was slight, but definite pitting edema of the feet and ankles; the reflexes were physiologic. Laboratory examination revealed the following representative findings: Urine: specific gravity, 1.010-1.031; pH, 5-7; glucose, O-4; erythrocytes and leukocytes consistently absent; occasional casts. Blood: hemoglobin, 13-14.4 Gm.; red cells, 5,040,OOO; leukocytes, 48007450, with a normal differential count. Blood chemistries: blood urea nitrogen, 11 mg. per cent; blood sugar, 67-327 mg. per cent; CO2 of Minnesota Minn.
Medical
School
AMERICAN
and
JOURNAL
University
OF
Hospital,
MEDICINE
Hemochromatosis-Horns combining power, 69 volumes per cent; blood chlorides, 596 mg. per cent; blood cholesterol, 148-189 mg. per cent. Total plasma proteins were 6.2 Gm. per cent, with 3.6 Gm. of albumin and 2.6 Gm. of globulin. Of the liver function studies the total serum bilirubin was 1.2 mg. per cent with 0.4 mg. per cent in the l-minute prompt reacting fraction; the cephalin cholesterol test showed 2+ and 3+ flocculation at twenty-four and forty-eight hours; there was 80 per cent of normal excretion of hippuric acid and the serum alkaline phosphatase value was 16 Bodansky units. There was 10 per cent retention of phenolsulfonphthalein dye and the urine urobilinogen was consistently elevated to 12 to 15 mg. daily. The arm to lung circulation time was 12 seconds and that for arm to tongue 19 seconds; a venous pressure of 7 cm. of citrate solution was recorded in the antecubital vein. Chest x-ray was interpreted as showing a slightly enlarged heart of the left ventriculae type. Electrocardiogram revealed borderlinr QRS voltage, isoelectric T1 and questionably diphasic TBDuring the course in the hospital a radical endaural mastoidectomy was done on the left side in the hope of relieving the facial paralysis. This was of no avail and lid suture was carried out to prevent injury of the left cornea. The clinical diagnosis of hemochromatosis was confirmed by liver biopsy. The diabetes was controlled
without
difficulty
edema disappeared on March During betes
and
the
ankle
with rest. He was discharged
17th. the succeeding
was controlled
ever. the patient ively increasing
two months
without
was incapacitated edema
the dia-
difficulty.
How-
by progress-
of the lower extremities,
with the ultimate development and ascites which necessitated
of scrotal edema re-admission to
the hospital on May 14th. At this time the physical findings differed from those of the previous admission in the presence of massive edema of the legs and scrotum, shifting dullness in the flanks
and
bases posteriorly. The laboratory
scattered findings
rales
the
same as before. The total serum protein 6.5 Gm. per cent with 3.7 Gm. of albumin.
was The
venous pressure was markedly elevated, being 18.5 cm. of citrate; arm to tongue and arm to lung circulation times were 13 and 29 seconds, respectively. The electrocardiogram at this 1949
time showed much lower QRS voltage in all leads and diphasic T1 and TP. The patient was treated with digitalis, low salt diet and mercurial diuretics; however, his edema progressively increased while at bed rest; dyspnea, orthopnea and mild cyanosis appeared. Terminally he developed convulsions which were not related to hypoglycemia: he then became comatose and rxpired on June 12th. At autopsy the body was that of a well developed male with pigmentation and marked edema as previously noted. The abdomen was protuberant with ascitic fluid. The pleural cavities each contained 600 cc. of clear yellow fluid. The right lung weighed 540 Grn.. the left 460 Gm.; bronchi and pulmonary vessels appeared normal. The heart weighed 440 Gm.. the ventricular walls were hypertrophied and there was some dilatation of the left ventricle. The valves were entirely normal. The muscle was quite brown and flabby; on cut section there was no evidence of infarction or fibrosis. The coronary arteries showed no evidence of arteriosclerosis; they were soft and easil) distensible throughout. The liver bveighed 1,940 Gm. and was finally nodular and pinmented. The spleen weighed 800 Gm. and was firm and dark red in color on section. The pancreas was deeply pigmented; the adrenals appeared normal. The right and left kidneys weighed 200 and 220 Gm., respectively; no abnormalities were noted. The aorta was normal. Microscopically. the lungs containrd man) heart failure cells and exhibited some areas of atelectasis. The muscle fibers of the heart were pale-staining. There was fragmentation in somt* areas, with an increase in the spaces between the fibers. Cross striations were only faintl!, present or were absent. The muscle fibers were heavily infiltrated with pigment which stained blue with ferrocyanide. In some areas the muscle substance appeared to be almost entirely replaced. The other organs showed the ordmar) findings of hemochromatosis.
