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Cholelithiasis: Familial Predisposition
Cholelithiasis: Familial Predisposition CLAUDE F. DIXON HOWARD W. OWEN
THE etiology of cholelithiasis is as yet unknown. Although many theories have been advanced and much has been written, no single factor has been shown to produce gallstones. The most commonly accepted theories concerning the origin of gallstones are (1) a change in the bile, (2) infection and (3) stasis; the first mentioned is of prime importance, however the mechanism of this alteration is unknown. Andrews and his co-workers concluded that the bile acid-cholesterol ratio has significance in the formation of stones. The normal ratio is from 20: 1 to 30: 1. If the ratio falls to less than 13: 1 cholesterol is precipitated. Dostal and Andrews gave the opinion that the concentration of fatty acid in the bile of the gallbladder is of greater importance in keeping cholesterol in solution than the concentration of bile salts. Dolkhart and associates have reported on experiments showing that the fatty acids in the bile are instrumental in keeping cholesterol in solution but that the addition of bile salts may increase or at times decrease the solubility of cholesterol. Naunyn's theory of ascending infection in the bile passages producing precipitation of calcium and cholesterol is thought to be erroneous. It is now the opinion of almost everyone that cholesterol stones are of metabolic origin and that they occur independently of infection in the biliary passages. However, some still hold to the opinion that mixed stones are the result of infection in the gallbladder. Many causes of stasis have been incriminated in the past but Copher and Illingworth were unable to induce gallstones in animals either by stasis or by stasis and infection, even in the presence of foreign bodies. Proof is lacking that stasis alone is ever the sole etiologic factor in gallstones. Numerous other possible influences have been recorded such as diabetes, sex (preponderance of occurrence among women) and familial tenaencies. This brief report emphasizes the familial incidence of cholecystic disease and cholelithiasis. For this purpose 3 families, having 11, 14, and 7 offspring respectively have been observed. In each family there was a definite indication of an hereditary factor predisposing to the development of gallstones. 1177
1178
Claude F. Dixon, Howard W. Owen FAMILY 1
Seven of the family of 11 children have had cholecystectomy with the removal of stones from the gallbladder. A summary of findings concerning the gallbladders of the 5 sisters observed primarily at the Clinic is being presented herewith; 2 other sisters had operations elsewhere. The other four siblings apparently are free from stones. Two of them have been observed by members of the staff at the Clinic; their histories were not suggestive of the presence of disease or stones in the biliary tract; however, cholecystograms were not made. The mother and father of this family are reported to be free of symptoms. The paternal grandmother is said to have had jaundice and periodic distress similar to that of gallbladder colic. CASE 1. This patient, a member of family 1, was a woman aged 35 years. Her first attack consisted of pain in the right upper quadrant of the abdomen of three hours' duration. Two subsequent attacks occurred. She had not had any jaundice. Cholecystograms revealed a functioning gallbladder with calculi. Cholecystectomy was performed. The pathologic findings were mucocele and chronic cholecystitis with two stones, one of which was impacted in the cystic duct. CASE 2. The patient, a woman aged 43 years, had epigastric distress and bloating after meals, especially after the ingestion of fatty food. Cholecystograms made at the Clinic showed a functioning gallbladder with stone. Cholecystectomy was performed. The pathologist's findings were chronic cholecystitis in a strawberry gallbladder with a single stone. CASE 3. This sister, aged 47 years, had had episodes of acute epigastric pain with associated nausea and vomiting, for one year before she came for examination. The attacks lasted several days and required narcotics for relief. Cholecystograms revealed a non functioning gallbladder. Cholecystectomy was performed. The pathologic findings were subacute cholecystitis, hydrops and two calculi. CASE 4. This sister, aged 47 years at the time of admission, had had one episode of acute epigastric distress which lasted two to three hours. She reported intolerance to fatty food of two or three years' duration. Cholecystogram revealed a functioning gallbladder containing stones.· Cholecystectomy was performed. The pathologic findings were chronic cholecystitis and a single stone. CASE 5. The sister, aged 30 years at the time of admission, gave a history of raving had epigastric distress and bloating following meals, and intolerance to fatty food for one year. The cholecystograms revealed a functioning gallbladder containing calculi. Cholecystectomy was performed. 'l'he pathologic findings were chronic cholecystitis and multiple mulberry stones. FAMILY 2 I
