Syndrome of cyanosis, digital clubbing, and hepatic disease in siblings

70

January, 1968 T h e Journal of P E D I A T R I C S

Syndrome of cyanosis, digital clubbing, and hepatic disease in siblings A 5-year-old boy and his 2~-year-old sister developed cyanosis and digital clubbing after the onset of hepatitis of undetermined etiology. Multiple, small, pulmonary arteriovenous fistulas seemed to be primarily responsible for the systemic arterial oxygen desaturation. Overt cyanosis appeared when pathological changes of liver disease were minimal. After the liver disease gradually subsided in the boy, his cyanosis, clubbing, and arterial desaturation completely disappeared. The liver disease was progressive in the girl, and her acquired cardiovascular abnormalities were fatal. Pulmonary arteriovenous fistulas were delineated by postmortem injectians of viscous radiopaque material. The observations suggest that liver injury may be the important event in initiation and maintenance of arteriovenous shu,nting in susceptible individuals.

Arnold Silverman, M.D.,* Max D. Cooper, M.D.,** James H. Moller, M.D., and Robert A. Good, M.D., Ph.D. *** MINNEAPOLIS~ MINN.

C v A N O s I S and digital clubbing are unusual consequences of liver disease, particularly in the pediatric age group? "~ We have recently observed 2 siblings who developed this syndrome less than 2 years after nonspecific hepatitis. Cardiopulmonary studies suggested multiple, small pulmonary arterioFrom the Pediatric Research Laboratories of the Variety Club Heart Hospital and the Departments of Pediatrics and Microbiology, University of Minnesota. Aided by grants, United States Public Health Service, HE-06314, HE-02085, Minnesota Heart Association and American Heart Association. ~Address, Division of Pediatric Gastroenterology. University of Colorado Medical Center, 4200 E. 9th Ave., Denver, Colo. 80220. ~ A m e r i e a n Cancer Society Faculty Research Associate. **'*American Legion Memorial Heart Research Prolessor o/ Pediatrics and Microbiology.

Vol. 72, No. 1, pp. 70-80

venous fistulas with resulting venoarteriai admixture as the basis of the arterial desaturation. Previous reports of this syndrome in adults and children led us to expect chronic and severe liver disease and portal hypertension; however, in these 2 instances the apparent arteriovenous shunting developed when only mild histopathological changes could be demonstrated in the liver and while the existence of portal hypertension was equivocal. It is most provocative that this syndrome occurred in siblings. While its familial nature suggests an underlying metabolic or anatomic abnormality, the mechanism by w h i c h cyanosis and digital clubbing occur as a

Volume 72 Number 1

consequence speculative.

Cyanosis, clubbing, and hepatitis

of

liver

disease

remains

CASE HISTORIES

Patient I. G. M. was referred to the University of Minnesota Hospitals at the age of 511~2 years for evaluation of persistent hepatomegaly, progressive dyspnea, and cyanosis. The patient was in good health until 4~2 years of age, when he experienced anorexia, abdominal pain, intermittent fever, and night sweats for 3 to 4 weeks. Dark-colored urine and pale stools were observed during this illness. At the same time, several documented cases of hepatitis were present in the community. A history of pica was obtained, but there were no pets in the household. Physical examination revealed a febrile, slightly icteric child with diffuse lymphadenopathy. A fine petechial rash was noted on the arms and trunk. The liver was enlarged to the iliac crest, but the spleen was not palpable. The lungs were clear by auscultation. He was admitted to a local hospital with a diagnosis of possible infectious hepatitis. Laboratory data are summarized in Table I. Tuberculin and fungal skin tests were negative, as was the direct Coombs test. Stool examination for ova, cysts, and parasites was negative on 2 occasions. Bentonite flocculation test was weakly positive to Ascaris antigens at a titer of 1:40 (Communicable Disease Center, Atlanta, Ga.). Examination of bone marrow revealed increased numbers of eosinophils. Evidence of a diffuse peribronchial infiltrative process, with areas of consolidation, was seen on roentgenogram of the chest. Laparotomy revealed an enlarged liver and free fluid in the peritoneal cavity. The predominant cell types in the ascitic fluid were lymphocytes and eosinophils. Liver biopsy revealed findings consistent with" a nonspecific hepatitis: focal celIular infiltrates of poIymorphonuclear leukocytes, lymphncytes, and eosinophils were located predominantly in the portal areas (Fig. 1). An axillary lymph node revealed benign hyperplasia, and muscle obtained from the abdominal incision was histologically normal. Bleeding at the site of the abdominal incision was a postoperative complication and led to the discovery of thrombocytopenia. Steroids were administered and the thrombocyte count returned toward normal. The suspected parasitic infestation was

