Incidence and prevalence of primary biliary cirrhosis in the city of Newcastle upon Tyne, England.

OBJECTIVE: To describe the incidence and prevalence of primary biliary cirrhosis in an urban population between 1987 and 1994, using stringent inclusion criteria and a well-defined study area and population. DESIGN: Descriptive study based on a case register compiled by a retrospective and prospective case-finding exercise and examination of case notes. SETTING: The city of Newcastle upon Tyne. MAIN INCLUSION CRITERIA: (1) Definite cases: fulfilling all three of the following diagnostic criteria: positive antimitochondrial antibody (AMA) > or = 1:40; cholestatic liver function tests (LFT); diagnostic or compatible liver histology. (2) Probable cases: fulfilling two of these criteria. SUBJECTS: All cases of primary biliary cirrhosis identified by multiple case-finding methods, alive from 1 January 1987 to 31 December 1994, in the defined area. MAIN OUTCOME MEASUREMENTS: Incidence and point prevalence rates by age and sex. RESULTS: In all, 202 potential cases were identified, of whom 160 met at least two inclusion criteria. In definite cases annual incidence varied from 14 to 32 (mean 22) per million whole population (with no clear trend) and point prevalence rose from 180 per million in 1987 to 240 in 1994. Mean age at diagnosis in cases incident during the study period was 63.2 years (S.D. 11.1 years, range 39.8-85.7 years). CONCLUSIONS: Primary biliary cirrhosis is much more common in Newcastle than has previously been reported anywhere in the world, and prevalence appears to be rising.

Incidence and causes of rectal bleeding in general practice as detected by colonoscopy.

BACKGROUND: Rectal bleeding is common, but it is still unclear which patients require investigation to exclude serious pathology, although it is known that colectoral cancer is very rare under the age of 40 years. Few studies have examined all patients presenting to their primary health physician rather than screening whole populations. AIM: The aim of this study was to investigate the view that all patients over the age of 40 who present to their general practitioner with rectal bleeding should undergo investigation by colonoscopy to rule out serious pathology, regardless of symptomatology. METHOD: A prospective study was carried out of 99 consecutive patients over 40 years presenting with rectal bleeding to 17 general practices in Newcastle upon Tyne. RESULTS: Serious pathology was detected by colonoscopy in 44.4% of patients. The diagnoses were: colorectal carcinoma, eight cases (two Dukes' grade A, two Dukes' grade B, four Dukes' grade C); one or more polyps, 25 cases (in 17 cases at least one polyp was 5 mm or greater in diameter); inflammatory bowel disease, 11 cases. In the remaining 55 patients, bleeding was associated with diverticular disease (16 cases) and haemorrhoids (28 cases). No cause was found in 11 patients. This high rate of pathology may be partly caused by selection of cases for referral by the general practitioner, despite efforts to minimize this. Three symptoms as elicited by the colonoscopist were found to be significantly associated with serious disease: blood mixed with stool (P < 0.001); change in bowel habit (P < 0.005); and the presence of abdominal pain (P < 0.025). However, symptoms elicited on primary presentation were less helpful and symptoms changed significantly between consultation with the general practitioner and colonoscopy. CONCLUSION: All patients over the age of 40 years presenting with rectal bleeding should be referred for flexible sigmoidoscopy or colonoscopy. Symptoms are unhelpful in deciding who requires investigation.

Hepatocellular carcinoma in primary biliary cirrhosis and its impact on outcomes.

In this study we have determined the incidence of hepatocellular carcinoma (HCC) development in primary biliary cirrhosis (PBC) and its effects on patient survival. Six hundred and sixty seven patients with liver histology compatible with or diagnostic of PBC were seen over a 20-year period. Two hundred and seventy three patients who had stage III or IV disease on their last biopsy and who had been followed up for at least 1 year following that biopsy (total follow-up with advanced disease 2,010 patient years) were identified (243 female, 30 male). Patients who developed HCC were identified and their confounding risk factors were excluded. Mayo risk scores were calculated for each clinic attendance and expected survival for each time point was compared with subsequent actual survival. Sixteen cases of HCC were seen in the patients with stage III or IV disease on last biopsy, providing an overall incidence of 5.9% in this group. Fourteen of these patients had died of HCC related causes, and 2 patients were alive at the census point. The incidence of HCC was significantly higher in males with stage III/IV disease than in females (20% vs. 4.1%, P < .005). Nine of one hundred and eight (8.3%) total female deaths in this group was attributable to HCC compared with 5 of 11 (45.5%, P < .05) male deaths. HCC was not seen in any of the 394 patients with stage I and II PBC followed-up over the same time period. Throughout the disease course of all PBC patients with HCC, the Mayo prognostic model over-predicted survival. Whereas it is a relatively rare complication of cirrhotic PBC in women, HCC is a relatively common cause of death in male PBC patients with cirrhosis. HCC typically develops several years after the onset of cirrhosis, and is poorly predicted by prognostic models. In view of these findings, consideration should be given to careful screening for HCC in male PBC patients with cirrhosis. The risk of HCC development may be an additional reason to consider earlier transplantation in these patients.