In the family of 14 children, 10 were fema,les of whom 9 lived to maturity, 6 of whom had undergone operation !for cholecystitis with calculous formation. Only 2 of these 6 sisters actually were observed at the
Cholelithiasis : Familial Predisposition
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Clinic. For 1, cholecystectomy was performed, for the other, choledochostomy with removal of a stone from the common duct, as cholecystectomy had been performed previously elsewhere. The 3 sisters who have not had operations are said to be having difficulty similar to that of those who have had operations. Two of the 4 males lived to maturity and have not had cholecystic disease. CASE 6. The patient, a woman aged 43 years, had been having attacks of pain in the right upper quadrant for about eight years. When she came to the Clinic, the pain had extended to the right scapula. She also had observed epigastric distress and bloating after meals. Cholecystograms depicted a poorly functioning gallbladder with cholelithiasis. Cholecystectomy was performed The pathologic findings were chronic cholecystitis with a single stone and cholesterosis. CASE 7. The other member of this family treated at the Clinic was a woman aged 35 years. Cholecystectomy had been performed elsewhere because of inflammatory disease, associated jaundice and gallstones. About three years subsequently the common duct had been explored because of obstructive phenomena. We saw her first, three years after the choledochostomy. For six months she had had episodes of pain in the right upper quadrant of the abdomen, lasting about three days, and requiring narcotics for relief. Choledocholithotomy with insertion of a T tube was performed. Three years later subacute pancreatitis without choledocholithiasis necessitated choledochostomy and drain3ge with a T tube. FAMILY 3
A third family seems worthy of mention from the standpoint of familial incidence of cholecystic disease. The histories of the cases being reported give information concerning three generations: A diabetic male and his hypertensive spouse lived to be more than 80 years of age. Of their 6 children, 1 son died from "fever" at 4 years of age, 1 son succumbed in youth following an accident, 1 son is living and well at 60 years of age. Two daughters, a son, and 3 granddaughters (all children of 1 daughter) had proved cholecystic disease with stones. Cholecystectomy was performed by our staff in 5 of the 6 cases. CASE 8. A woman 57 years of age, had had mild epigastric distress and bloating for three years without severe colic or jaundice. Roentgenograms of her biliary tract revealed a normally functioning gallbladder and multiple stones. Cholecystectomy was performed. The pathologic finding was chronic cholecystitis with multiple calculi. CASE 9. This patient, a woman 45 years of age, had had attacks of pain in the right upper quadrant of the abdomen at intervals for more than fifteen years. She had jaundice for two to three weeks at the age of 33 years but never had it previously or subsequently. Cholecystograms revealed a nonfunctioning gallbladder and stones. Cholecystectomy was performed. The pathologic finding was chronic ulcerative cholecystitis with multiple calculi. Death occurred on the seventh postoperative day from generalized peritonitis.
Claude F. Dixon, Howard W. Owen
1180
CASE 10. The patient was a woman, 27 years of age, one of the twiri daughters of the patient whose condition was described in case 9. This patient gave a twoyear history of intolerance to fatty food and mild epigastric distress after meals. One attack of severe pain in the right upper quadrant of the abdomen had extended to the right shoulder; nausea and vomiting were associated but there had been no jaundice. A cholecystogram revealed a poorly functioning gallbladder with cholelithiasis. Cholecystectomy was performed .. The pathologic findings were chronic cholecystitis, multiple stones and cholesterosis of the gallbladder. CASE 11. A sister of the patient whose condition was described in case 10, who was 30 years of age, had an attack of acute pain in the right upper quadrant of the abdomen, nausea and vomiting three months before admission. A cholecystogram revealed It nonfunctioning gallbladder with stones. Cholecystectomy, choledochotomy and appendectomy were performed. The pathologic findings were chronic cholecystitis, multiple stones in the gallbladder and three stones itt the cystic duct. CASE 12. A sister of the previous 2 patients (cases 10 and 11) was 17 years of age at the time of admission. When 16 years of age she had had a normal full term pregnancy. During gestation there were attacks of distress in the right upper quadrant of the abdomen, nausea and vomiting but no jaundice. Cholecystograms revealed a functioning gallbladder with cholelithiasis. Cholecystectomy, choledochostomy and choledocholithotomy were performed with T tube drainage. The pathologic findings were cholecystitis with multiple mulberry calculi and three stones in the cystic duct.
