The impact of increased immigration to Sweden on the incidence and treatment of patients with HCC and underlying liver disease.

Background: Sweden has traditionally been considered a country with a low incidence of hepatocellular carcinoma (HCC). However, the increasing number of immigrants from areas with a high incidence of HCC might affect the number of HCC patients in Sweden. Aim: To examine trends in the incidence, treatment and overall survival of patients with HCC and an underlying liver disease (ULD) from a restricted, well-defined region of Sweden, between 2000 and 2014. Patients and methods: Nine hundred and eight patients with HCC were identified. Subjects were grouped into 5-year periods, and analysed for HCC diagnosis, ULD, staging and treatment selection in populations born outside Sweden versus non-immigrants and patient survival. The regions were Africa, Asia, EU-28 together with America and the Nordic countries, eastern Europe and Sweden. Results: Over the time periods, the patients with HCC and ULD increased. More patients from Africa had HCC and ULD than what would have been expected based on the number of immigrants from this region and they were also significantly younger than Sweden-born patients. For patients from Africa, Asia and eastern Europe; viral hepatitis was dominating ULDs. Patients from Africa, Asia and eastern Europe were subjected to liver transplantation (LT) in higher proportions than patients from Sweden. The survival rate for patients from eastern Europe was significantly better. Conclusions: Immigration increased the incidence of HCC and the need for active treatment such as LT. This fact raises the question of whether immigrants from regions with a high incidence of HCC ought to be subjected to mandatory hepatitis B and C virus (HBV and HCV) diagnosis and consequent liver ultrasounds for diagnosis of occult HCC. With such strategies, the morbidity and mortality of HCC could be reduced.

Steroid-free immunosuppression with low-dose tacrolimus is safe and significantly reduces the incidence of new-onset diabetes mellitus following liver transplantation.

OBJECTIVES: Corticosteroids (CS) are traditionally used as part of the basal immunosuppression (IS) following liver transplantation (LT) but are known to be associated with an increased risk of new-onset diabetes mellitus (NODM), cardiovascular morbidity and mortality. The aim of this study was to retrospectively compare the incidence of transient as well as persistent NODM, rejection rate and patient- and graft survival between patients receiving steroid-based and steroid-free maintenance IS. MATERIALS AND METHODS: A total of 238 patients liver transplanted (2008-2011) with deceased donor livers were divided into two groups, one group that received steroid-based IS (tacrolimus (TAC), corticosteroids (CS), ± mycophenolate mofetil (MMF); n = 155) (2008-2011) and another group of non-autoimmune recipients that received steroid-free IS (TAC, MMF; n = 83) according to our new maintenance IS-protocol starting January 2010. The primary and secondary end-points were patient- and graft survival, rejection rates and the incidence of NODM. The median follow-up times were 1248 days and 681 days, respectively. RESULTS: The one-year patient- and graft survival in the steroid-based and steroid-free group was 92.7% and 93.3% (ns) and 87.6% and 84.9% (ns), respectively. The incidence of biopsy proven acute rejection (BPAR) was 27.7% in both groups (ns) during follow-up. The overall incidence of persistent NODM in the two groups were 16.8% and 2.9%, respectively (p < .01). CONCLUSIONS: The results show that steroid-free low-dose tacrolimus-based IS following LT is safe and decreases the incidence of NODM significantly.

Excellent liver transplantation survival and prevention of hepatitis B recurrence using hepatitis B immunoglobulin and nucleoside or nucleotide analogue along with treating physician adherence to treatment protocol.

INTRODUCTION: The introduction of hepatitis B immunoglobulin (HBIG) in the early 1990s dramatically reduced recurrence of hepatitis B after orthotopic liver transplantation (OLT) and thus improved survival. Today a combination of HBIG and a nucleoside or nucleotide analogue (NUC) is recommended as prophylaxis. The optimal protocol is yet to be commonly agreed upon. The aim of this study was to review our results over 25 years. PATIENTS AND METHODS: All 56 patients (45 males and 11 females) who underwent OLT due to hepatitis B infection between 1985-2009 were included in the review. Median age at transplantation was 51 years (range, 18-66). Seventeen patients (30%) had hepatocellular carcinoma (HCC) at transplantation. RESULTS: The 1- and 5-year overall survival rates were 89% and 77%, respectively. The 23 patients who underwent transplantation before 2000 showed 1- and 5-year survival rates of 82% and 61%, respectively; the 33 who underwent transplantation between 2000 and 2009, the rates were 94% and 90%, respectively (P < .01). There was no difference in the 5-year survival rate between patients who had or did not have been HCC (75% vs 78%, respectively). Recurrence of hepatitis B, defined as seroconversion to HBsAg positivity, was observed in 9 patients. Three transplantation cases before 1992 consequently did not receive HBIG. The remaining 6, who all underwent OLT between 1993 and 2001, were administered HBIG. In all 6 cases periods of low anti-HBs titers were registered prior to recurrence; treating physician noncompliance with the protocol may have contributed to the low anti-HBs titers. No recurrence was registered after 2001. CONCLUSION: With a combination of HBIG and NUC, excellent OLT results can be achieved for hepatitis B. It is, however, still important to maintain sufficient anti-HBs titers to prevent recurrence.