Asymptomatic primary biliary cirrhosis: clinical features, prognosis, and symptom progression in a large population based cohort.

BACKGROUND: Many patients with primary biliary cirrhosis (PBC) are asymptomatic at the time of diagnosis. However, because most studies of asymptomatic PBC have been small and from tertiary centres, asymptomatic PBC remains poorly characterised. AIMS: To describe the features and progression of initially asymptomatic PBC patients. METHODS: Follow up by interview and note review of a large geographically and temporally defined cohort of patients with PBC, collected by multiple methods. RESULTS: Of a total of 770 patients, 469 (61%) were asymptomatic at diagnosis. These patients had biochemically and histologically less advanced disease than initially symptomatic patients. Median survival was similar in both groups (9.6 v 8.0 years, respectively) possibly due to excess of non-liver related deaths in asymptomatic patients (31% v 57% of deaths related to liver disease). Survival in initially asymptomatic patients was not affected by subsequent symptom development. By the end of follow up, 20% of initially asymptomatic patients had died of liver disease or required liver transplantation. The majority of initially asymptomatic patients developed symptoms of liver disease if they were followed up for long enough (Kaplan-Meier estimate of proportion developing symptoms: 50% after five years, 95% after 20 years). However, 45% of patients remained asymptomatic at the time of death. CONCLUSIONS: Although asymptomatic PBC is less severe at diagnosis than symptomatic disease, it is not associated with a better prognosis, possibly due to an increase in non-hepatic deaths. The reasons for this are unclear but may reflect confounding by other risk factors or surveillance bias. These findings have important implications for future treatment strategies.

An exploratory population-based case-control study of primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is a disease of unknown etiology, with unexplained geographical variation. Various exposures have been suggested as triggers for disease development-possibly in susceptible individuals, but the evidence was not always well founded. We therefore conducted a population-based case-control study in Northeast England to investigate these and other exposures. All cases incident during 1993 to 1995 in a defined area of Northeast England were identified, and age- and sex-matched population controls were identified from primary care population registers. Cases and controls were sent postal self-completion questionnaires covering medical history and lifestyle. Information was received from 100 cases and 223 controls. The familial tendency of PBC was found to be less marked than has been claimed: Only weak associations were found with other autoimmune diseases. Among factors considered previously, no significant associations were found with surgical procedures, events in pregnancy, past infections, vaccinations, and medications. No significant associations were found for previously unconsidered lifestyle factors (drinking alcohol, previous pets, or stressful events), but there was an unexpected association with past smoking (ever smoked: 76% in cases vs. 57% in controls, odds ratio 2.4; smoked for 20 years or more: 64% vs. 35%, odds ratio 3.5). There were also unexpected significant associations with psoriasis (13% in cases vs. 3% in controls, odds ratio 4.6) and eczema (3% in cases vs. 11% in controls, odds ratio 0. 13). These findings merit further investigation.

The geographical distribution of primary biliary cirrhosis in a well-defined cohort.

The incidence of primary biliary cirrhosis (PBC) varies widely between regions. However, little is known about variation within regions and the degree to which this may reflect environmental risk factors. The aim of this study was to describe the spatial distribution of cases of PBC in a defined region of Northeast England over a defined period, and to assess the magnitude of any departure from random spatial distribution. Seven hundred seventy patients with established PBC were identified in a previous comprehensive case finding study. A total of 3,044 control locations were randomly selected from postcode (zip code) data weighted for number of drop off points per postcode. Geographical analysis was performed by testing both for spatial variation in risk and local clustering by using previously described point process methods. Both tests used the same null hypothesis that risk of disease does not vary spatially and cases occur independently of each other. Statistically significant spatial variations in risk were found in the whole study region (P <.001) and in the major urban area within the region (P <.004). Risk was higher in the urban area of Tyneside than in the surrounding rural area. Within the rural area, spatial variation in risk was equivocal (P =.012), but there was significant (P =.001) clustering of cases (estimated average cluster effect approximately 10 excess cases within a 7-km radius). PBC occurred to a density of 10.7 cases/km(2) in the highest risk areas. In conclusion, PBC is unevenly distributed in Northeast England. This may reflect one or more environmental risk factors in its etiology.