SUMMARY Data on 3 family groups have been presented in which cholecystitis and cholelithiasis are prevalent: Of 11 siblings, 7 females had proved cholelithiasis; 3 male members and 1 female apparently are free of symptoms of cholelithiasis. The second group consisted of 14 siblings, 10 of whom were females and 4 males; 2 of the 4 male members lived to maturity and are well. Six of the females have had proved cholelithiasis and the other 3 who are still living have symptoms of cholecystic disease. In a third group, 3 sisters, their mother, maternal aunt and uncle all have had proved cholelithiasis. This resume seems to present rather con· vincing evidence of a familial predisposition to cholecystic disease. REFERENCES 1. Andrews, Edmund, Schoenheimer, Rudolf and Hrdina, Leo: EtiOlogy of Gall-
stones. I. Chemical Factors and the Role of the Gallbladder. Arch. Surg. 25: 796-810 (Oct.) 1932 .. 2. Copher, G. H. and Illingworth, C. F. W.: Experimental Study of the Factor of Biliary Stasis in the Production of Gall Stones. Surg., Gynec. & Obst. 46: 658-659 (May) 1928. 3. Dolkhart, R. E., Lorenz, Marie, Jones, K. K. and Brown, C. F. G.: Relation of Fatty Acids and Bile Salts to the Formation of Gallstones. Arch. Int. Med. 66: 1087-1094 (Nov.) 1940. 4. Dostal, L. E. and Andrews, Edmund: Etiology of Gallstones. III. Effect of Diet on the Bile Salt-cholesterol Ratio. Arch. Surg. 26: 21)8-271 (Feb.) 1933.
THE etiology of cholelithiasis is as yet unknown. Although many theories have been advanced and much has been written, no single factor has been shown to produce gallstones. The most commonly accepted theories concerning the origin of gallstones are (1) a change in the bile, (2) infection and (3) stasis; the first mentioned is of prime importance, however the mechanism of this alteration is unknown. Andrews and his co-workers concluded that the bile acid-cholesterol ratio has significance in the formation of stones. The normal ratio is from 20: 1 to 30: 1. If the ratio falls to less than 13: 1 cholesterol is precipitated. Dostal and Andrews gave the opinion that the concentration of fatty acid in the bile of the gallbladder is of greater importance in keeping cholesterol in solution than the concentration of bile salts. Dolkhart and associates have reported on experiments showing that the fatty acids in the bile are instrumental in keeping cholesterol in solution but that the addition of bile salts may increase or at times decrease the solubility of cholesterol. Naunyn's theory of ascending infection in the bile passages producing precipitation of calcium and cholesterol is thought to be erroneous. It is now the opinion of almost everyone that cholesterol stones are of metabolic origin and that they occur independently of infection in the biliary passages. However, some still hold to the opinion that mixed stones are the result of infection in the gallbladder. Many causes of stasis have been incriminated in the past but Copher and Illingworth were unable to induce gallstones in animals either by stasis or by stasis and infection, even in the presence of foreign bodies. Proof is lacking that stasis alone is ever the sole etiologic factor in gallstones. Numerous other possible influences have been recorded such as diabetes, sex (preponderance of occurrence among women) and familial tenaencies. This brief report emphasizes the familial incidence of cholecystic disease and cholelithiasis. For this purpose 3 families, having 11, 14, and 7 offspring respectively have been observed. In each family there was a definite indication of an hereditary factor predisposing to the development of gallstones. 1177
1178
Claude F. Dixon, Howard W. Owen FAMILY 1
Seven of the family of 11 children have had cholecystectomy with the removal of stones from the gallbladder. A summary of findings concerning the gallbladders of the 5 sisters observed primarily at the Clinic is being presented herewith; 2 other sisters had operations elsewhere. The other four siblings apparently are free from stones. Two of them have been observed by members of the staff at the Clinic; their histories were not suggestive of the presence of disease or stones in the biliary tract; however, cholecystograms were not made. The mother and father of this family are reported to be free of symptoms. The paternal grandmother is said to have had jaundice and periodic distress similar to that of gallbladder colic. CASE 1. This patient, a member of family 1, was a woman aged 35 years. Her first attack consisted of pain in the right upper quadrant of the abdomen of three hours' duration. Two subsequent attacks occurred. She had not had any jaundice. Cholecystograms revealed a functioning gallbladder with calculi. Cholecystectomy was performed. The pathologic findings were mucocele and chronic cholecystitis with two stones, one