Familial

hyperlipoproteinemia and gallstones

AKBAL SlNGH,* MB,

BS

(LOND),

MRCP,

FRCP[c]

108 patients with familial hyperlipoproteinemia between the ages of 22 and 85 years (mean, 55.1 years) 46 (42.6%) had cholelithiasis. Among the 53 patients with type II hyperlipoproteinemia 20 (38%) had gallstones; the male.-female ratio was 1:2; the mean serum triglyceride value was significantly higher in those with gallstones. Among the 50 patients with type IV hyperlipoproteinemia 25 (50%) had gallstones; the male:female ratio was 1:1;

Summary: Of

mean age was significantly higher in those with gallstones. Among the five patients with type V hyperlipoproteinemia one had gallstones. Electrocardiographic evidence of myocardial damage was present in 47 (44%) of the 108 patients; 18 (39%) of the 46 patients with gallstones showed such abnormalities, while 26 (24%) showed sinus bradycardia. Resume: L'hyperlipoproteinemie familiale et les calculs

the

biliaires

Sur 108 malades souffrant d'hyperlipoproteinemie familiale et dont I'age variait de 22 a 85 ans (moyenne d'age, 55.1 ans) 46 (42.6%) avaient des calculs biliaires. Parmi les 53 malades souffrant d'hyperlipoproteinemie du type II, 20 (38%) avaient des calculs biliaires. Le rapport hommes:femme etait de 1:2; la triglyceridemie moyenne etait significativement plus eleve chez les porteurs de calculs. Chez les 50 malades souffrant d'hyperlipoproteinemie du type IV, 25 (50%) avaient des calculs; le rapport homme:femme etait de 1:1; I'age moyen etait significativement plus eleve chez les malades ayant des calculs. Quant aux cinq malades souffrant d'hyperlipoproteinemie du type V, un seul avait des calculs biliaires. Chez 47 (44%) des 108 malades il y avait des signes electrocardiographiques de lesions du myocarde; 18 (39%) des 46 malades souffrant de cholelithiase presentaient ces anomalies, tandis que 26 (24%) presentaient une bradycardie sinusale.

Hyperlipoproteinemia has recently aroused much interest. A detailed study of some of the facets of this condition in a homogeneous white population demonstrated a high prevalence of gallstones in patients with familial hyperlipo¬ proteinemia. To confirm this observation I investigated 108 patients with familial hyperlipoproteinemia for gall¬ stones.

?Clinical instructor in medicine, University of Saskatchewan, Saskatoon Reprint requests to: Dr. A. Singh, 800 Spadina Cres. E, Saskatoon, SK S7K 0B3 '

Methods A total of 108 patients known to have hyperlipopro¬ teinemia were interviewed and examined and are being followed up. Details of the family background were substantiated by at least one immediate member of the family, and the familial pattern was established in every case by the presence of the same phenotype in at least one imme¬ diate member of the family. Other causes of hyperlipopro¬ teinemia were excluded. Once the diagnosis of familial hyperlipoproteinemia was established, the objective of the study was explained to the patients with intact gallbladders and they were requested to undergo standard oral cholecystography. Patient coop¬ eration was 100%. The patients were instructed to abstain from alcohol for at least 5 to 7 days before blood testing. They also fasted for 12 to 14 hours before the testing and were permitted only water; smoking was not permitted then. Investigations included measurement of hemoglobin con¬ centration, packed cell volume, leukocyte count (total and differential), erythrocyte sedimentation rate, concentrations of blood glucose, serum thyroxine, blood urea, serum cholesterol and serum triglycerides, lipoprotein electro¬ phoresis, urinalysis and 12-lead electrocardiography. Cho¬ lesterol assays were carried out on unextracted serum using the Hycel Mark X with Lieberman-Burchard reagent; the normal range of values in the provincial laboratory is 150 to 270 mg/dl. Triglycerides were measured by a method previously described;1 the normal range of values is 60 to 240 mg/dl. Lipoprotein electrophoresis was carried out by the method recommended by the Gelman Instrument Com¬ pany on Gelman Sepraphore 111 membrane with a Beckman Microzone System. Staining with oil red "O" was followed by washing with dimethyl formamide to clear the

strip.