in the lung
were essentially
PEBKUARY.
“73
(:OMMENTS
Hemosiderin deposition of severe degree within the muscle fibers of the myocardium is a common autopsy finding in cases of hemochromatosis. Sheldon’ in his extensive review reported such deposits present in 90 per cent of the cases which included ade-
274 quate microscopic
Hemochromatosis-Horns
data to permit evaluation. Althausen and Kerr2 noted this finding in thirty-three of forty cases they reviewed. Despite this frequency of demonstrable involvement, cardiac symptoms have not been a conspicuous feature in the clinical picture of hemochromatosis. Sheldon1 notes that there have been some instances of heart failure and in classifying his cases as to cause of death he groups 10 per cent under %arious intercurrent conditions and myocardial failure.” He fails to state whether any of the ordinary causes of heart failure were present in these cases. However, he apparently did not consider the cases remarkable so presumably the heart failure was considered due to the ordinary causes. In French literature3’4 heart failure is noted to be a regular occurrence in what is perhaps a special group of cases of hemochromatosis. A symptom complex is described under the name of the endocrino-hepatocardiac syndrome which is characterized by the following features: occurrence in a younger age group; multiple involvement of the endocrine glands, particularly the testes which are atrophic; infantilism and death from cardiac decompensation. Because myocardial infiltration could not be demonstrated in the autopsy material of some of these cases, most of these authors thought that the heart failure was not explained on a basis of myocardial damage by hemosiderin deposits but rather was due to a generalized metabolic disorder of uncertain nature. Recent English and American literature a total of contains reports +* describing nine cases of hemochromatosis in which cardiac symptoms have been prominent. Of these subjects six died and autopsies have been performed. In all of them extensive hemosiderin deposits were present
in the myocardium; one,6 however, had coronary disease in addition. In the others the coronary arteries were normal, no valvular lesions were present and there were no histories of hypertension. It is of interest that in three of these cases severe precordial pain with radiation was such a prominent symptom that in two a diagnosis of coronary occlusion was made and later disproved at autopsy. The most common electrocardiographic change has been low voltage. There was complete heart block in two and auricular fibrillation in two others. In the present case it is believed that with the exclusion of valvular lesions, coronary disease and hypertension as causes of heart failure the cardiac symptoms must be attributed to myocardial degeneration associated with extensive hemosiderin deposits within the heart muscle. REFERENCES 1. 2.
3.
4.
5. 6.
J. H. Haematochromatosis. London, 1935. Oxford university Press. KERR, W. J. and ALTHAUSEN,T. L. Hemochromatosis. Report of three cases with endocrine disturbances and notes on previously reported case. Discussion of etiology. Endocrinology, 17: 621, 1933. BEZANCON, P., DEGENNES, L., DELARUE, J. and avec inOUMANSKY, V. Cirrhose pigmentaire fantilisme, insuBisance cardiaque et aplasies endocriniennes multiples. Bull. et m&z. Sm. mid. d. h6p. de Paris, 48: 967, 1932. DEGENNES,L. and GERMAIN,A. Sur deux nouveaus cas de cirrhose pigmentaire avec infantilisme et dtfaillance cardiaque (syndrome endocrino-hepatocardiaque), Bull. et. n&n. Sm. mid. d. h6p. de Paris, 56: 665, 1940. PETIT, DONALD W. Hemochromatosis with complete heart block. Am. Heart 3., 29: 253, 1945. BLUMER, G. and NESBIT, R. R. Case of hemochromatosis with degeneration of heart muscle and death from coneestive heart failure. _NewEneland 7. Med., 218: 295,-1938. MURRAY, LYON, R. M. Haemochromatosis: report on 3 cases. Brit. M. J., 1: 1297, 1936. MALING, T. C. and RILEY, G. Haemochromatosis: report on case. New Zealand M. J., 36: 314, 1937. SHELDON,
”
7. 8.