Are liver transplant recipients protected against hepatitis A and B?

BACKGROUND: Liver transplant recipients are at an increased risk for liver failure when infected with hepatitis A virus (HAV) and hepatitis B virus (HBV). Therefore, it is important to vaccinate these individuals. The aim of the study was to evaluate how well liver transplanted patients in our unit were protected against HAV and HBV infection. Furthermore we investigated the vaccination rate and the antibody response to vaccination in these liver transplanted patients. METHODS: Patients liver transplanted from January 2007 until August 2010 with a posttransplant check-up during the period March-November 2010 were included (n = 51). Information considering diagnose, date of transplantation, Child-Pugh score, and vaccination were collected from the patient records. Anti-HAV IgG and anti-HBs titers in serum samples were analyzed and protective levels were registered. RESULTS: Of the patients 45% were protected against hepatitis A infection and 29% against hepatitis B infection after transplantation. Only 26% were vaccinated according to a complete vaccination schedule and these patients had a vaccine response for HAV and HBV of 50% and 31%, respectively. An additional 31% received ≥ 1 doses of vaccine, but not a complete vaccination and the vaccine response was much lower among these patients, stressing the importance of completing the vaccination schedule. CONCLUSION: Even when patients were fully vaccinated, they did not respond to the same degree as healthy individuals. Patients seemed to be more likely to respond to a vaccination if they had a lower Child-Pugh score, suggesting that patients should be vaccinated as early as possible in the course of their liver disease.

Long-term follow-up of living liver donors.

OBJECTIVES: At our center living donor liver transplantation (LDLT) represents 4% of all transplantations. The aim of this cross-sectional study was to clarify the current well-being of the donors, their experiences of being a donor, as well as the regenerative capacity of the liver. PATIENTS AND METHOD: Thirty-six healthy subjects donated a part of their liver between 1996 and 2007. Thirty-four patients participated in the study and completed our questionnaire. We performed magnetic resonance imaging (MRI) of the liver, physical examination, and blood chemistry. RESULTS: Twenty-three subjects had donated the left lateral segment and 11 the right lobe. Their hospital stay ranged from 5-15 days (median, 10). Mostly, the sick-leave period was 8-12 weeks and time for recovery was 3-6 months. Long-term problems were heartburn, abdominal discomfort, incisional hernia, and fatigue. Twenty-six (76.5%) subjects viewed the donation experience as entirely positive; no one was regretful. Liver function tests were normal. The MRI data at follow-up of 13 left lateral segment and 11 right lobe grafts showed recovery of the total liver volume to almost preoperative values, mean 1522 ± 241 mL versus 1552 ± 219 mL, respectively. CONCLUSION: Living liver donors commonly recovered after 3-6 months, perceiving donation as a positive experience with no regret. Durable side effects were mainly heartburn and abdominal discomfort, but the symptoms were mostly mild. Liver function was normal. The MRI data showed a mean regeneration of liver volume to 98.6% of the preoperative values.

Calculation and comparison of the model for end-stage liver disease (MELD) score in patients accepted for liver transplantation in 1999 and 2004.

There has been a need to assess the "sickness degree" in patients with acute and chronic hepatic failure. The Model for End-Stage Liver Disease (MELD) score was developed as a tool for a more objective estimate of the "degree" of sickness in patients with chronic liver disease. In this study, the MELD score was retrospectively calculated and compared in adult patients accepted for orthotopic liver transplantation (OLT) in our institution in 1999 and 2004. We analyzed the gender, age, and MELD score associated with different indications for OLT during this period.

MELD [corrected] score in patients accepted for liver transplantation 1994 to 2004.