71

treated with Hetrazan.* Both medications were continued for an additional month following discharge. Within 6 weeks the lymphocytosis and eosinophilia had resolved. During the following year, platelet counts remained low, and he had skin bruises, repeated epistaxis, and bleeding from the gums. Hepatomegaly was present during this interval and liver function tests were compatible with a smoldering hepatitis (Table I). Cyanosis was first observed at age 51A2 years, approximately 11 months following his initial illness. Upon admission to our hospital, the patient was 5 1 ~ years of age. Development and nutritional status were normal. Blood pressure was 110/70 mm. Hg; pulse, 100 per minute; and respirations, 36 per minute at rest. There was cyanosis of the lips and fingers and moderate clubbing of the digits. The skin and mucous membranes were free of telangiectases. A systolic bruit was audible throughout the thorax, as well as over the temporal and occipital areas. The heart size was normal and a "functional heart murmur" was heard at the apex. A smooth, soft liver was palpable 6 cm. below the rib cage, while the spleen was palpable 1 cm. below the left costal margin. Initial laboratory results are recorded in Table I. In addition, hemoglobin "A" was present by electrophoresis. Methemoglobin level was less than 0.1 Gm. per cent. The blood group was A, and anti-B isoagglutinins were present in a saline titer of 1/40. Stools examined for ova, cysts, and parasites were consistently negative. Antibodies to Leptospira canicola or L. icterohaemorrhagiae were absent. A chest roentgenogram showed prominence of the bronchovascular markings in the peripheral lung fields. An electrocardiogram was norreal. At cardiac catheterization the brachial arterial oxygen saturation, as determined by the Van Slyke method, was 79 per cent while breathing room air. Following the administration of I00 per cent oxygen for 20 minutes, the brachiaI arterial oxygen saturation rose to 95 per cent. The failure of the oxygen saturation to rise to a level of 105 to 110 per cent (Van Slyke method) indicated the presence of a right-to-left shunt. The pressures in the right side of the heart were normal and analysis of oxygen content of samples from the right side of the heart *:Lederle Labs., Div. of American Cyanamid Co., Pearl River, N. Y. 10965.

7 2 SiIverman et aI.

The Journal o[ Pediatrics January 1968

Table I. Laboratory studies--Patient G. M. Hemoglobin (Gin. per cent)

Age 4~2 ~

9.6

White blood cells (per C.DInZ.)

58.000

Polymorphonuclears (per cent)

Lymphocytes (per cent)

Eosinophils (per cent)

Basophils (per cent)

9

54

35

2

Erythrocyte sedimentation rate (ram. per hour)

Platelets (per c.mm.) 180,000

4.~i2f

50,000 120.000

4~2

11.0

12,200

31

58

47A2

13.1

10,000

22

60

3

5~e:~

13.5

8,400

58

36

3

511/~2

13.3

6188

14.0

6,850

50

36

2

91

126,000

1

54

32,000

2

12

126,000

6

14,000

22

240,000

3

eBronchopneurnonia, hepatitis. ~Laparotomy; steroids started. Treatment with I-Ietrazan. +Cyanosis first observed.

Fig. l

Fig. 2

Fig. 1. Section of liver biopsy from G. M. during his initial illness. Evidence of a fairly diffuse inflammatory process is seen which consists mainly of mononuclear ceil infiltration but includes. as well, polymorphs and some eosinophils. Evidence of cell necrosis is also present. Fig. 2. Section of liver biopsy from G. M. taken 1w years after initial bout of hepatitis. No abnormalities were seen.

gave no indication of an intracardiac left-toright shunt. Indicator dye dilution curves following cardiogreen injection into the right side of the heart revealed an early appearance time at the brachial artery sampling site and a slow falloff. Venous angiocardiography and selective right ventriculography failed to show an intracardiac right-to-left shunt or to localize pulmonary arteriovenous communications. The transit time of the opaque material from the right ven-

tricle to the left atrium during angiocardiography was 2 seconds, reflecting a rapid puhnonary circulation. The right-to-left shunt was calculated to be 50 per cent of the cardiac output. Satisfactory pulmonary function studies were not obtained. Art open liver biopsy was performed, and tissues were obtained from both lobes. The liver was thought to be slightly enlarged, but otherwise was normal in appearance. No gross evi-

Volume 72 Number 1

Bromsulphalein retention (45 minutes) (per cent) (5 mg. per kg.)

