Vol. 15, No. 4, 1992
737
HEPATOLOGY Elsewhere
correlates with bleeding at other sites, that it is diagnostic and prognostic in von Willebrand’s disease, that drugs altering platelet function have a consistent effect on the bleeding time and that “surgical” bleeding, such as that caused by biopsy, is synonymous with “clinical” bleeding. Specifically, with respect to liver biopsy Lind found only one paper addressing the bleeding time in this situation. Blake and colleagues (2) studied 100 consecutive patients with cirrhosis, 42 of whom had prolonged bleeding times, which was defined as more than 10 min by the Simplate I1 method. Although not specifically stated, all patients apparently underwent liver biopsy, most during a previous admission. Complications of biopsy are not discussed, but because the bleeding time was measured at least 10 days after any bleeding episode, it seems unlikely that any serious postbiopsy bleeding occurred. They found that of the parameters they measured only serum bilirubin and platelet count were independently correlated with bleeding time. Fourteen patients had prolonged bleeding times despite normal platelet counts. These authors, citing other authorities, consider a platelet count of greater than 80 x 109/Land PT less than 17 sec to be “safe limits” for performing percutaneous liver biopsy, criteria that seem overly conservative in light of the studies of McVay and Toy. The authors also recommend that “before having invasive procedures patients with raised bilirubin concentrations or poor hepatic function should have their bleeding time measured,’’ but they do not suggest how this information is to be used in planning the procedure. Indeed, from their data, if a normal bleeding time and their “safe limits” are used as selection criteria, only 29% of patients with cirrhosis may have biopsies without risk of hemorrhage. Although it is interesting that many cirrhotic patients have an unexpected prolonged bleeding time, it clearly is of little value in assessing the need for prophylactic transfusion before invasive procedures. When should one administer prophylactic blood products to patients with liver disease? The jury is still out; however, it appears that even though we have no reliable means of predicting who will bleed after an invasive procedure, mild-to-moderate coagulopathy seems to pose little, if any, increased risk of bleeding. Therefore we may conclude the prophylactic plasma or platelet transfusions, with their attendant hazards, are not indicated in this setting.
ROBERTSOND. DAVENPORT,M.D. Blood Bank and Transfusion Service The University of Michigan Hospitals Ann Arbor, Michigan 48109-0054 REFERENCES 1. Lind SE. The bleeding - Blood - time does not predict surgical bleeding. 1991;77:2547-2552. D. Grech P. McCormick PA. McIntvre N. 2. Blake JC., Sureneers . Burroughs AK.Bleeding time in patients with hepatic cirrhosis: BMJ 1990;301:12-15.
-
CHOLESCINTIGRAPHY IN ACALCULOUS BILIARY PAIN: IF ABNORMAL, SHOULD CHOLECYSTECTOMY FOLLOW?
Yap L, Wycherley AG, Morphett AD, Toouli J . Acalculous biliary pain: cholecystectomy alleviates symptoms in patients with abnormal cholescintigraphy. Gastroenterology 1991;101:786-793. ABSTRACT
A 45-minute infusion of an octapeptide of cholecystokinin (Kinevac; SquibbDiagnostics,New Brunswick, NJ) was used to measure the gallbladder ejection fraction during cholescintigraphyin 40 normal volunteers. Cholecystokinincholescintigraphywas shown to be a reproducible test. The maximum mean gallbladder ejection fraction occurred 15 minutes after cholecystokinin infusion and was 74.5% f 1.9%(mean -+ SEM). A gallbladder ejection fraction >40% (mean - 3SD) was arbitrarily defined to be normal. The gallbladder ejection fraction test was then used to identify patients with acalculous biliary symptoms who may respond to cholecystectomy. A total of 103patients was tested; 2 1 had abnormal gallbladder ejection fractions and were randomized into two groups, cholecystectomy or no operation. These patients were followed up symptomatically at 3-month intervals for 13-54 months (mean, 34 months). Of the 11 patients who underwent cholecystectomy, 10 (91%)lost their symptoms and 1 improved. Of the 10 patients in the group that did not undergo surgery, all continued to be symptomatic, 2 of whom requested cholecystectomy after 13 and 24 months, respectively. Of the 13 gallbladders obtained from surgery, 12 showed evidence of chronic cholecystitis, muscle hypertrophy, and/or narrowed cystic duct. A normal gallbladder ejection fraction was recorded in 82 patients, and further treatment was left to the discretion of their referring clinician. On follow-up,50 patients were asymptomatic and 10 were symptomatic without specific treatment of the biliary tract; 14 underwent cholecystectomy, 8 of whom were asymptomatic. Pathological abnormalities were recorded in 6 of the removed gallbladders. It is concluded that the gallbladder ejection fraction obtained after a 45minute infusion of cholecystokinin during cholescintigraphy is a reproducible measure of gallbladder emptying, and that cholecystectomy alleviates the biliary-typepain of patients with a reduced gallbladder ejection fraction. COMMENTS