There has been a need to be able to grade the "degree of sickness" in patients with acute and chronic hepatic failure. The Model for End-Stage Liver Disease (MELD) score was developed as a tool to give a more objective estimate of the degree of sickness in patients with chronic liver disease. In this study the MELD score was compared retrospectively in adult patients accepted for liver transplantation (OLT) at our institution in 1994, 1999, and 2004. Gender, age, and MELD score associated with different indications for OLT were analyzed for the same period. The MELD scores were unchanged between the examined years, and there was no difference between male and female patients accepted for OLT. Comparing MELD score between male and female patients, there was a potential risk for discrimination of female patients due to their reduced muscle mass, resulting in a lower serum creatinine and a lower MELD score. There was no difference in MELD score comparing 1994, 1999, and 2004 for patients with cirrhosis. Patients with acute hepatic failure had the highest MELD scores while patients undergoing OLT because of malignancy had the lowest MELD score. MELD score seemed to be a useful tool for retrospective analyzes of potential OLT recipients.

Preemptive therapy with pegylated interferon alpha-2b and ribavirin after liver transplantation for hepatitis C cirrhosis.

UNLABELLED: We present our results of preemptive treatment with pegylated interferon and ribavirin after liver transplantation for hepatitis C cirrhosis. PATIENTS: Between September 2001 and August 2002, four patients were started on combination therapy with pegylated interferon-alpha-2b (1microg/kg weekly) and ribavirin (400-1000 mg/d) 3 to 4 weeks' posttransplant. Treatment was continued for 6 (genotype 3a, 2 patients) or 12 (genotype 1b, 2 patients) months. Virologic and biochemical responses as well as side effects were evaluated. RESULTS: Two patients (genotype 3a) became HCV (hepatitis C virus)-RNA negative after 3 months of therapy and are persistently negative 20 and 14 months after end of therapy. One patient (genotype 1b) became HCV-RNA negative 6 months after start of treatment, but therapy had to be withdrawn after 9 months owing to fatigue and suspicion of angina pectoris. One patient who was later retransplanted because of hepatic artery thrombosis discontinued therapy after 2.5 months owing to anemia, leukopenia, and no signs of HCV-RNA reduction. Interestingly, two of the responders were nonresponders prior to liver transplant. Median ALT levels at start of therapy were 98 U/L (r = 60-126) and 12 months later 40 U/L (r = 24-58) (n = 4). No rejection episode was detected. CONCLUSION: In patients liver-transplanted due to HCV-cirrhosis, combination therapy with pegylated interferon and ribavirin can be effective and safe in the early posttransplant period, thus preventing recurrent hepatitis C.

High-resolution analysis of the duodenal interdigestive phase III in humans.

To study the spatial organization of the propagating pressure waves of duodenal phase III, we performed fasting antroduodenal high-resolution manometry with a 16-channel catheter in 12 healthy subjects. The phase III pressure waves diverged in an anterograde and retrograde direction from the start site of each pressure wave. The pressure waves maintained this configuration as the activity front moved distally in the duodenum. The start site of the pressure waves moved gradually to a point approximately 12 cm (median) distal to the pylorus and remained at this point for about 40% of the phase III time before moving further distally. The length of retrograde pressure wave propagation increased to 6 cm (median) as the pressure wave origin moved aborally to a point 10-14 cm distal to the pylorus, and then decreased when the origin of pressure waves reached the distal end of the duodenum. Bidirectional pressure waves dominated in both retrograde and anterograde activity fronts. Three pressure-wave mechanisms behind the duodenal phase IV were observed. Isolated pyloric pressure waves were absent during late duodenal phase III retroperistalsis. Thus, a number of new features of the duodenal phase III-related motility were observed using high-temporospatial resolution recordings.

Scintigraphic assessment of interdigestive duodenogastric reflux in humans: distinguishing between duodenal and biliary reflux material.

BACKGROUND: Late duodenal phase III is characterized by retroperistalsis. The physiologic function of this phenomenon is unknown. Our aim was to study the relationship between duodenal motility and the transport of duodenal contents from the biliary tract and the duodenum by using a double-isotope technique. METHODS: Manometric analysis of the direction of interdigestive duodenal pressure waves was performed in 12 volunteers. Duodenal marker was infused directly into the proximal duodenum, and bile marker was infused intravenously for 2 h. Radionuclide activity was examined for regions corresponding to the stomach, gallbladder, and duodenum. RESULTS: In phase II, antegrade pressure waves dominated with propulsion of both markers to the jejunum. Retroperistalsis occurred in 90% of the activity fronts and was always (100%) followed by retropulsion of duodenal marker to the stomach. A clear-cut reflux of bile marker was seen in only 17% of the activity fronts. The incidence rate of duodenogastric reflux was highest in phase III (P=0.008) compared with phase II with an infrequent (P=0.002) admixture of bile. Bile marker contents increased abruptly in the gallbladder during phase III. CONCLUSIONS: Late phase III acts as a retroperistaltic pump, retropelling duodenal contents to the stomach. In this physiologic duodenogastric reflux. bile is avoided by deviation to the gallbladder, probably by a phase lll-associated occlusion of the sphincter Oddi.