Classification of hyperlipoproteinemias was based on the appearance of the serum after standing overnight in a refrigerator, the results of the cholesterol and triglyceride assays, and the electrophoretogram. Results

The mean age of the 108 patients was 55.1 years (range, 22 to 85 years). Nine patients had had cholecystectomies before the study, and the study revealed that 37 of the patients had cholesterol gallstones; the overall prevalence of cholelithiasis was thus 42.6%. Details of the 53 patients with type II hyperlipoproteineCMA JOURNAL/OCTOBER 18, 1975/VOL. 113 733

given in Table I. The prevalence of cholelithiasis 38%. The male:female ratio of those with gallstones 1:2 and of those without gallstones, 1:1. When the values for patients with and without gallstones were com¬ pared, only the triglyceride concentrations were significantly different: the mean value for those with gallstones was significantly higher at the 10% level. In each group there were no significant differences between the values for men and women. Details of the 50 patients with type IV hyperlipoproteine¬ mia are shown in Table II. The prevalence of cholelithiasis was 50%. Only three patients were under the age of 50 years. The male:female ratio was 1:1 for both those with mia

are

was was

Table I.Details* of patients with type II With gallstones

hyperlipoproteinemia

(n 20) =

Without gallstones

(n 33) =

Sex

*Mean values

±

standard deviation.

Table II.Details* of patients with type IV

hyperlipoproteinemia

With gallstones

(n=25)

Without gallstones

(n 25) =

Sex

and those without gallstones. In comparing the values for patients with and without gallstones, only the mean age was found to be significantly different: in those with stones it was significantly higher at the 10% level. There were only five patients with type V hyperlipopro¬ teinemia one with and four without gallstones; the prevalence of cholelithiasis was thus 20%. The numbers were too few for statistical analysis. Electrocardiograms (ECGs) were abnormal in 47 (44%) of the 108 patients (Table III); the specific abnormalities will be the subject of a separate report. Among patients with cholelithiasis 18 (39%) had definite electrocardio¬ graphic evidence of myocardial damage. Sinus bradycardia, though not an abnormality itself, was present in 26 (24%) of the ECGs.

Discussion Data are lacking on the prevalence of gallstone disease in a white general population. In a 1959 study the pre¬ valence in "normal" men aged 20 to 70 years was 7.5%.2 Necropsy studies3'4 suggested a prevalence of 10 to 20% in a white population, with a higher rate in women. Though small, the present prospective study, part of a continuing protocol, revealed a prevalence of cholelithiasis of 42.6%. This finding was unexpected but is supported by the results of a recent independent study by Einarsson, Hellstrom and Kallner.5 The reasons for this high prevalence are not clear. A necropsy study8 revealed a high prevalence of gallstones in patients on hypocholesterolemic diets, and the diet was assumed to be the cause. None of the patients in the pres¬ ent study were on any form of lipid-lowering diet or medication before or during these investigations. Among the patients with type II hyperlipoproteinemia the prevalence of cholelithiasis was 38%. In the study by Einarsson and colleagues5 the prevalence was 13% in men and 22% in women; the mean age was lower than, but the weights were similar to those in our study. Whether the age difference accounts for the difference in prevalence of cholelithiasis in the two studies is not clear. The male:female ratio for those with cholelithiasis, 1:2, was identical in the two studies. Among the patients with type IV hyperlipoproteinemia the prevalence of cholelithiasis was 50%. This figure agrees closely with that of the study by Einarsson and colleagues5 55% (41% in men and 68% in women). In the present study the male:female ratio was 1:1, whereas in that of Einarsson and colleagues it was 1:1.7. The results of the two studies are not strictly comparable because the present study excluded patients with diabetes, whereas Einarsson and colleagues included diabetics in their study. It seems clear that patients with hyperlipoproteinemia have a high prevalence of cholelithiasis. What factors predispose to this disease have not been established. Recent investigation into cholelithiasis has been directed towards bile salts, bile acids, lecithins and cholesterol. Little atten¬ tion has been paid to other factors such as bile proteins. Results of a previous study7 of human gallbladder bile, a complex of bile salts, lecithin, protein and cholesterol, sugTable lll.Prevalence of

