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The etiology of digital clubbing
A nnotuticw2.s
atheroma. It was his hypothesis that the process of thrombosis represented largely a natural reaction to injury of the endothelium of the intima overlying the atheroma. Some occlusions were shown to be the result of hematomatous enlargement of the plaques in the absence of the formation of thrombus. Studies designed to observe these phenomenaz-l h,ive all supported the view that such might bc important. These studies are exceptionally tedious, not suitable for routine application to autops) nlatcrial, and rarely done. They have emphasized, though, that the coronary artery is not an inert polyethylene tube, but a complicated organ subject to disease of its blood supply just like other organs. By the same token that the coronary artery is important to the economy of the orgal;ism, the blood suppI>of the coronary artery is important and dcser\~~s more investigation. One of the dangers of the Midespread complacent use of anticoagulants in the management of symptomatic coronary atherosclerosis is that it may stifle the investigation of other approaches to the probletn.
The etiology
of digital
Digital clubbing, which occurs in a number of different diseases, remains one of the partially unexplained states in medicine. Hippocrates has been credited with the first description of the increase in volume of the finger tip as the important feature in clubbing.’ One author even referred to clubbing as “The Hippocratic Fingers.“* Actually, it was Caelius Aurelianus,3 in 200 AD., who first drew attention to the features of digital clubbing in chronic diseases. Apparently, there was little interest in the subject until Pigeaux” published the first definitive bvork on clubbing in 1832. Bomberger,4 in 1889 and 1891, and Marie,* in 1890, first described the syndrome of hypertrophic pulmonary osteoarthropathy. Since that time numerous writings on the possible etiology of digital clubbing have appeared in the literature. Pigeaux’s4 description of clubbing, in 1832, attributed the phenomenon to the formation of bloodtinged fluid in the soft tissue beneath the nail. Grafe and Schneider,4 in 1913, first concluded that the abnormal curvature of the nail was due to increased thicknessof the nail bed. Schirmer,4 in 1923, reported that fine connective tissue fibrils in a homogeneous basophilic ground substance which contain many capillaries and a few round cells are the main constituents of the thickened subcutaneous tissue of the nail bed. In 1924, Campbell2 compared a clubbed finger accidentally removed during life with a normal finger and concluded that edema of the nail bed was the cause of clubbing; however, he was unable to give any explanation for the edema or passive congestion. Bigler’~‘” described coils of arteriovenous anastomoses in sagittal sections of
139
r\ttention directed to measures which would diminish the propensity to intra-atheromatous hemorrhage might result in fewer catastrophic acute occlusive complications of atherosclerosis. Thomas Jf. Blake, U.D.
REFEKESCES 1. Paterson, J. C.: \‘ascularization and hemorrhage of the intima in arteriosclerotic coronary arteries, ;\rrh. Path. 22:313, 1936. 2. \Vinternitz, >I. C., Thomas, R. &I., and Lecompte, I’. &I.: The biology of arteriosclerosis, Springlield, Ill., 1938, Charles C Thomas, Publisher. 3. ~\~artman, ff. B.: Occlusion of the coronaryarteries by hemorrhage into their walls, :\M. HEART J. 15:459, 1938. 4. Morgan, .A. D.: The pathogenesis of coronary occlusion, Springfield, Ill., 1956, Charles C Thomas, Publisher.