Chronic right upper quadrant pain without gallstones, usually identified as “acalculous biliary pain,” has been clinically difficult to define in the absence of gallstones. The advent of more simplified surgery in the form of laparoscopic cholecystectomy presents, perhaps, too easy an alternative to a challenging question: what test will detect subtle gallbladder-biliary tract disease and predict a favorable outcome from surgery? The prospective study by Yap et al. would indicate that eholecystokinin (CCK) cholescintigraphy is the answer. Using a standard infusion of CCK-8 (9 ngkghr) for 45 min in 108 patients considered to have biliary-type pain, 21 were found to have a gallbladder ejection fraction less
738
HEPATOLOGY Elsewhere
than .40% (below the mean -3 S.D. of 40 control subjects). Randomized to cholecystectomy or no surgery and observed at 3-mo intervals for an average of 3 yr, 11 patients underwent cholecystectomy and dramatically improved: symptoms disappeared in 10 patients and the one other patient improved. All 10 patients who did not have cholecystectomy continued to have symptoms; 2 of these patients eventually underwent cholecystectomy. Of the total of 13 gallbladders obtained at the time of surgery, 12 had significant morphological features, which included the following: chronic cholecystitis, muscular hypertrophy or a narrowed cystic duct. The one failure in these 13 patients was subsequently thought to have a motility disorder involving the sphincter of Oddi. The authors concluded the following: (a) patients with an abnormal ejection fraction had a n excellent response to cholecystectomy but continued to be symptomatic if the gallbladder was not removed, and (b) their gallbladders exhibited pathological changes consistent with chronic cholecystitis. These results are almost too good to be true. This study was designed to answer the following question: does cholecystectomy alleviate symptoms in patients with biliary-type pain when the ejection fraction is reduced? The answer from this controlled surgical trial in 21 patients with low ejection fractions would appear to be yes. The 82 patients who did not have operations and who had “normal” ejection fractions were observed in a more haphazard manner. Of the 82 patients, 50 became asymptomatic and 10 remained symptomatic; 14 underwent cholecystectomy; 8 became asymptomatic; and 6 had pathological changes in the gallbladder. This subgroup blurs the message: 50 of 82 patients without surgery and 8 of 14 patients with surgery (i.e., about 60% each) improved. Six of 14 patients had gallbladder pathological results despite a normal evacuation on cholescintigraphy. A more critical question would have been the following: do those with reduced ejection fractions respond better than those with normal contraction? The discrepancy in the quality of follow-up between the two groups makes this difficult to answer. When surgery is involved, difficulty always exists in obtaining an adequate control group. Sham cholecystectomy is clearly reprehensible. Early studies using CCK cholecystography found that as many as 90% or so of patients with an abnormal response to CCK (defined as either decreased evacuation or reproduction of their pain) could be cured by cholecystectomy (1). Such response rates for acalculous biliary pain compare favorably with the results from cholecystectomy in patients with gallstones. Nonphysiological, bolus infusions of CCK without quantitating gallbladder evacuation have also been used t o reproduce the abdominal pain as the basis for selecting patients who would benefit from cholecystectomy. This “CCK test” has met with some success (21, but reproducibility and false-positives have clouded its usefulness. Further, CCK cholecystography was a relatively primitive technique, depending on serial x-ray examinations and
HEPATOLOGY