AMERICAN
JOURNAL
OF
-
MEDICINE
of the
Myocardium HOWARD
L.
Minneapolis, LTHOUGH the
occurrence of extensive hemosiderosis of the myocardium in cases of hemochromatosis is a frequent autopsy finding, associated disturbances of cardiac function have rarely been noted. For this reason the present case is of- interest.
A
CASE REPORT The patient, a fifty-four year old male, entered the University of Minnesota Hospital on the otolaryngology service February 10, 1945, with complaints of bilateral hearing loss and leftsided facial paralysis of eight months’ duration. He had had chronic otitis media since the age of two following scarlet fever, and in June, 1944 he had suffered acute bilateral ear infections followed by complete hearing loss. Two weeks later complete left facial paralysis suddenly appeared. In July of the same year an increase in thirst, appetite and urine output was noted and at the same time a brownish pigmentation of the hands, arms and groins was observed for the first time. The diabetes was controlled with 35 to 40 units of protamine insulin daily. Three years before admission the patient had a series of attacks of transient, severe precordial pain radiating into the neck. The attacks were not related to exertion and were untreated; after a few weeks they ceased and did not recur. However, during the succeeding months he noted mild exertional dyspnea and orthopnea requiring two pillows for comfortable slumber. For one month prior to admission slight ankle edema which disappeared with rest was present. The past history was otherwise non-contributory. By occupation he had been a farmer and day laborer. His alcohol consumption was limited to an occasional glass of beer. There were no other * From the Department of Internal Medicine, University Minneapolis,
272
HORNS,
M.D.
Minnesota instances of diabetes or of excessive pigmentation in members of his family. He was married and had two children. Upon physical examination the patient was found to be a well developed, middle-aged male in no acute distress. The skin was diffusely pigmented with a grayish brown color marked on the face, hands, forearms, linea alba, intercrural regions and scrotum. Except for ectropion of the left lower lid the eyes were normal. There was paralysis of both upper and lower facial muscles on the left side and the tympanic membranes of both ears were completely destroyed. No other abnormalities of the head and neck were noted. The chest was of normal contour and the lung fields were clear. The heart was slightly enlarged, a soft systolic murmur was audible over the entire precordium but was not transmitted to the axilla. The pulse rate was 80 with a regular rhythm; blood pressure ranged from 106/60 to 120/70 on a series of determinations. The liver was found to extend 9 cm. below the costal margin in the right mid-clavicular line and the spleen was palpable 3 cm. below the costal margin. Both were described as being smooth, firm and non-tender. Except for the scar of an old hernial repair the remainder of the abdomen was normal. There was slight, but definite pitting edema of the feet and ankles; the reflexes were physiologic. Laboratory examination revealed the following representative findings: Urine: specific gravity, 1.010-1.031; pH, 5-7; glucose, O-4; erythrocytes and leukocytes consistently absent; occasional casts. Blood: hemoglobin, 13-14.4 Gm.; red cells, 5,040,OOO; leukocytes, 48007450, with a normal differential count. Blood chemistries: blood urea nitrogen, 11 mg. per cent; blood sugar, 67-327 mg. per cent; CO2 of Minnesota Minn.