clubbing
clubbed thumbs. The nail beds were thickened also with primitive fibroblasts and round cells. In 1937, Mendlowitzs,7 reported the temperatures of fingers in 11 normal subjects and 11 subjects with unilateral clubbing, and calculated the maximum elimination of heat from the finger tip. He concluded that the flow of blood per unit of surface area was greater in the clubbed finger tips than in the normal ones. In 1941, he’s8 found that arterial blood pressure and blood flow in the digits were also increased in clubbed digits, except in those of familial variety. Wilson,9 in 1959, confirmed Mendlowitz’s findings of increased blood flow in the finger tips of these subjects and noted that clubbing on the left hand regressed after ligation of the left subclavian artery in patients with the tetralogy of Fallot who were operated upon by the Blalock technique. He also concluded that the increased flow of blood to clubbed digits is considered to be in excess of physiologic requirements, and passes largely through numerous arteriovenous anastomoses in the distal segments. This congestion of the venules with oxygenated blood under relatively high pressure produces hypertrophy of the local tissue similar to the enlargement of a limb which contains a sizable arteriovenous fistula. The restriction of hypertrophy to fingers, toes, and, occasionally, the nose is explained by the fact that these areas are more richly endowed with vascular shunts. Short-” described a vasodepressor material (VD,M) that produced a dilatation of the arteriovenous anastomosis in the mesentery and intestines of animals. This material was found to be produced
140
Annotations
by ischemic skeletal muscle, spleen, and liver, and the material from the liver was identified as ferritin. Ferritin, in its reduced form, blocked the vasoconstrictive action of epinephrine, but in its oxidized form it was inert against epinephrine. Crismon and co-workersr3 reported from their studies on rabbits and rats that the flavonoid rutin, given intravenouslyor orally, blocked the vasodepressor effect of ferritin. Clark and MacKay’l had pre\-iously reported that rutin does not exert any specific chemical or therapeutic elect when administered orally, but that it is destroyed at body temperature. In 1959, Hallr5 postulated that clubbing vv‘rs caused by the presence in peripheral blood of a substance normally. inactivated by the lungs which dilated the small vascular shunts. He suggested that this substance might be ferritin. On the basis of the reported findings on ferritin and rutin, he performed a study on 8 subjects with clubbing and on 8 subjects without clubbing. The capillary blood flow through the finger tips was evaluated by a clearance technique utilizing radiosodium (Nnza) which was described by Kety.‘G Radiosodium (Na2*) was injected 2 to 3 mm. proximal to the nail fold of the middle finger and, when 50 per cent activity had disappeared, 50 mg. of rutin in 10 cc. of normal saline was injected intravenously into the opposite arm within 20 to 30 seconds. There was a notable increase in the slope of the absorption curve in subjects with clubbing. This revealed that the rate of absorption of radiosodium from clubbed fingers was much slower than from normal fingers, and the rate increased after rutin was administered. Hall concluded from these findings that digital clubbing may be the long-term result of dilatation of arteriovenous anastomosis in the nail beds by reduced ferritin which had evaded oxidation. Mendlowitz7*8 has confirmed the basic concept of what happens in digital clubbing by a demonstration of the ability of arteriovenous fistulas to open in the terminal digits. Hall’s concept may; be reasonable in cases of clubbing in which obvroue right-to-left shunts or pulmonary diffusion defects exist, but it hardly seems feasible when clubbing occurs unilaterally, or when no such cardiac shunts or pulmonary diffusion defects are detectable. 12 review of the literature on rutin and its effect on vasodepressor materials (VDnI), such as ferritin, shows that there is controversial evidence on the action of rutin. No reports were found on the comparison of the amount of reduced fcrritin as opposed to oxidized ferritin in subjects with clubbing and in
normal subjects. Hall’s work is stimulating, but needs confirmation, because digital clubbing may have multiole causes. Julian Williams, Bf.D. Medical College of Georgia Augusta, Ga. REFERENCES 1.
2. 3.
4. 5. 6.
7.
8. 9.
10. 11. 12. 13.
14.
1.5. 16.
Hippocrates: The book of prognostics, in The genuine works of Hippocrates, translated by F. Adams. London, 1849, The Sydenham Society, \iol. I, p. 219. Campbell, I).: The Hippocratic fingers, Brit. M. J. 1:145. 192-L. Caelius Aurelianus: On chronic diseases, in Drabkin, I. E. : On acute diseases and on chronic diseases, Chicago, 1950, University of Chicago Press, Book 2, Section 14, p. 679. Bigler, F. C.: The morphology of clubbing, Am. J. Path. 34:237, 1958. Mendlowitz, M.: Some observations on clubbed fingers, Clin. SC. 3:387, 1937-38. Dormev. , E. Ii.. et al.: Unilateral clubbing of the fingers due to absence of the aortic arch, Am. J. Med. 18:150, 1955. Mendolwitz, M.: Measurements of blood flow and blood pressure in clubbed fingers, J. Clin. Invest. 20:113, 1941. Mendlowitz, M. : The digital circulation, .A?x. HEART J. 57:309, 1959. Wilson. G. M.: Local circulatorv . changes associated with clubbing of the fingers and toes, Quart. J. Med. 21:201, 1959. Bigler, F. C.: The morphologyof clubbing, Circulation 19:312, 1959. Shorr, E.: Intermediary and biological activities of ferritin, Harvey Lectures SO:112, 1954. Granick, S.: Structure and physiological functions of ferritin. Phvsiol. Kev. 31:489. 1951. , Crismon, et al.: Rutin and other flavonoids as potentiators of terminal vascular responses to epinephrine and as antagonists of vasodepressor materials, Am. J. Physiol. 164:391, 1951. Clark, \I:. G., and MacKay, E. M.: The absorption and excretion of rutin and related tlavonoid substances, J.n.Rl1.A. 143:1411, 1950. Hall. G. H.: The cause of digital clubbing. C.. Lancet 1:7.50, 1959. Kety, S. S.: Quantitative measurement of regional circulation by the clearance of radioactive sodium, Am. J. M. SC. 215:352, 1948. C.