assuming that planigraphic models represented threedimensional structures. The advent of nuclear medicine scans (3) and serial ultrasounds (4)has more accurately quantified gallbladder evacuation in response to either CCK infused at a more physiological dose or a standard meal. Our evaluation of quantitative cholescintigraphy in patients with right upper quadrant pain and no gallstones came to a different conclusion ( 5 ) . In this study, the limit for an abnormal ejection fraction was identified as less than 0.65 ( - 2 S.D. below the mean in 38 normal controls but a value higher than that identified in the study by Yap et al.). In our report, 26 patients with “abnormal” emptying on the HIDA scan underwent cholecystectomy. Eighteen (69%) of the 26 patients were considered therapeutic successes, whereas 8 (31%)patients were failures after an average of 2 yr of follow-up. Ironically, the decreased ejection fraction did not predict clinical outcome because the failure group had an even lower ejection fraction (0.25) than those who responded to cholecystectomy (0.39). Only seven surgically obtained gallbladders (from five success and two failure patients) demonstrated chronic cholecystitis, whereas the remainder were relatively normal, findings at odds with the report by Yap et al. We concluded that the diagnostic value of cholescintigraphy in patients with acalculous right upper quadrant pain was poor. Further, the frequency of pathological findings in the gallbladder was also low. The gallbladder ejection fraction did not predict abnormal gallbladder histological results. If the ejection fraction were lowered to 0.49 (mean - 2 S.D. of control from another study 1631, the results would change only slightly. The “success” group would shrink by five, and the “failure” group would shrink by only two. With this criteria, 13 of 18 (72%) would be surgical successes, whereas 6 of 18 (33%)would be failures - not very different. Deficiencies in our study, however, included the absence of a control group and the design; all patients had an abnormal gallbladder emptying. A decreased ejection fraction may result from an abnormal contraction of the gallbladder, increased cystic duct resistance or obstruction and/or impairment of the sphincter of Oddi with reduced emptying into the duodenum. Undefined in any of these gallbladder emptying studies is patency of the ductal system. Assessment of cystic duct size is fraught with problems from subjective interpretation and inadequate standardization. One prediction even suggested that some two thirds of patients with typical pancreatic or biliary symptoms and an abnormal ejection fraction may have sphincter of Oddi abnormalities (7). Another important factor is the natural history of acalculous biliary pain, which may represent an early stage of cholesterol gallstone formation that is associated with abnormal gallbladder motility (6,8).Brugge et al. (9) found cholesterol crystals (indicating lithogenic bile) in the aspirated duodenal bile of these symptomatic patients without overt evidence of gallstones and correlated this with poor gallstone emptying. Careful histo-
Vol. 15, No. 4,1992
739
HEPATOLOGY Elsewhere
logical studies (5) have eliminated chronic acalculous cholecystitis as a pathological entity characterized by chronic inflammation and fibrous and muscular thickness of the gallbladder wall. Undoubtedly, chronic right upper quadrant pain in the absence of gallstone disease is multifactorial. Sludge and gallstones must be eliminated by ultrasonography; abnormal bile should be sought by examining the duodenal aspirate for the presence of cholesterol crystals. Overt causes of impairing gallbladder motor function (e.g., progesterone, obesity and diabetes) must be eliminated (10). Only then will impaired gallbladder evacuation be properly related to symptoms and outcome. In the interim the ejection fraction ascertained by quantitative cholescintigraphy is a reasonable tool for identifying disordered gallbladder motility and relating this to biliary symptoms. Even pain relief soon after surgery is an imperfect endpoint because of placebo effect. The advent of laparoscopic cholecystectomy will be a temptingly easy solution to difficult cases. Before becoming too haphazard, a more complete, careful evaluation of gallbladder function and contents is essential. The once elusive testb) to diagnose acalculous biliary pain are being clarified. Cholescintigraphy may yet provide the best bet.
ELDONA.SHAFFER, M.D., F.R.C.P.C., F.A.C.P. Department of Medicine The University of Calgary Calgary AB, T2N 2T9, Canada
GENETIC STRUCTURE AND HETEROGENEITY OF HEPATITIS C VIRUS: A VACCINE IMPEDIMENT?