Cyanosis, clubbing, and hepatitis

Serum gIutamicoxalacetic transaminase (pyruvate units)

Cephalin

culation

Prothrombin time (seconds) (patient/ control)

173

2+

15.8/14.0

71

cholesterol ]~oc-

Total Albumin Gamma serum globulin globulin bilirubin (Gin. (Gin. (mg. per cent) per cent) per cent) 3.2/3.4

1.7

3+

3.4/5.8

2.4

53

2+

3.5/4.9

2.6

2

63

3+

17.3/14.0

3.9/3.7

1.7

9.5

20

14.5/11.5

3.5/3.4

1.3

13.7/11.0

3.8/2.9

3

2+

73

Heterophil titer

1.4 1/56

1/28

2

dence of collateral circulation was seen and the portal vein pressure was 18 cm. of saline. Except for randomly scattered small foci of round cells, the liver was histologically normal (Fig. 2). A lung biopsy obtained by thoracotomy was also interpreted as normal. Subsequent course. During the next 2 years there was gradual improvement in his clinical status. The liver became smaller, episodes of bleeding into the skin ceased, and the cyanosis, clubbing, and bruit over the chest disappeared. By 8 years of age he appeared to be in perfect health. While breathing room air, his femoral arterial oxygen saturation was 98 per cent (Van Slyke method). Patient II. C. M., sister of G. M., was referred to the hospital at age 2'912 years because of dyspnea, cyanosis, and persistent hepatomegaly. At age 1~2 years, approximately 4 weeks after her brother became ill, this child also developed fever, anorexia, irritability, and an enlarged abdomen. When admitted to a local hospital for these symptoms, her temperature was 102 ~ F. and scattered ecchymoses and petechiae were present on her extremities. Periorbital edema and abdominal distention were noted and the liver edge was palpable at the level of the umbilicus. An abdominal fluid wave was demonstrated. Initial laboratory findings are summarized in Table II. Skin tests for tuberculin, trichinella, and fungi were negative. The bentonite floccula-

tion test for Ascaris antibodies was negative. The child was started on steroids and Hetrazan, with some improvement in her hematological status (Table II) and therapy was continued for 1 month. Persistent anorexia, irritability, and lethargy led to readmission at the age of l~A2 years, when she was noted to be mildly cushingold and pale. Lymphadenopathy and hepatomegaly were present and rMes were heard in both lung bases. Chest roentgenogram revealed a bronchopneumonie process, and the child was treated with antibiotics and transfusion of whole blood. During the next year thrombocytopenia and laboratory evidence of low-grade liver disease persisted (Table II). She continued to bruise easily during this time, but otherwise seemed well. She was again hospitalized and treated successfully for pneumococcal meningitis and mastoiditis at 2w years of age. Cyanosis was first noted on this occasion. Also, during this illness an adult ascaris was passed per rectum and Ascaris lumbricoides eggs were found in her stools. Tt~is infestation was eradicated with Hetrazan. One month later she was hospitalized and successfully treated for bronchopneumonia. Upon admission to the hospital, the vital signs were: temperature, 99.6 ~ F.; pulse, 160 per minute; respirations, 28 per minute; and blood pressure, 112/64. Moderate cyanosis, mild digital clubbing and periorbital edema were found. A

74

Silvermalt ut al.

The ]ournal of Pediatrics January 196(t

Table II. Laboratory studies---Patient C. M.