Effects of midazolam on small bowel motility in humans.

BACKGROUND: Benzodiazepines are used as sedatives for some intestinal procedures and as hypnotics, and this is the reason for studying their effects on duodenojejunal motility. METHODS: Antroduodenojejunal manometry was performed in 13 healthy volunteers on two different occasions, when placebo or midazolam were given intravenously (randomized, double-blind). A bolus dose of midazolam 0.03 mg/kg was followed by 0.015 mg/kg after 1.5, 3 and 4.5 h. After 5 h observation of interdigestive motility, the volunteers were given a test meal and recording continued for another hour. Twenty-eight motility variables were compared. RESULTS: With midazolam the median motility index of phase III in the proximal duodenum was increased by 37% (P < 0.05), which was a consequence of both a longer duration (P < 0.01) and higher pressure amplitudes (P < 0.05), compared with placebo. A longer duration (9%) of phase III was also seen in the distal duodenum (P < 0.05). With midazolam the duration of the migrating motor complex was shortened by 27% (P < 0. 05). No statistically significant difference was found for the number of episodes of phase III registered (P=0.09), or for the other 22 motility variables compared including the duodenal retroperistalsis in late phase III. CONCLUSION: Midazolam does affect some aspects of duodenal motility, especially in the proximal part, but phase III-related retroperistalsis is not affected.

Identification of Helicobacter pylori and other Helicobacter species by PCR, hybridization, and partial DNA sequencing in human liver samples from patients with primary sclerosing cholangitis or primary biliary cirrhosis.

Helicobacter pylori was identified in human liver tissue by PCR, hybridization, and partial DNA sequencing. Liver biopsies were obtained from patients with primary sclerosing cholangitis (n = 12), primary biliary cirrhosis (n = 12), and noncholestatic liver cirrhosis (n = 13) and (as controls) normal livers (n = 10). PCR analyses were carried out using primers for the Helicobacter genus, Helicobacter pylori (the gene encoding a species-specific 26-kDa protein and the 16S rRNA), Helicobacter bilis, Helicobacter pullorum, and Helicobacter hepaticus. Samples from patients with primary biliary cirrhosis and primary sclerosing cholangitis (11 and 9 samples, respectively) were positive by PCR with Helicobacter genus-specific primers. Of these 20 samples, 8 were positive with the 16S rRNA primer and 9 were positive with the 26-kDa protein primer of H. pylori. These nine latter samples were also positive by Southern blot hybridization for the amplified 26-kDa fragment, and four of those were verified to be H. pylori by partial 16S rDNA sequencing. None of the samples reacted with primers for H. bilis, H. pullorum, or H. hepaticus. None of the normal livers had positive results in the Helicobacter genus PCR assay, and only one patient in the noncholestatic liver cirrhosis group, a young boy who at reexamination showed histological features suggesting primary sclerosing cholangitis, had a positive result in the same assay. Helicobacter positivity was thus significantly more common in patients with cholestatic diseases (20 of 24) than in patients with noncholestatic diseases and normal controls (1 of 23) (P = <0.00001). Patients positive for Helicobacter genus had significantly higher values of alkaline phosphatases and prothrombin complex than Helicobacter-negative patients (P = 0.0001 and P = 0.0003, respectively). Among primary sclerosing cholangitis patients, Helicobacter genus PCR positivity was weakly associated with ulcerative colitis (P = 0.05). Significant differences related to blood group or HLA status were not found.

Abnormal propagation pattern of duodenal pressure waves in the irritable bowel syndrome (IBS) [correction of (IBD)].