Choo QL, Richman KH, Han JH, Berger K, Lee C, Dong C, Gallegos C, et al. Genetic organization and diversity of the hepatitis C virus. Proc Natl Acad Sci USA 1991;88:2451-55. ABSTRACT
The nucleotide sequence of the RNA genome of the human hepatitis C virus (HCV) has been determined from overlapping cDNA clones. The sequence (9379 nucleotides)has a single large open reading frame that could encode a viral polyprotein precursor of 3011 amino acids. While there is little overall amino acid and nucleotide sequence homology with other viruses, the 5' HCV nucleotide sequence upstream of this large open reading frame has substantial similarity to the 5' termini of pestiviral genomes. The polyprotein also has significant sequence similarity to helicases encoded by animal pestiviruses, plant potyviruses, and human flaviviruses, and it contains sequence motifs widely conserved among viral replicases and trypsin-like proteases. A basic, presumed nucleocapsid domain is located at the N terminus upstream of a region containing numerous potential N-linked glycosylation sites. These HCV domains are located in the same relative position as observed in the pestiviruses and flaviviruses and the hydrophobic profiles of all three viral polyproteins are similar. These combined data indicate that HCV is an unusual virus that is most related to the pestiviruses. Significant genome diversity is apparent within the putative 5' structural gene region of different HCV isolates, suggesting the presence of closely related but distinct viral genotypes.
Kato N , Hijikata M, Ootsuyarna Y, Nakagawa M , Ohkoshi S, Shimotohno K. Sequence diversity of hepatitis C viral genomes. Mol Biol Med 1990;7:495-501. 1. Goldberg HI. CCK cholecystography. Semin Roentgen01 1976;ll: REFERENCES
175-179. 2. Lennard TWJ, Farndon JR, Taylor RMR. Acalculous biliary pain: diagnosis and selection for cholecystectomy using the cholecystokinin test for pain reproduction. Br J Surg 1984;71:368-370. 3. Shaffer EA, McOrmond P, Duggan H. Quantitative cholescintigraphy: assessment of gallbladder filling and emptying and duodenogastric reflux. Gastroenterology 1980;7:899-906. 4. Everson GT, Braverman DZ, Johnson MI, Kern F. A critical evaluation of real time ultrasonography for the study of gallbladder volume and contraction. Gastroenterology 1980;79:40-46. 5. Westlake PJ, Hershfield NB, Kelly JK, Kloiber R, Lui R, Sutherland LR, Shaffer EA. Chronic right upper quadrant pain without gallstones: does HIDA scan predict outcome after cholecystectomy? Am J Gastroenterol 1990;85:986-990. 6. Pomeranz IS, Shaffer EA. Abnormal gallbladder emptying in a subgroup of patients with gallstones. Gastroenterology 1985;88: 787-791. 7. Gregg JA. Function and dysfunction of the sphincter of Oddi. In: Jackson IM, ed. ERCP: Diagnostic and therapeutic applications. Elsevier Science, 1989. 8. Shaffer EA. Gallbladder disease. In: Walker WA, Durie PR, Hamilton JR, Walker-Smith JA, Watkins JB, eds. Pediatric gastrointestinal disease. Philadelphia: BC Decker Inc, 1991:11521170. 9. Brugge WR, Brand DL, Atkins HL, Lane BP, Abel WG. Gallbladder dyskinesia in chronic acalculous cholecystitis. Dig Dis Sci 1986; 31:461-467. 10 Everson GT. Gallbladder function in gallstone disease. Gastroenterol Clin North Am 1991;20:85-110.