Primary biliary cirrhosis once rare, now common in the United Kingdom?

There is a widespread impression that the number of patients with the autoimmune liver disease primary biliary cirrhosis (PBC) is increasing, although its incidence and prevalence vary widely. Using thorough case-finding methods and rigorous definitions to assess changes in incidence and prevalence with time and to explore the symptomatology and mortality of the disease in a large group of unselected patients, we performed a descriptive epidemiological study of PBC in a well defined population over a fixed period of time using established diagnostic criteria and with clinical follow-up of all cases. In a population of 2.05 million in northern England 770 definite or probable PBC cases were identified. Prevalence rose from 201.9 per 10(6) in the adult population and 541. 4 per 10(6) women over 40 in 1987 to 334.6 per 10(6) adults and 939. 8 per 10(6) women over 40 in 1994. Incidence was 23 per 10(6) in 1987 and 32.2 per 10(6) in 1994. Three hundred patients died in median follow-up of 6.27 years (141 liver deaths); the standardized mortality ratio was 2.85. At presumed diagnosis, 60.9% had no symptoms of liver disease. By June 1994 62% of prevalent patients had liver symptoms. PBC is apparently increasing. It is still unclear whether this is because of a true increase, case finding, or increased disease awareness. The study draws attention to (1) high mortality from liver disease and non-liver-related causes even in patients initially with no liver symptoms and (2) apparently poor diagnostic awareness of the disease.

Natural history of early primary biliary cirrhosis.

BACKGROUND: In 1986, we reported a group of 29 patients who were positive in serum for antimitochondrial antibody (AMA), the disease-specific marker for primary biliary cirrhosis (PBC), but who had normal liver function test results and no symptoms of liver disease. However, liver histology was diagnostic or compatible with PBC in 24 patients and normal in only two. The aims of this 10-year follow-up study were to establish whether patients with AMA have very early PBC, to assess the outlook for such patients, and to follow the progression of the disease. METHODS: All patients were assessed every year at our PBC clinic: records were reviewed, cause of death verified when applicable, and current clinical and biochemical data collected, including repeat liver histology as indicated. Serum samples from the original study were located. Original and follow-up serum samples were tested by ELISA for E2 components of pyruvate dehydrogenase complex and 2-oxoglutarate dehydrogenase complex. FINDINGS: Five patients died during follow-up; no deaths were attributable to liver disease. Median follow-up of patients who survived was 17.8 years (range 11.0-23.9) from first-detected AMA to the last follow-up review. Overall, 22 (76%) developed symptoms of PBC and 24 (83%) had liver function tests persistently showing cholestasis. Repeat liver biopsy samples were obtained from ten patients; among these patients PBC progressed from Scheuer grade 1 to grade 2 in two and from grade 1 to grade 3 in two. No patient developed clinically apparent cirrhosis. ELISA of baseline serum samples from 27 patients was positive in 21, all of whom had original liver histology compatible with or diagnostic of PBC. Of the six patients who tested negative, only one had an original liver biopsy sample that was compatible with PBC. INTERPRETATION: This study confirms that before the advent of any clinical or biomedical indications, individuals positive for AMA do have PBC. This finding extends the natural history of PBC back in some cases for many years. What determines the eventual progression to biochemically and clinically apparent disease is not yet understood. During our study no patient developed clinically apparent portal hypertension or cirrhosis. Thus, although the finding of a solitary persistently raised AMA is confirmation of a diagnosis of PBC, patients with AMA but no other signs or symptoms of PBC seem to have slow progression of the disease.

Cancer risk in primary biliary cirrhosis: a study in northern England.