Age 1

2/12

Hospital day 1 3 6~ 8

Hemoglobin (Gin. per cent)

PolyErythrocyte White blood morpho- LymphoEosi,no- sedimentacells (per nuclears cytes phils tion rate c.mm,) (per cent) (per cent) (per cent) (mm./hour)

9.6

28,700

12

17,000

44

43

3O

Platelets (per s 108,000 30,000

0 82,000

1

4/12~

6.2

7,750

1

26

22,00/)

1

6/12

11.7

13.750

0

12

113,000

1 11/12

12.0

11,700

1

39

90,000

2

I1.7

9.050

1

9.8

8,000

1

15.3

10,200

0

17.2

7,850

8/12:~

2 10/12 3

6/12

4 4

9/12

249,000 60 154,000 (102,000) 170,000 7

16.2

-~Treatment with steroids and ltetrazan, "~Bronchopneumonia; antibiotics and transfusion. ++Meningitis and mastoiditis; t~eatment with Hetrazan. Cyanosis first observed. w Carbamyl Transfeiase (normal, up to 22 deca units).

soft systolic bruit was audible over the temples, lower occiput, and throughout the thorax. A grade I I / V I puhnonary flow type of systolic murmur and an intermittent apical third heart sound were present. The smooth, sharp-edged liver was palpable 4 cm. below the rib cage, while the spleen was not felt. The superficial veins were prominent in the neck and extremities, but no telangiectases or spider nevi of the skin or mucous membranes were seen. The retinal vessels appeared normal. Admission laboratory studies appear in Table II. In addition, the stools were negative for ova and parasites. Methemoglobin level was less tllan 0.1 Gm. per cent. Antibodies to Leptospira organisms were not found. A chest roentgenogram and esophagram were normal, as was an electrocardiogram. At cardiac catheterization, the brachial arterial oxygen saturation, as determined by the Van Slyke method, was 75 per cent, rising to 93 per cent after the administration of 100 per cent oxygen for 20 minutes. Analysis of the oxygen content of samples obtained from the vena cava, right atrium, right ventricle, and pulmonary artery revealed no evidence of an intracardiac left-to-right shunt. Extensive angiographic studies

did not demonstrate an intracardiac right-to-left shunt or anomalous pulmonary arteriovenous communications. Dye-dilution curves were obtained with cardiogreen dye injections into the main pulmonary artery and branches (including several wedge injections), right atrium, and superior vena cava. From each location an early corrected appearance time was demonstrated in the brachial artery blood: the curves exhibited an early rise and slow falloff. The blood volume, with the use of U sl albumin, was 159 c.c. per kilogram. The cardiac output was 2.8 L. per minute as calculated by the Fick principle (normal 1.7 to 2.9 L. per minute), with a rightto-left shunt of approximately 48 per cent of the cardiac output. The total pulmonary vascular resistance was normal (344 dynes per second cm. :'). The wedged hepatic vein pressure was normal (10 ram. H g ) . A transeptat catheterization of the left atrium revealed persistent desaturation following administration of 100 per cent oxygen (Table I I I ) , while selective angiography from the left innominate vein did not demonstrate anomalous venous drainage to the left atrium. An open liver biopsy was performed. The liver appeared slightly enlarged, with areas of patchy

Volume 72 Number I

Cyanosis, clubbing, and hepatitis

Cephalin cholesterol flocculation

Prothrombin time (seconds) (patient/ cantrol)

Albumin globulin (Gin. per cent)

106

3+

15.2/13.8

3.0/2.5

31

2+

Bromsulphalein Serum glutamic-oxalacetic retention transaminase (45 minutes) (pyruvate (per cent) units) (5 mg./kg.)

Gamma Total serum globulin bilirubin (Gm. (mg. Heterophil per cent) per cent) titer 0.6

0.2

1.2

62

1+

3.2/3.5

1.1

1:112

87

4+

15.2/14.0

3.6/4.0

2.0

1:28

70

3+

16.5/15.7

3.5/4.0

1.1

1:56

14.9/11.9

3.3/4.1

1.5

3+

17.5/13.5

2.4/3.7

1.6

2+

12.7/11.1

3.1/4.2

31 36

4

2.6/3.2

75

32w

Table III. Transeptal catheterization data o n P a t i e n t C. M .

Arterial pO~ Alveolar pO.* (le[t atrium) Rest, breathing room air 10 min., 100 per cent 02 4 min., 38 per cent O..

100 ram. Hg

46.0 ram. Hg

650 mm. Hg 272.5 mm. Hg 240 ram. Hg

660 ram. Hg

cyanosis on the capsule. Ascites was absent, as was gross evidence of collateral circulatory changes. The spleen was of normal size. The portal pressure was 24 cm. of physiological saline, and a portal venogram failed to demonstrate portaI-pulmonary or portal-systemic communications. Histologically, the liver revealed mild central fatty changes without inflammation or fibrosis (Fig. 3). A mesenteric lymph node showed mild hyperplasia. During the next 2 years there was no detectable change in her clinical status. Therapeutic trials of rutin and thiamine did not improve her oxygen saturation.