ABSTRACT
The nucleotide sequences of cDNAs (275 base-pairs) in the non-structural protein 5 regions of Japanese isolates of hepatitis C virus (HCV-J)from the plasma of 11 patients with non-A, non-B hepatitis and the livers of five patients with hepatocellular carcinoma were analyzed. Approximately 14 to 17% of nucleotide sequences of the HCV-Js examined differed from that of the original isolate in the United States (HCV-US). Furthermore, 2.5 to 11% sequence diversity was found among the HCV-Js. The nucleotide sequences of the HCV-J s showed characteristic common differences from that of HCV-US, although they also showed some random substitutions. Plural HCV-J genomes were found in two of the cDNAs derived from liver specimens, and a deletion of 102 nucleotides was found in the cDNA derived from one plasma specimen. These results suggest that HCV-J is a strain different from the HCV-US and that mutation of the viral genome occurs at as high a frequency as in that of the human immunodeficiency virus. COMMENTS
Recently, several groups reported the initial structural details of the hepatitis C viral genome (1,2). Two
737
HEPATOLOGY Elsewhere
correlates with bleeding at other sites, that it is diagnostic and prognostic in von Willebrand’s disease, that drugs altering platelet function have a consistent effect on the bleeding time and that “surgical” bleeding, such as that caused by biopsy, is synonymous with “clinical” bleeding. Specifically, with respect to liver biopsy Lind found only one paper addressing the bleeding time in this situation. Blake and colleagues (2) studied 100 consecutive patients with cirrhosis, 42 of whom had prolonged bleeding times, which was defined as more than 10 min by the Simplate I1 method. Although not specifically stated, all patients apparently underwent liver biopsy, most during a previous admission. Complications of biopsy are not discussed, but because the bleeding time was measured at least 10 days after any bleeding episode, it seems unlikely that any serious postbiopsy bleeding occurred. They found that of the parameters they measured only serum bilirubin and platelet count were independently correlated with bleeding time. Fourteen patients had prolonged bleeding times despite normal platelet counts. These authors, citing other authorities, consider a platelet count of greater than 80 x 109/Land PT less than 17 sec to be “safe limits” for performing percutaneous liver biopsy, criteria that seem overly conservative in light of the studies of McVay and Toy. The authors also recommend that “before having invasive procedures patients with raised bilirubin concentrations or poor hepatic function should have their bleeding time measured,’’ but they do not suggest how this information is to be used in planning the procedure. Indeed, from their data, if a normal bleeding time and their “safe limits” are used as selection criteria, only 29% of patients with cirrhosis may have biopsies without risk of hemorrhage. Although it is interesting that many cirrhotic patients have an unexpected prolonged bleeding time, it clearly is of little value in assessing the need for prophylactic transfusion before invasive procedures. When should one administer prophylactic blood products to patients with liver disease? The jury is still out; however, it appears that even though we have no reliable means of predicting who will bleed after an invasive procedure, mild-to-moderate coagulopathy seems to pose little, if any, increased risk of bleeding. Therefore we may conclude the prophylactic plasma or platelet transfusions, with their attendant hazards, are not indicated in this setting.
ROBERTSOND. DAVENPORT,M.D. Blood Bank and Transfusion Service The University of Michigan Hospitals Ann Arbor, Michigan 48109-0054 REFERENCES 1. Lind SE. The bleeding - Blood - time does not predict surgical bleeding. 1991;77:2547-2552. D. Grech P. McCormick PA. McIntvre N. 2. Blake JC., Sureneers . Burroughs AK.Bleeding time in patients with hepatic cirrhosis: BMJ 1990;301:12-15.
-
CHOLESCINTIGRAPHY IN ACALCULOUS BILIARY PAIN: IF ABNORMAL, SHOULD CHOLECYSTECTOMY FOLLOW?
Yap L, Wycherley AG, Morphett AD, Toouli J . Acalculous biliary pain: cholecystectomy alleviates symptoms in patients with abnormal cholescintigraphy. Gastroenterology 1991;101:786-793. ABSTRACT