atheroma. It was his hypothesis that the process of thrombosis represented largely a natural reaction to injury of the endothelium of the intima overlying the atheroma. Some occlusions were shown to be the result of hematomatous enlargement of the plaques in the absence of the formation of thrombus. Studies designed to observe these phenomenaz-l h,ive all supported the view that such might bc important. These studies are exceptionally tedious, not suitable for routine application to autops) nlatcrial, and rarely done. They have emphasized, though, that the coronary artery is not an inert polyethylene tube, but a complicated organ subject to disease of its blood supply just like other organs. By the same token that the coronary artery is important to the economy of the orgal;ism, the blood suppI>of the coronary artery is important and dcser\~~s more investigation. One of the dangers of the Midespread complacent use of anticoagulants in the management of symptomatic coronary atherosclerosis is that it may stifle the investigation of other approaches to the probletn.
The etiology
of digital
Digital clubbing, which occurs in a number of different diseases, remains one of the partially unexplained states in medicine. Hippocrates has been credited with the first description of the increase in volume of the finger tip as the important feature in clubbing.’ One author even referred to clubbing as “The Hippocratic Fingers.“* Actually, it was Caelius Aurelianus,3 in 200 AD., who first drew attention to the features of digital clubbing in chronic diseases. Apparently, there was little interest in the subject until Pigeaux” published the first definitive bvork on clubbing in 1832. Bomberger,4 in 1889 and 1891, and Marie,* in 1890, first described the syndrome of hypertrophic pulmonary osteoarthropathy. Since that time numerous writings on the possible etiology of digital clubbing have appeared in the literature. Pigeaux’s4 description of clubbing, in 1832, attributed the phenomenon to the formation of bloodtinged fluid in the soft tissue beneath the nail. Grafe and Schneider,4 in 1913, first concluded that the abnormal curvature of the nail was due to increased thicknessof the nail bed. Schirmer,4 in 1923, reported that fine connective tissue fibrils in a homogeneous basophilic ground substance which contain many capillaries and a few round cells are the main constituents of the thickened subcutaneous tissue of the nail bed. In 1924, Campbell2 compared a clubbed finger accidentally removed during life with a normal finger and concluded that edema of the nail bed was the cause of clubbing; however, he was unable to give any explanation for the edema or passive congestion. Bigler’~‘” described coils of arteriovenous anastomoses in sagittal sections of
139
r\ttention directed to measures which would diminish the propensity to intra-atheromatous hemorrhage might result in fewer catastrophic acute occlusive complications of atherosclerosis. Thomas Jf. Blake, U.D.
REFEKESCES 1. Paterson, J. C.: \‘ascularization and hemorrhage of the intima in arteriosclerotic coronary arteries, ;\rrh. Path. 22:313, 1936. 2. \Vinternitz, >I. C., Thomas, R. &I., and Lecompte, I’. &I.: The biology of arteriosclerosis, Springlield, Ill., 1938, Charles C Thomas, Publisher. 3. ~\~artman, ff. B.: Occlusion of the coronaryarteries by hemorrhage into their walls, :\M. HEART J. 15:459, 1938. 4. Morgan, .A. D.: The pathogenesis of coronary occlusion, Springfield, Ill., 1956, Charles C Thomas, Publisher.
clubbing
clubbed thumbs. The nail beds were thickened also with primitive fibroblasts and round cells. In 1937, Mendlowitzs,7 reported the temperatures of fingers in 11 normal subjects and 11 subjects with unilateral clubbing, and calculated the maximum elimination of heat from the finger tip. He concluded that the flow of blood per unit of surface area was greater in the clubbed finger tips than in the normal ones. In 1941, he’s8 found that arterial blood pressure and blood flow in the digits were also increased in clubbed digits, except in those of familial variety. Wilson,9 in 1959, confirmed Mendlowitz’s findings of increased blood flow in the finger tips of these subjects and noted that clubbing on the left hand regressed after ligation of the left subclavian artery in patients with the tetralogy of Fallot who were operated upon by the Blalock technique. He also concluded that the increased flow of blood to clubbed digits is considered to be in excess of physiologic requirements, and passes largely through numerous arteriovenous anastomoses in the distal segments. This congestion of the venules with oxygenated blood under relatively high pressure produces hypertrophy of the local tissue similar to the enlargement of a limb which contains a sizable arteriovenous fistula. The restriction of hypertrophy to fingers, toes, and, occasionally, the nose is explained by the fact that these areas are more richly endowed with vascular shunts. Short-” described a vasodepressor material (VD,M) that produced a dilatation of the arteriovenous anastomosis in the mesentery and intestines of animals. This material was found to be produced