BACKGROUND: Suggestions that breast cancer may be more common in patients with primary biliary cirrhosis (PBC) have been challenged. It has recently been proposed that total cancer rates may be higher in patients with PBC, as well as liver cancers. AIMS: To investigate these proposals on a strictly defined case series. SUBJECTS: A total of 769 prevalent or incident PBC patients with "definite" or "probable" disease detected in a defined area of the north-east of England during 1987-94. METHODS: Cancer events and deaths were identified by obtaining information from one or more of the following sources: Office for National Statistics (ONS) Central Registers, Regional Cancer Registry, and clinical case records. Standardised cancer incidence (SIR) and mortality ratios (SMR) were calculated using the local region as the standard population. RESULTS: There were 97 cancer events during 1987-96. SIR from cancer registrations for all cancers was 1.7 (95% confidence interval (CI) 1.3 to 2.2), for liver cancer was 74 (95% CI 32 to 146), and for breast cancer was 1.1 (95% CI 0.4 to 2.4). SMR for all cancers was 1. 8 (95% CI 1.4 to 2.4), for liver cancer was 39 (95% CI 20 to 68), and for breast cancer was 0.4 (95% 0.1 to 1.6). The results were similar after excluding the first year of follow up after PBC diagnosis. CONCLUSIONS: There was some evidence of a small increase in overall cancer incidence and mortality in PBC patients. With the exception of liver cancer, it is unlikely that there is a high excess incidence for PBC patients from any cancer at a particular site, and specifically breast cancer.

Familial primary biliary cirrhosis reassessed: a geographically-based population study.

BACKGROUND/AIMS: Development of primary biliary cirrhosis in the close relatives of patients with the disease has been reported in several series, suggesting a genetic component to disease susceptibility. In this study we set out to calculate, as accurately as possible, the prevalence of familial primary biliary cirrhosis in a geographically-based population. Using local population prevalence data, we have also calculated the first-degree relative, sibling and offspring relative risks of overt primary biliary cirrhosis development. METHODS: All patients with definite or probable primary biliary cirrhosis in the city of Newcastle-upon-Tyne, England, were identified by an exhaustive case-finding search and were prospectively interviewed by a single investigator. Full details of family pedigree and familial primary biliary cirrhosis history were obtained. RESULTS: One hundred and seventy-three patients were identified, with 160 participating in the study. Thirteen reported a family history of primary biliary cirrhosis. In three cases, both relative pairs were within the study group. The prevalence of a positive family history of primary biliary cirrhosis was therefore 10/157 (6.4% [95% Confidence Interval 2.6-10.2%]), 8/10 cases occurring in first-degree relatives. The patients had a total of 1118 first-degree relatives (live or dead) and 468 siblings. The first-degree relative prevalence of primary biliary cirrhosis was 0.72% [0.2-1.2%] (siblings 0.41% [-0.2-1.0%]). The offspring prevalence was 1.2% [0.04-2.4%], (2.3% [0.1-4.5%] for daughters). The sibling relative risk (lambda(s)) was 10.5. CONCLUSIONS: The overall prevalence of definite or probable primary biliary cirrhosis in the first-degree relatives of existing patients is <1%. The risk of disease is not, however, uniform, the highest prevalence being seen in the daughters of patients. Suspicion of disease should therefore be highest in this relative group. The calculated lambda(s) for primary biliary cirrhosis in this geographically-based study is significantly lower than previous estimates from case-note-derived case series, but similar to values seen in other autoimmune diseases.

Presentation and mortality of primary biliary cirrhosis in older patients.

OBJECTIVES: many patients with primary biliary cirrhosis present for the first time aged over 65, but it is unclear whether the disease is different in older patients. We have examined presentation and mortality in relation to age at which primary biliary cirrhosis was first suspected clinically. DESIGN: we identified 1023 patients from our regional primary biliary cirrhosis database with definite or probable primary biliary cirrhosis (689 definite); 397 (39%) presented aged > or =65. Definite primary biliary cirrhosis was defined as a positive antimitochondrial antibody titre > or =1/40, abnormal liver enzymes and compatible/diagnostic histology; probable as the presence of two of these indications. RESULTS: there was no difference in presenting clinical features between the older and younger groups. Older patients were significantly less likely than younger to have had liver biopsy (50% vs 78%; P < 0.001). The 1023 patients had been followed for 8561 patient years. Follow-up was shorter (5.9+/-4 vs 9.8+/-5.5 years; P < 0.001) in the older group because of higher cumulative mortality (59% vs 33%; P < 0.001). Liver-related deaths were significantly commoner in the older group (18% vs 13%; P < 0.05). The mortality ratio for liver deaths (liver deaths per year of follow-up) was 2.4 times higher in the older group (0.031 vs 0.013). CONCLUSIONS: patients with primary biliary cirrhosis who are over and under 65 have similar features on presentation. The annual risk of liver death is 2.4 times higher in those presenting over 65, reaffirming the importance of age as an independent prognostic factor in an unselected primary biliary cirrhosis population.