Fig. 3. Section of liver biopsy from C. M. 18~2 years after initial illness. The centrally distributed fatty changes are illustrated. Other significant abnormalities were not found.

At age 4t~2 years she was again admitted to the University of Minnesota Hospitals with epistaxis, bilateral bronchopneumonia, and congestive heart failure. Despite intensive therapy including blood transfusions, oxygen, digitalis and antibiotics, she became progressively worse and terminally developed severe hypoxemia (ar-

76

Silverman et aL

The Journal o[ Pediatric*" January 1968

Fig. 4. Sagittal section of the left lung from C. M. after postmortem barium sulfate injection into the pulmonary artery. Arterial branches (A) and 3 veins (V) (lower right and lower center of illustration) are both visualized.

terial pO,, 16 mm. Hg; venous pO~, 14 mm. Hg; arterial pCO~, 22.8 mm. Hg; and venous pCO~, 31 mm. Hg) and acidosis (blood, pH 7.32). She was placed in a hyperbaric oxygen chamber but died within a few hours. At postmortem examination, the heart was twice normal weight, with prominent right ventricular hypertrophy. There was no evidence of congenital cardiac malformation or anomalous systemic venous connection. Infarction of a papillary muscle of the left ventricle was histologically confirmed. The puhnonary arteries were injected with a barium sulfate (Micropaque)-gelatin (225 Bloom) suspension which does not traverse the normal pulmonary capillary bed. In this instance, however, the barium mixture immediately appeared in the pulmonary veins. The injected lungs were then treated by the method of Wagner, 8 and |he resulting radiographs of sagittal slices confirmed filling of the pulmonary veins (Fig. 4). Thus, the abnormal pulmonary arteriovenous shunting, which had been physiologically defined during life, was directly confirmed after death. In the lungs, microabscesses were evident and

polymorphonuclear leukocytes were seen in peribronchial areas. Masses of fibrocytic proliferation protruded into the lumen of many bronchioles. The large smooth liver was firm and the cut surface appeared nodular. Each major hepatic vessel was injected with a viscous plastic material of different color. After digestion of the liver, neither mixing of the colors nor gross vascular abnormalities were seen. Sections from 2 liver tissue specimens revealed impressive histological differences. In 1 specimen some centrilobular congestion and minimal fibrosis of the portal areas were found. In the olher specimen, early cirrhosis was evident (Fig. 5). DISCUSSION

T h e children r e p o r t e d here represent a peculiar v a r i a n t of the cyanosis-digital clubbing syndrome known to occur in patients with cirrhosis of the liver. O u r patients are unusual in that systemic arterial oxygen desaturation a n d cyanosis a p p e a r e d at a time when evidence of severe liver diseases and

Volume 72 Number 1

Fig. 5. Section of liver from C. M. after death. Polyrnorphonuclear and mononuclear leukocyte infiltrations are prominent in the portal triads and along the scar. Although not prominent, an increase of fibrous tissue is seen with some "entrapped" liver cells. Some disorganization of lobular architecture is present with evidence of nodular regeneration. These changes are consistent with early cirrhosis.

significant portal hypertension were lacking. These observations emphasize the significance of the initial liver injury in the subsequent course of the children. Further, they direct attention to the pulmonary vascular bed as the major site of arteriovenous shunting. The occurrence of this unusual syndrome in 2 young siblings suggests that hereditary factors may play a role in its pathogenesis. The search for the mechanism of arterial oxygen desaturation as a complication of liver disease was initiated in 1935 when Snell 9 observed that more than 50 per cent of a group of patients with cirrhosis, some of whom had no detectable cyanosis, were desaturated. Since this early report, desaturation has been documented in 7 to 50 per cent of adults with cirrhosis. 7, 10-15 The explanation first given for the desaturation was an abnormality of hemoglobin, ~6 a thesis that has never found substantial support.12, la, 17 Even though displacement of the hemoglobin oxygen dissociation curve to the right may be found in cirrhotic individuals, this change is not of sufficient magnitude to explain the degree of arterial desaturation observed in such patients.