140
Annotations
by ischemic skeletal muscle, spleen, and liver, and the material from the liver was identified as ferritin. Ferritin, in its reduced form, blocked the vasoconstrictive action of epinephrine, but in its oxidized form it was inert against epinephrine. Crismon and co-workersr3 reported from their studies on rabbits and rats that the flavonoid rutin, given intravenouslyor orally, blocked the vasodepressor effect of ferritin. Clark and MacKay’l had pre\-iously reported that rutin does not exert any specific chemical or therapeutic elect when administered orally, but that it is destroyed at body temperature. In 1959, Hallr5 postulated that clubbing vv‘rs caused by the presence in peripheral blood of a substance normally. inactivated by the lungs which dilated the small vascular shunts. He suggested that this substance might be ferritin. On the basis of the reported findings on ferritin and rutin, he performed a study on 8 subjects with clubbing and on 8 subjects without clubbing. The capillary blood flow through the finger tips was evaluated by a clearance technique utilizing radiosodium (Nnza) which was described by Kety.‘G Radiosodium (Na2*) was injected 2 to 3 mm. proximal to the nail fold of the middle finger and, when 50 per cent activity had disappeared, 50 mg. of rutin in 10 cc. of normal saline was injected intravenously into the opposite arm within 20 to 30 seconds. There was a notable increase in the slope of the absorption curve in subjects with clubbing. This revealed that the rate of absorption of radiosodium from clubbed fingers was much slower than from normal fingers, and the rate increased after rutin was administered. Hall concluded from these findings that digital clubbing may be the long-term result of dilatation of arteriovenous anastomosis in the nail beds by reduced ferritin which had evaded oxidation. Mendlowitz7*8 has confirmed the basic concept of what happens in digital clubbing by a demonstration of the ability of arteriovenous fistulas to open in the terminal digits. Hall’s concept may; be reasonable in cases of clubbing in which obvroue right-to-left shunts or pulmonary diffusion defects exist, but it hardly seems feasible when clubbing occurs unilaterally, or when no such cardiac shunts or pulmonary diffusion defects are detectable. 12 review of the literature on rutin and its effect on vasodepressor materials (VDnI), such as ferritin, shows that there is controversial evidence on the action of rutin. No reports were found on the comparison of the amount of reduced fcrritin as opposed to oxidized ferritin in subjects with clubbing and in
normal subjects. Hall’s work is stimulating, but needs confirmation, because digital clubbing may have multiole causes. Julian Williams, Bf.D. Medical College of Georgia Augusta, Ga. REFERENCES 1.
2. 3.
4. 5. 6.
7.
8. 9.
10. 11. 12. 13.
14.
1.5. 16.
Hippocrates: The book of prognostics, in The genuine works of Hippocrates, translated by F. Adams. London, 1849, The Sydenham Society, \iol. I, p. 219. Campbell, I).: The Hippocratic fingers, Brit. M. J. 1:145. 192-L. Caelius Aurelianus: On chronic diseases, in Drabkin, I. E. : On acute diseases and on chronic diseases, Chicago, 1950, University of Chicago Press, Book 2, Section 14, p. 679. Bigler, F. C.: The morphology of clubbing, Am. J. Path. 34:237, 1958. Mendlowitz, M.: Some observations on clubbed fingers, Clin. SC. 3:387, 1937-38. Dormev. , E. Ii.. et al.: Unilateral clubbing of the fingers due to absence of the aortic arch, Am. J. Med. 18:150, 1955. Mendolwitz, M.: Measurements of blood flow and blood pressure in clubbed fingers, J. Clin. Invest. 20:113, 1941. Mendlowitz, M. : The digital circulation, .A?x. HEART J. 57:309, 1959. Wilson. G. M.: Local circulatorv . changes associated with clubbing of the fingers and toes, Quart. J. Med. 21:201, 1959. Bigler, F. C.: The morphologyof clubbing, Circulation 19:312, 1959. Shorr, E.: Intermediary and biological activities of ferritin, Harvey Lectures SO:112, 1954. Granick, S.: Structure and physiological functions of ferritin. Phvsiol. Kev. 31:489. 1951. , Crismon, et al.: Rutin and other flavonoids as potentiators of terminal vascular responses to epinephrine and as antagonists of vasodepressor materials, Am. J. Physiol. 164:391, 1951. Clark, \I:. G., and MacKay, E. M.: The absorption and excretion of rutin and related tlavonoid substances, J.n.Rl1.A. 143:1411, 1950. Hall. G. H.: The cause of digital clubbing. C.. Lancet 1:7.50, 1959. Kety, S. S.: Quantitative measurement of regional circulation by the clearance of radioactive sodium, Am. J. M. SC. 215:352, 1948. C.