Medical
School
AMERICAN
and
JOURNAL
University
OF
Hospital,
MEDICINE
Hemochromatosis-Horns combining power, 69 volumes per cent; blood chlorides, 596 mg. per cent; blood cholesterol, 148-189 mg. per cent. Total plasma proteins were 6.2 Gm. per cent, with 3.6 Gm. of albumin and 2.6 Gm. of globulin. Of the liver function studies the total serum bilirubin was 1.2 mg. per cent with 0.4 mg. per cent in the l-minute prompt reacting fraction; the cephalin cholesterol test showed 2+ and 3+ flocculation at twenty-four and forty-eight hours; there was 80 per cent of normal excretion of hippuric acid and the serum alkaline phosphatase value was 16 Bodansky units. There was 10 per cent retention of phenolsulfonphthalein dye and the urine urobilinogen was consistently elevated to 12 to 15 mg. daily. The arm to lung circulation time was 12 seconds and that for arm to tongue 19 seconds; a venous pressure of 7 cm. of citrate solution was recorded in the antecubital vein. Chest x-ray was interpreted as showing a slightly enlarged heart of the left ventriculae type. Electrocardiogram revealed borderlinr QRS voltage, isoelectric T1 and questionably diphasic TBDuring the course in the hospital a radical endaural mastoidectomy was done on the left side in the hope of relieving the facial paralysis. This was of no avail and lid suture was carried out to prevent injury of the left cornea. The clinical diagnosis of hemochromatosis was confirmed by liver biopsy. The diabetes was controlled
without
difficulty
edema disappeared on March During betes
and
the
ankle
with rest. He was discharged
17th. the succeeding
was controlled
ever. the patient ively increasing
two months
without
was incapacitated edema
the dia-
difficulty.
How-
by progress-
of the lower extremities,
with the ultimate development and ascites which necessitated
of scrotal edema re-admission to
the hospital on May 14th. At this time the physical findings differed from those of the previous admission in the presence of massive edema of the legs and scrotum, shifting dullness in the flanks
and
bases posteriorly. The laboratory
scattered findings
rales
the
same as before. The total serum protein 6.5 Gm. per cent with 3.7 Gm. of albumin.
was The
venous pressure was markedly elevated, being 18.5 cm. of citrate; arm to tongue and arm to lung circulation times were 13 and 29 seconds, respectively. The electrocardiogram at this 1949
time showed much lower QRS voltage in all leads and diphasic T1 and TP. The patient was treated with digitalis, low salt diet and mercurial diuretics; however, his edema progressively increased while at bed rest; dyspnea, orthopnea and mild cyanosis appeared. Terminally he developed convulsions which were not related to hypoglycemia: he then became comatose and rxpired on June 12th. At autopsy the body was that of a well developed male with pigmentation and marked edema as previously noted. The abdomen was protuberant with ascitic fluid. The pleural cavities each contained 600 cc. of clear yellow fluid. The right lung weighed 540 Grn.. the left 460 Gm.; bronchi and pulmonary vessels appeared normal. The heart weighed 440 Gm.. the ventricular walls were hypertrophied and there was some dilatation of the left ventricle. The valves were entirely normal. The muscle was quite brown and flabby; on cut section there was no evidence of infarction or fibrosis. The coronary arteries showed no evidence of arteriosclerosis; they were soft and easil) distensible throughout. The liver bveighed 1,940 Gm. and was finally nodular and pinmented. The spleen weighed 800 Gm. and was firm and dark red in color on section. The pancreas was deeply pigmented; the adrenals appeared normal. The right and left kidneys weighed 200 and 220 Gm., respectively; no abnormalities were noted. The aorta was normal. Microscopically. the lungs containrd man) heart failure cells and exhibited some areas of atelectasis. The muscle fibers of the heart were pale-staining. There was fragmentation in somt* areas, with an increase in the spaces between the fibers. Cross striations were only faintl!, present or were absent. The muscle fibers were heavily infiltrated with pigment which stained blue with ferrocyanide. In some areas the muscle substance appeared to be almost entirely replaced. The other organs showed the ordmar) findings of hemochromatosis.
in the lung
were essentially
PEBKUARY.