Cyanosis, clubbing, and hepatitis

77

The presence of a significant right-to-left shunt as an explanation for the arterial oxygen desaturation stemmed from the observation in cirrhotic patients that arterial oxygen unsaturation was not completely corrected by breathing 100 per cent oxygen. 9 Subsequently, 2 sites for the abnormal venoarterial shunting have received much attention. Portal pulmonary shunts have been proposed as sites for the venoarterial admixture noted in certain patients with liver disease. 12-14, as-21 While venous communications between these 2 systems have been demonstrated by injection techniques in chronic liver disease,19, 2~ assessments of the contribution of portal venous blood to systemic desaturatlon with the use of krypton and tritium have yielded inconsistent results. 13, 19 Portal blood has a relatively high oxygen saturation (75 to 80 per cent) and portal blood flow seldom exceeds 25 per cent of the cardiac outp u t / , 20 Therefore, even an enormous shunt through a portal-pulmonary circuit could not account for the degree of arterial desaturation observed in these patients and in our cases. Furthermore, the desaturation may persist following successful portal-systemic shunting operations. ~5 Our patients had no significant portal hypertension and no portalpulmonary communication was demonstrable by operative portal venogram. The pulmonary vascular bed was shown to be a possible site of the right-to-left shunt when postmortem examinations revealed small multiple pulmonary arteriovenous fistulas in patients dying of cirrhosis 6, 22, 23 even when neither routine pulmonary angiography nor histological study had disclosed evidence of such fistulas2, 6, 10, 1~0,13, 22, 24 Subsequent postmortem injection studies by R o d m a n and associates 1~ failed to demonstrate suspected pulmonary arteriovenous fistulas, while Berthelot and his colleagues 2~ could detect them in only 1 of 14 cases. Meanwhile, attempts to confirm the presence of pulmonary arteriovenous shunts during life in patients with liver disease and arterial desaturation have also yielded inconsistent results.T, 14, 19 O u r patients again emphasize the impor-

78

SiIverman et al.

tance of the pulmonary vascular bed as the major site of venoarterial shunting. In accord with previous reports we could not directly demonstrate the puhnonary arteriovenous fistulas by angiography nor lung biopsy. Indirect evidence of their existence was obtained during life by dye-dilution studies, the rapid transit time from right to left atrium, the marked desaturation in the left atrium, and the persisting desaturation when breathing 100 per cent oxygen. There was no evidence of intracardiac right-to-left shunt, anomalous systemic venous drainage, or portal-pulmonary shunts in these children. Confirmation of the suspected pulmonary venoarterial shunts was obtained by the postmortem pulmonary artery injection studies in 1 of our patients. It has been proposed that a humoral substance released by the damaged liver leads to the development of pulmonary arteriovenous shunting, perhaps by acting on existing but nonfunctioning precapillary anastomoses. 2G Reduced ferritin, when released from the hypoxic or injured liver, has a vasodilatory action, 2:-29 and circulating reduced ferritin has been implicated in digital clubbing by virtue of its ability to open precapillary arteriovenous anastomoses in the fingers. 3~ That reduced ferritin has similar action on pulmonary arteriovenous anastomoses has not been shown experimentally, but is an attractive possibility. A vicious cycle might then be entered: the activity of reduced ferritin would be maintained since it would escape alveolar oxidation, 3~ and the arterial oxygen desaturation might then favor further release of ferritin by the liver. 27, 2s The development of pulmonary arteriovenous shunting in the absence of cirrhosis and portal hypertension in the siblings reported argues strongly for the importance of hepatocellular damage as the initiating component in the development of this syndrome. Our patients may have been particularly vulnerable to this development for 3 reasons. It has been suggested that the juvenile pulmonary vascular bed may be more sensitive to influences producing arteriovenous shunt-