A 45-minute infusion of an octapeptide of cholecystokinin (Kinevac; SquibbDiagnostics,New Brunswick, NJ) was used to measure the gallbladder ejection fraction during cholescintigraphyin 40 normal volunteers. Cholecystokinincholescintigraphywas shown to be a reproducible test. The maximum mean gallbladder ejection fraction occurred 15 minutes after cholecystokinin infusion and was 74.5% f 1.9%(mean -+ SEM). A gallbladder ejection fraction >40% (mean - 3SD) was arbitrarily defined to be normal. The gallbladder ejection fraction test was then used to identify patients with acalculous biliary symptoms who may respond to cholecystectomy. A total of 103patients was tested; 2 1 had abnormal gallbladder ejection fractions and were randomized into two groups, cholecystectomy or no operation. These patients were followed up symptomatically at 3-month intervals for 13-54 months (mean, 34 months). Of the 11 patients who underwent cholecystectomy, 10 (91%)lost their symptoms and 1 improved. Of the 10 patients in the group that did not undergo surgery, all continued to be symptomatic, 2 of whom requested cholecystectomy after 13 and 24 months, respectively. Of the 13 gallbladders obtained from surgery, 12 showed evidence of chronic cholecystitis, muscle hypertrophy, and/or narrowed cystic duct. A normal gallbladder ejection fraction was recorded in 82 patients, and further treatment was left to the discretion of their referring clinician. On follow-up,50 patients were asymptomatic and 10 were symptomatic without specific treatment of the biliary tract; 14 underwent cholecystectomy, 8 of whom were asymptomatic. Pathological abnormalities were recorded in 6 of the removed gallbladders. It is concluded that the gallbladder ejection fraction obtained after a 45minute infusion of cholecystokinin during cholescintigraphy is a reproducible measure of gallbladder emptying, and that cholecystectomy alleviates the biliary-typepain of patients with a reduced gallbladder ejection fraction. COMMENTS
Chronic right upper quadrant pain without gallstones, usually identified as “acalculous biliary pain,” has been clinically difficult to define in the absence of gallstones. The advent of more simplified surgery in the form of laparoscopic cholecystectomy presents, perhaps, too easy an alternative to a challenging question: what test will detect subtle gallbladder-biliary tract disease and predict a favorable outcome from surgery? The prospective study by Yap et al. would indicate that eholecystokinin (CCK) cholescintigraphy is the answer. Using a standard infusion of CCK-8 (9 ngkghr) for 45 min in 108 patients considered to have biliary-type pain, 21 were found to have a gallbladder ejection fraction less
738
HEPATOLOGY Elsewhere
than .40% (below the mean -3 S.D. of 40 control subjects). Randomized to cholecystectomy or no surgery and observed at 3-mo intervals for an average of 3 yr, 11 patients underwent cholecystectomy and dramatically improved: symptoms disappeared in 10 patients and the one other patient improved. All 10 patients who did not have cholecystectomy continued to have symptoms; 2 of these patients eventually underwent cholecystectomy. Of the total of 13 gallbladders obtained at the time of surgery, 12 had significant morphological features, which included the following: chronic cholecystitis, muscular hypertrophy or a narrowed cystic duct. The one failure in these 13 patients was subsequently thought to have a motility disorder involving the sphincter of Oddi. The authors concluded the following: (a) patients with an abnormal ejection fraction had a n excellent response to cholecystectomy but continued to be symptomatic if the gallbladder was not removed, and (b) their gallbladders exhibited pathological changes consistent with chronic cholecystitis. These results are almost too good to be true. This study was designed to answer the following question: does cholecystectomy alleviate symptoms in patients with biliary-type pain when the ejection fraction is reduced? The answer from this controlled surgical trial in 21 patients with low ejection fractions would appear to be yes. The 82 patients who did not have operations and who had “normal” ejection fractions were observed in a more haphazard manner. Of the 82 patients, 50 became asymptomatic and 10 remained symptomatic; 14 underwent cholecystectomy; 8 became asymptomatic; and 6 had pathological changes in the gallbladder. This subgroup blurs the message: 50 of 82 patients without surgery and 8 of 14 patients with surgery (i.e., about 60% each) improved. Six of 14 patients had gallbladder pathological results despite a normal evacuation on cholescintigraphy. A more critical question would have been the following: do those with reduced ejection fractions respond better than those with normal contraction? The discrepancy in the quality of follow-up between the two groups makes this difficult to answer. When surgery is involved, difficulty always exists in obtaining an adequate control group. Sham cholecystectomy is clearly reprehensible. Early studies using CCK cholecystography found that as many as 90% or so of patients with an abnormal response to CCK (defined as either decreased evacuation or reproduction of their pain) could be cured by cholecystectomy (1). Such response rates for acalculous biliary pain compare favorably with the results from cholecystectomy in patients with gallstones. Nonphysiological, bolus infusions of CCK without quantitating gallbladder evacuation have also been used t o reproduce the abdominal pain as the basis for selecting patients who would benefit from cholecystectomy. This “CCK test” has met with some success (21, but reproducibility and false-positives have clouded its usefulness. Further, CCK cholecystography was a relatively primitive technique, depending on serial x-ray examinations and