*Mean values ± standard deviation. 734 CMA JOURNAL/OCTOBER 18, 1975/VOL. 113

*

+

=

with stones;

.

=

electrocardiographic abnormalities

without stones,

gested that the complex also includes a lipoprotein. It seems not unreasonable to suggest that the lipoproteins in the bile of our patients must be more critically appraised. The molecular structure of lipoproteins seems a more appropriate nidus for a cholesterol gallstone than other organic niduses such as bacteria and parasites. The occurrence of coronary artery disease in patients with hyperlipoproteinemia is well recognized but the true incidence is still unknown, despite intensive recent work. Of the patients in this study 44% had definite myocardial damage, as evidenced by abnormal EGGs, and 39% of the patients with cholelithiasis showed such damage. While the results of necropsy studies suggest that coronary artery and gallstone diseases may be associated,8 our results in living patients do not support this suggestion. This may be because of the small number of patients in the present series. An additional frequent, though not abnormal, EGG feature was sinus bradycardia in 24% of the patients.

The prevalence of cholelithiasis in patients with hyperlipoproteinemia seems distinctly high. Whether hyperlipoproteinemia is prevalent in patients with cholelithiasis is not known. References 1. BUCKLEY GC. CUTLER JM, LITTLE JA: Serum triglyceride: estimation and levels in normal humans. Can Med Assoc J 94: 886, 1966 2. WILBUR RS, BOLT RJ: Incidence of gallbladder disease in normal men. Gastroenterology 36: 251, 1959 3. TORVIK A, HoIVIK B: Gallstones in an autopsy series. Incidence, complications and correlations with carcinoma of the gallbladder. Acia Chir Scand 120: 168, 1960 4. LIEBER ME: The incidence of gallstones and their correlation with other diseases. Ann Sure 135: 394, 1952 5. EINARssor.s K, HELLSTR6M K, KALLNER M: Gallbladder disease in hyperlipoproteinemia. Lancet 1: 484, 1975 6. STURDEVANT RAL, PEARCE ML, DAYTON 5: Increased prevalence of cholelithiasis in men ingesting a serum cholesterol lowering diet. N Engi I Med 288: 24, 1973 7. VER5CHURE JCM: Electro-chromograms of human bile. Clin Chim Acta 1: 38, 1956 8. SHERLOCK 5: Diseases of the Liver and Biliary System, fourth ed. Oxford, Edinburgh, Blackwell, 1944, p 744

After Mary-Liz's accident

The meeting of the streets of dreams and reality is the loneliest corner of the world, like that of personal intimate pain from body or soul; for who can remember release when gnawed and hollowed by torments, and who can enter the battle to help? We are alone, totally, with those who love us best looking on in helpless despair. Who can remember the purity of peace from complete comfort while enduring the tempering by ordeal of the primitives? That the being will be altered after the firing is not questioned, and the very threat of change to be met at the other side of the darkness is another unknown. Yet the minute-by-minute flowing of time gives a strength of just "being", the consciousness of time passing and the devils held back for another little while gradually build a strength found in some unsuspected corner. PATRICIA J. HARPER, MB, BS 12711 - 39th Ave. Edmonton, AB

CMA JOURNAL/OCTOBER 18, 1975/VOL. 113 735

Familial hyperlipoproteinemia and gallstones.

Familial hyperlipoproteinemia and gallstones AKBAL SlNGH,* MB, BS (LOND), MRCP, FRCP[c] 108 patients with familial hyperlipoproteinemia between...
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