of which was impacted in the cystic duct. CASE 2. The patient, a woman aged 43 years, had epigastric distress and bloating after meals, especially after the ingestion of fatty food. Cholecystograms made at the Clinic showed a functioning gallbladder with stone. Cholecystectomy was performed. The pathologist's findings were chronic cholecystitis in a strawberry gallbladder with a single stone. CASE 3. This sister, aged 47 years, had had episodes of acute epigastric pain with associated nausea and vomiting, for one year before she came for examination. The attacks lasted several days and required narcotics for relief. Cholecystograms revealed a non functioning gallbladder. Cholecystectomy was performed. The pathologic findings were subacute cholecystitis, hydrops and two calculi. CASE 4. This sister, aged 47 years at the time of admission, had had one episode of acute epigastric distress which lasted two to three hours. She reported intolerance to fatty food of two or three years' duration. Cholecystogram revealed a functioning gallbladder containing stones.· Cholecystectomy was performed. The pathologic findings were chronic cholecystitis and a single stone. CASE 5. The sister, aged 30 years at the time of admission, gave a history of raving had epigastric distress and bloating following meals, and intolerance to fatty food for one year. The cholecystograms revealed a functioning gallbladder containing calculi. Cholecystectomy was performed. 'l'he pathologic findings were chronic cholecystitis and multiple mulberry stones. FAMILY 2 I
In the family of 14 children, 10 were fema,les of whom 9 lived to maturity, 6 of whom had undergone operation !for cholecystitis with calculous formation. Only 2 of these 6 sisters actually were observed at the
Cholelithiasis : Familial Predisposition
1tr9
Clinic. For 1, cholecystectomy was performed, for the other, choledochostomy with removal of a stone from the common duct, as cholecystectomy had been performed previously elsewhere. The 3 sisters who have not had operations are said to be having difficulty similar to that of those who have had operations. Two of the 4 males lived to maturity and have not had cholecystic disease. CASE 6. The patient, a woman aged 43 years, had been having attacks of pain in the right upper quadrant for about eight years. When she came to the Clinic, the pain had extended to the right scapula. She also had observed epigastric distress and bloating after meals. Cholecystograms depicted a poorly functioning gallbladder with cholelithiasis. Cholecystectomy was performed The pathologic findings were chronic cholecystitis with a single stone and cholesterosis. CASE 7. The other member of this family treated at the Clinic was a woman aged 35 years. Cholecystectomy had been performed elsewhere because of inflammatory disease, associated jaundice and gallstones. About three years subsequently the common duct had been explored because of obstructive phenomena. We saw her first, three years after the choledochostomy. For six months she had had episodes of pain in the right upper quadrant of the abdomen, lasting about three days, and requiring narcotics for relief. Choledocholithotomy with insertion of a T tube was performed. Three years later subacute pancreatitis without choledocholithiasis necessitated choledochostomy and drain3ge with a T tube. FAMILY 3
A third family seems worthy of mention from the standpoint of familial incidence of cholecystic disease. The histories of the cases being reported give information concerning three generations: A diabetic male and his hypertensive spouse lived to be more than 80 years of age. Of their 6 children, 1 son died from "fever" at 4 years of age, 1 son succumbed in youth following an accident, 1 son is living and well at 60 years of age. Two daughters, a son, and 3 granddaughters (all children of 1 daughter) had proved cholecystic disease with stones. Cholecystectomy was performed by our staff in 5 of the 6 cases. CASE 8. A woman 57 years of age, had had mild epigastric distress and bloating for three years without severe colic or jaundice. Roentgenograms of her biliary tract revealed a normally functioning gallbladder and multiple stones. Cholecystectomy was performed. The pathologic finding was chronic cholecystitis with multiple calculi. CASE 9. This patient, a woman 45 years of age, had had attacks of pain in the right upper quadrant of the abdomen at intervals for more than fifteen years. She had jaundice for two to three weeks at the age of 33 years but never had it previously or subsequently. Cholecystograms revealed a nonfunctioning gallbladder and stones. Cholecystectomy was performed. The pathologic finding was chronic ulcerative cholecystitis with multiple calculi. Death occurred on the seventh postoperative day from generalized peritonitis.