HEPATOLOGY
assuming that planigraphic models represented threedimensional structures. The advent of nuclear medicine scans (3) and serial ultrasounds (4)has more accurately quantified gallbladder evacuation in response to either CCK infused at a more physiological dose or a standard meal. Our evaluation of quantitative cholescintigraphy in patients with right upper quadrant pain and no gallstones came to a different conclusion ( 5 ) . In this study, the limit for an abnormal ejection fraction was identified as less than 0.65 ( - 2 S.D. below the mean in 38 normal controls but a value higher than that identified in the study by Yap et al.). In our report, 26 patients with “abnormal” emptying on the HIDA scan underwent cholecystectomy. Eighteen (69%) of the 26 patients were considered therapeutic successes, whereas 8 (31%)patients were failures after an average of 2 yr of follow-up. Ironically, the decreased ejection fraction did not predict clinical outcome because the failure group had an even lower ejection fraction (0.25) than those who responded to cholecystectomy (0.39). Only seven surgically obtained gallbladders (from five success and two failure patients) demonstrated chronic cholecystitis, whereas the remainder were relatively normal, findings at odds with the report by Yap et al. We concluded that the diagnostic value of cholescintigraphy in patients with acalculous right upper quadrant pain was poor. Further, the frequency of pathological findings in the gallbladder was also low. The gallbladder ejection fraction did not predict abnormal gallbladder histological results. If the ejection fraction were lowered to 0.49 (mean - 2 S.D. of control from another study 1631, the results would change only slightly. The “success” group would shrink by five, and the “failure” group would shrink by only two. With this criteria, 13 of 18 (72%) would be surgical successes, whereas 6 of 18 (33%)would be failures - not very different. Deficiencies in our study, however, included the absence of a control group and the design; all patients had an abnormal gallbladder emptying. A decreased ejection fraction may result from an abnormal contraction of the gallbladder, increased cystic duct resistance or obstruction and/or impairment of the sphincter of Oddi with reduced emptying into the duodenum. Undefined in any of these gallbladder emptying studies is patency of the ductal system. Assessment of cystic duct size is fraught with problems from subjective interpretation and inadequate standardization. One prediction even suggested that some two thirds of patients with typical pancreatic or biliary symptoms and an abnormal ejection fraction may have sphincter of Oddi abnormalities (7). Another important factor is the natural history of acalculous biliary pain, which may represent an early stage of cholesterol gallstone formation that is associated with abnormal gallbladder motility (6,8).Brugge et al. (9) found cholesterol crystals (indicating lithogenic bile) in the aspirated duodenal bile of these symptomatic patients without overt evidence of gallstones and correlated this with poor gallstone emptying. Careful histo-
Vol. 15, No. 4,1992
739
HEPATOLOGY Elsewhere
logical studies (5) have eliminated chronic acalculous cholecystitis as a pathological entity characterized by chronic inflammation and fibrous and muscular thickness of the gallbladder wall. Undoubtedly, chronic right upper quadrant pain in the absence of gallstone disease is multifactorial. Sludge and gallstones must be eliminated by ultrasonography; abnormal bile should be sought by examining the duodenal aspirate for the presence of cholesterol crystals. Overt causes of impairing gallbladder motor function (e.g., progesterone, obesity and diabetes) must be eliminated (10). Only then will impaired gallbladder evacuation be properly related to symptoms and outcome. In the interim the ejection fraction ascertained by quantitative cholescintigraphy is a reasonable tool for identifying disordered gallbladder motility and relating this to biliary symptoms. Even pain relief soon after surgery is an imperfect endpoint because of placebo effect. The advent of laparoscopic cholecystectomy will be a temptingly easy solution to difficult cases. Before becoming too haphazard, a more complete, careful evaluation of gallbladder function and contents is essential. The once elusive testb) to diagnose acalculous biliary pain are being clarified. Cholescintigraphy may yet provide the best bet.
ELDONA.SHAFFER, M.D., F.R.C.P.C., F.A.C.P. Department of Medicine The University of Calgary Calgary AB, T2N 2T9, Canada
GENETIC STRUCTURE AND HETEROGENEITY OF HEPATITIS C VIRUS: A VACCINE IMPEDIMENT?