“73
(:OMMENTS
Hemosiderin deposition of severe degree within the muscle fibers of the myocardium is a common autopsy finding in cases of hemochromatosis. Sheldon’ in his extensive review reported such deposits present in 90 per cent of the cases which included ade-
274 quate microscopic
Hemochromatosis-Horns
data to permit evaluation. Althausen and Kerr2 noted this finding in thirty-three of forty cases they reviewed. Despite this frequency of demonstrable involvement, cardiac symptoms have not been a conspicuous feature in the clinical picture of hemochromatosis. Sheldon1 notes that there have been some instances of heart failure and in classifying his cases as to cause of death he groups 10 per cent under %arious intercurrent conditions and myocardial failure.” He fails to state whether any of the ordinary causes of heart failure were present in these cases. However, he apparently did not consider the cases remarkable so presumably the heart failure was considered due to the ordinary causes. In French literature3’4 heart failure is noted to be a regular occurrence in what is perhaps a special group of cases of hemochromatosis. A symptom complex is described under the name of the endocrino-hepatocardiac syndrome which is characterized by the following features: occurrence in a younger age group; multiple involvement of the endocrine glands, particularly the testes which are atrophic; infantilism and death from cardiac decompensation. Because myocardial infiltration could not be demonstrated in the autopsy material of some of these cases, most of these authors thought that the heart failure was not explained on a basis of myocardial damage by hemosiderin deposits but rather was due to a generalized metabolic disorder of uncertain nature. Recent English and American literature a total of contains reports +* describing nine cases of hemochromatosis in which cardiac symptoms have been prominent. Of these subjects six died and autopsies have been performed. In all of them extensive hemosiderin deposits were present
in the myocardium; one,6 however, had coronary disease in addition. In the others the coronary arteries were normal, no valvular lesions were present and there were no histories of hypertension. It is of interest that in three of these cases severe precordial pain with radiation was such a prominent symptom that in two a diagnosis of coronary occlusion was made and later disproved at autopsy. The most common electrocardiographic change has been low voltage. There was complete heart block in two and auricular fibrillation in two others. In the present case it is believed that with the exclusion of valvular lesions, coronary disease and hypertension as causes of heart failure the cardiac symptoms must be attributed to myocardial degeneration associated with extensive hemosiderin deposits within the heart muscle. REFERENCES 1. 2.
3.
4.
5. 6.
J. H. Haematochromatosis. London, 1935. Oxford university Press. KERR, W. J. and ALTHAUSEN,T. L. Hemochromatosis. Report of three cases with endocrine disturbances and notes on previously reported case. Discussion of etiology. Endocrinology, 17: 621, 1933. BEZANCON, P., DEGENNES, L., DELARUE, J. and avec inOUMANSKY, V. Cirrhose pigmentaire fantilisme, insuBisance cardiaque et aplasies endocriniennes multiples. Bull. et m&z. Sm. mid. d. h6p. de Paris, 48: 967, 1932. DEGENNES,L. and GERMAIN,A. Sur deux nouveaus cas de cirrhose pigmentaire avec infantilisme et dtfaillance cardiaque (syndrome endocrino-hepatocardiaque), Bull. et. n&n. Sm. mid. d. h6p. de Paris, 56: 665, 1940. PETIT, DONALD W. Hemochromatosis with complete heart block. Am. Heart 3., 29: 253, 1945. BLUMER, G. and NESBIT, R. R. Case of hemochromatosis with degeneration of heart muscle and death from coneestive heart failure. _NewEneland 7. Med., 218: 295,-1938. MURRAY, LYON, R. M. Haemochromatosis: report on 3 cases. Brit. M. J., 1: 1297, 1936. MALING, T. C. and RILEY, G. Haemochromatosis: report on case. New Zealand M. J., 36: 314, 1937. SHELDON,
”
7. 8.
AMERICAN
JOURNAL
OF
-
MEDICINE