Claude F. Dixon, Howard W. Owen
1180
CASE 10. The patient was a woman, 27 years of age, one of the twiri daughters of the patient whose condition was described in case 9. This patient gave a twoyear history of intolerance to fatty food and mild epigastric distress after meals. One attack of severe pain in the right upper quadrant of the abdomen had extended to the right shoulder; nausea and vomiting were associated but there had been no jaundice. A cholecystogram revealed a poorly functioning gallbladder with cholelithiasis. Cholecystectomy was performed .. The pathologic findings were chronic cholecystitis, multiple stones and cholesterosis of the gallbladder. CASE 11. A sister of the patient whose condition was described in case 10, who was 30 years of age, had an attack of acute pain in the right upper quadrant of the abdomen, nausea and vomiting three months before admission. A cholecystogram revealed It nonfunctioning gallbladder with stones. Cholecystectomy, choledochotomy and appendectomy were performed. The pathologic findings were chronic cholecystitis, multiple stones in the gallbladder and three stones itt the cystic duct. CASE 12. A sister of the previous 2 patients (cases 10 and 11) was 17 years of age at the time of admission. When 16 years of age she had had a normal full term pregnancy. During gestation there were attacks of distress in the right upper quadrant of the abdomen, nausea and vomiting but no jaundice. Cholecystograms revealed a functioning gallbladder with cholelithiasis. Cholecystectomy, choledochostomy and choledocholithotomy were performed with T tube drainage. The pathologic findings were cholecystitis with multiple mulberry calculi and three stones in the cystic duct.
SUMMARY Data on 3 family groups have been presented in which cholecystitis and cholelithiasis are prevalent: Of 11 siblings, 7 females had proved cholelithiasis; 3 male members and 1 female apparently are free of symptoms of cholelithiasis. The second group consisted of 14 siblings, 10 of whom were females and 4 males; 2 of the 4 male members lived to maturity and are well. Six of the females have had proved cholelithiasis and the other 3 who are still living have symptoms of cholecystic disease. In a third group, 3 sisters, their mother, maternal aunt and uncle all have had proved cholelithiasis. This resume seems to present rather con· vincing evidence of a familial predisposition to cholecystic disease. REFERENCES 1. Andrews, Edmund, Schoenheimer, Rudolf and Hrdina, Leo: EtiOlogy of Gall-
stones. I. Chemical Factors and the Role of the Gallbladder. Arch. Surg. 25: 796-810 (Oct.) 1932 .. 2. Copher, G. H. and Illingworth, C. F. W.: Experimental Study of the Factor of Biliary Stasis in the Production of Gall Stones. Surg., Gynec. & Obst. 46: 658-659 (May) 1928. 3. Dolkhart, R. E., Lorenz, Marie, Jones, K. K. and Brown, C. F. G.: Relation of Fatty Acids and Bile Salts to the Formation of Gallstones. Arch. Int. Med. 66: 1087-1094 (Nov.) 1940. 4. Dostal, L. E. and Andrews, Edmund: Etiology of Gallstones. III. Effect of Diet on the Bile Salt-cholesterol Ratio. Arch. Surg. 26: 21)8-271 (Feb.) 1933.