Choo QL, Richman KH, Han JH, Berger K, Lee C, Dong C, Gallegos C, et al. Genetic organization and diversity of the hepatitis C virus. Proc Natl Acad Sci USA 1991;88:2451-55. ABSTRACT
The nucleotide sequence of the RNA genome of the human hepatitis C virus (HCV) has been determined from overlapping cDNA clones. The sequence (9379 nucleotides)has a single large open reading frame that could encode a viral polyprotein precursor of 3011 amino acids. While there is little overall amino acid and nucleotide sequence homology with other viruses, the 5' HCV nucleotide sequence upstream of this large open reading frame has substantial similarity to the 5' termini of pestiviral genomes. The polyprotein also has significant sequence similarity to helicases encoded by animal pestiviruses, plant potyviruses, and human flaviviruses, and it contains sequence motifs widely conserved among viral replicases and trypsin-like proteases. A basic, presumed nucleocapsid domain is located at the N terminus upstream of a region containing numerous potential N-linked glycosylation sites. These HCV domains are located in the same relative position as observed in the pestiviruses and flaviviruses and the hydrophobic profiles of all three viral polyproteins are similar. These combined data indicate that HCV is an unusual virus that is most related to the pestiviruses. Significant genome diversity is apparent within the putative 5' structural gene region of different HCV isolates, suggesting the presence of closely related but distinct viral genotypes.
Kato N , Hijikata M, Ootsuyarna Y, Nakagawa M , Ohkoshi S, Shimotohno K. Sequence diversity of hepatitis C viral genomes. Mol Biol Med 1990;7:495-501. 1. Goldberg HI. CCK cholecystography. Semin Roentgen01 1976;ll: REFERENCES
175-179. 2. Lennard TWJ, Farndon JR, Taylor RMR. Acalculous biliary pain: diagnosis and selection for cholecystectomy using the cholecystokinin test for pain reproduction. Br J Surg 1984;71:368-370. 3. Shaffer EA, McOrmond P, Duggan H. Quantitative cholescintigraphy: assessment of gallbladder filling and emptying and duodenogastric reflux. Gastroenterology 1980;7:899-906. 4. Everson GT, Braverman DZ, Johnson MI, Kern F. A critical evaluation of real time ultrasonography for the study of gallbladder volume and contraction. Gastroenterology 1980;79:40-46. 5. Westlake PJ, Hershfield NB, Kelly JK, Kloiber R, Lui R, Sutherland LR, Shaffer EA. Chronic right upper quadrant pain without gallstones: does HIDA scan predict outcome after cholecystectomy? Am J Gastroenterol 1990;85:986-990. 6. Pomeranz IS, Shaffer EA. Abnormal gallbladder emptying in a subgroup of patients with gallstones. Gastroenterology 1985;88: 787-791. 7. Gregg JA. Function and dysfunction of the sphincter of Oddi. In: Jackson IM, ed. ERCP: Diagnostic and therapeutic applications. Elsevier Science, 1989. 8. Shaffer EA. Gallbladder disease. In: Walker WA, Durie PR, Hamilton JR, Walker-Smith JA, Watkins JB, eds. Pediatric gastrointestinal disease. Philadelphia: BC Decker Inc, 1991:11521170. 9. Brugge WR, Brand DL, Atkins HL, Lane BP, Abel WG. Gallbladder dyskinesia in chronic acalculous cholecystitis. Dig Dis Sci 1986; 31:461-467. 10 Everson GT. Gallbladder function in gallstone disease. Gastroenterol Clin North Am 1991;20:85-110.
ABSTRACT
The nucleotide sequences of cDNAs (275 base-pairs) in the non-structural protein 5 regions of Japanese isolates of hepatitis C virus (HCV-J)from the plasma of 11 patients with non-A, non-B hepatitis and the livers of five patients with hepatocellular carcinoma were analyzed. Approximately 14 to 17% of nucleotide sequences of the HCV-Js examined differed from that of the original isolate in the United States (HCV-US). Furthermore, 2.5 to 11% sequence diversity was found among the HCV-Js. The nucleotide sequences of the HCV-J s showed characteristic common differences from that of HCV-US, although they also showed some random substitutions. Plural HCV-J genomes were found in two of the cDNAs derived from liver specimens, and a deletion of 102 nucleotides was found in the cDNA derived from one plasma specimen. These results suggest that HCV-J is a strain different from the HCV-US and that mutation of the viral genome occurs at as high a frequency as in that of the human immunodeficiency virus. COMMENTS
Recently, several groups reported the initial structural details of the hepatitis C viral genome (1,2). Two