The ]ournal o[ Pediatrics January 1968

ing than that of the adult. 11 Both of our patients had been subjected to local irritation of the lungs during the episodes of bronchopneumonia concurrent with their hepatitis. There is some evidence 31-a3 that local irritation in normal lungs may initiate blood flow through the potential arteriovenous pathways. Since our patients were siblings, and this development in conjunction with such mild liver disease has not to our knowledge been previously observed, a genetic factor may have made their pulmonary vasculature more sensitive to reduced ferritin. The most unique observation in these siblings was the complete reversal of the cyanosis, clubbing, and arterial desaturation in the brother. Reversal of these features occurred after all evidences of active liver disease had disappeared. It seems reasonable to interpret these observations to indicate that the original liver injury was the significant event in initiating the opening of pulmonary arteriovenous communications, and that continuing liver disease is the major determinant in maintaining patency of these precapillary arteriovenous channels. In support of the latter conclusion, the girl's liver did not heal; rather, her clubbing and arterial oxygen desaturation was progressive, and by the time of her death early cirrhotic changes of the liver were present. An important but unanswered question remains: What is the physiological sig-nificanoe of these potentially patent precapillary arteriovenous channels in the normal pulmonary vascular bed? SUMMARY

Described are siblings who manifested dyspnea, cyanosis, and digital clubbing 11 and 18 months, respectively, after episodes of hepatitis. Liver biopsy revealed persistent mild pathological changes in the livers of both children, while significant portal hypertension was not found. Multiple, small pulmonary arteriovenous fistulas, not demonstrable by angiography or lung biopsy, appear to be the most likely cause of their arterial oxygen desaturation. In 1 of these children,

Volume 72 Number 1

postmortem vascular injection studies revealed multiple p u l m o n a r y arteriovenous fistulas to be present in the lungs. By the time of death, this child h a d developed cirrhosis of the liver. * I t is suggested that liver i n j u r y releases a h u m o r a l substance, possibly ferritin, which in susceptible individuals leads to p u l m o n a r y a n d peripheral arteriovenous shunts with consequent arterial desaturation.

Cyanosis, clubbing, and hepatitis

13. 14.

15.

The authors wish to thank G. Wayne Silvers and W. Wagner, Jr., of the Cardiopulmonary Laboratory at the University of Colorado Medical Center, for performing the barium sulfate injection studies and interpreting the results.

16.

9In the other patient, the cyanosis and clubbingdisappeared; when he was restudied, the systemic arterial saturation was found to be nolmal.

17.

REFERENCES 1. Fliickiger, M.: Vorkommen von trommelsch/igelformigen Fingerendphalangen ohne chronische Ver~inderungen an den lungen oder am Herzen, Wien. reed. Wchuschr. 34: 1457, 1884. 2. Gilbert, A., and Fournier, L.: La cirrhose hypertrophique avec ictSre chez les enfants, Comptes rend. Soc. biol. Paris 47: 419, 1895. 3. Evans, P. R., and Sheldon, W.: Biliary cirrhosis with cyanosis and finger-clubbing, Proc. Roy. Soc. Med. 30: 406, 1937. 4. Perozzi, T.: Juvenile cirrhosis, Thesis, University of Minnesota, 1938. 5. Rydell, R., and Hoffbauer, F. W.: Multiple pulmonary arteriovenous fistulas in juvenile cirrhosis, Am. J. Med. 21: 450, 1956. 6. Groth, J. F., Jr., and Friedman, S.: The occurrence of cyanosis in chronic hepatic disease, Pediatrics 25: 63, 1960. 7. Fritts, H. W., Jr.: Systemic circulatory adjustment in hepatic disease, M. Clin. North America 47: 563, 1963. 8. Wagner, W., Jr.: Alveolar ductectasia as studied by microradiography, 7th Conference on Research in Emphysema, Aspen, 1964, M. Thorac. 22: 188, 1965. 9. Snell, A. M.: The effects of chronic disease of the liver on the composition and physicochemical properties of blood: Changes in the serum proteins; reduction in the oxygen saturation of the arterial blood, Ann. Int. Med. 9: 690, 1935. I0. Murray, J. F., Dawson, A. M., and Sherlock, S.: Circulatory changes in chronic liver disease, Am. J. Med. 24: 358, 1958. 11. Heinemann, H. O., Emirgil, C., and Mijnssen, J. P.: Hyperventilation and arterial hypoxemia in cirrhosis of the liver, Am. J. Med. 28: 239, 1960. 12. Rodman, T., Hurwitz, J. K., Pastor, B. H., and Close, H. P.: Cyanosis, clubbing and arterial oxygen unsaturation associated with

18.

19.

20.

21. 22.

23. 24.

25.

26. 27.

28.

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The Journal of Pediatrics January 196,~

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