The propagation pattern of individual pressure waves in the gastroduodenal area in IBS is unexplored. We performed antroduodenojejunal manometry on 26 patients with IBS--13 with diarrhea predominant IBS (IBS-D) and 13 with constipation predominant IBS (IBS-C)--and 32 healthy controls. Neuropathic-like motor abnormalities were found in 38% of the patients with conventional manometric evaluation. With high-resolution analysis additional abnormalities were observed in the majority of the patients, with increased frequency of retrograde pressure waves postprandially in both IBS subgroups and in phase II in IBS-D. A correlation between subjective gastrointestinal symptoms and the frequency of retrograde pressure waves in phase II in IBS-D was demonstrated. Motility indices and the number of long clusters were also higher in patients compared to controls. To conclude, an abnormal propagation pattern of individual duodenal pressure waves in IBS patients was demonstrated and found to be related to symptom severity in diarrhea-predominant IBS. High-resolution analysis adds information to standard manometry.

Detection of Helicobacter in the liver of patients with chronic cholestatic liver diseases.

Helicobacter species were identified in human liver tissues by PCR. Biopsies were obtained from patients with primary sclerosing cholangitis, primary biliary cirrhosis and noncholestatic liver cirrhosis. One set of Helicobacter genus-specific primers and two different primer sets for Helicobacter pylori were used in the PCR-assays. Using Helicobacter genus-specific primers 80% (8/10) of patients with primary sclerosing cholangitis and 90% (9/10) of patients with primary biliary cirrhosis were positive. Seven of these 17 samples were positive using two different primers for H. pylori and Southern blot hybridization. Among the non-cholestatic liver cirrhosis controls, only one sample was positive in the Helicobacter genus-specific PCR-assay. Significantly higher values of alkaline phosphatases and prothrombin complex was found for the patients positive for Helicobacter genus. In conclusion, gene sequences of Helicobacter species and H. pylori were detected in human liver tissue using PCR and DNA hybridization in patients with a cholestatic liver disease, but rarely in noncholestatic liver cirrhosis.

Postprandial peristalsis in the human duodenum.

MMC-related retroperistalsis is a cyclical phenomenon in the duodenum linked to phase III. The aim of this study was to elucidate the direction of propagation of juxtapyloric duodenal pressure waves in the postprandial state in healthy humans and to compare with the contractions in the interdigestive phase II. Antroduodenal manometry was performed in 11 healthy subjects. Individual pressure waves propagating along a 6-cm duodenal segment were analysed with respect to the proportions of antegrade and retrograde propagation in the four duodenal subsegments (D1-D2) to (D4-D5), each subsegment being 15 mm. A test meal was given 30 min after a phase III had passed and motility recording continued for 60 min after the meal. During both the first and the second 30-min period of postprandial recording the proportion of retrograde pressure waves was larger just distal to the pylorus, (D1-D2), 40% (23-68) and 50% (23-68), respectively, compared to the distal part, (D4-D5), of the duodenal segment, 29% (12-30) and 10% (10-24), respectively (P < 0.05 and 0.01). In contrast, during late phase II of the interdigestive state antegrade pressure waves predominated in all four duodenal subsegments. We conclude that in the postprandial state a high proportion of the duodenal pressure waves (40-50%) is retrograde in the immediate juxtapyloric area while antegrade contractions predominate at a distance 5-6 cm distal to the pylorus. These manometric data together with recent observations of postprandial transpyloric liquid flow, indicate that retrograde duodenogastric propelling of contents may be an important determinant for the gastric emptying rate.

Fulminant hepatic failure associated with dicoumarol therapy.

Coumarins have been associated with non-predictable hepatic injury. In the case of dicoumarol, there is no hard evidence in the literature of a causal connection with liver damage. We report the case of a 73-year-old woman who developed a fatal liver disease of a mixed hepatocellular-cholestatic type after 3 months of treatment with dicoumarol. A thorough diagnostic work-up did not reveal any other possible cause of the liver disease.

Duodenal juxtapyloric retroperistalsis in the interdigestive state in humans.

BACKGROUND: The last part of phase III of the migrating motor complex (MMC) is characterized by retroperistalsis in the descending duodenum. This study focused on MMC-related juxtapyloric peristalsis. METHODS: Antroduodenal manometry was performed in 10 healthy subjects. Pressure was recorded in the distal antrum and in four consecutive subsegments (DS1-DS4), 15 mm each, in the juxtapyloric duodenum. RESULTS: In the period with ongoing antral phase-III activity (early duodenal phase III) the antral pressure waves were antegrade, but in the juxtapyloric duodenum (DS1) retrograde waves predominated (median, 66%; interquartile range (IQR), 33-83%); that is, most duodenal pressure waves were directed against the antral ones. More distally, in DS3 and DS4, only 17% and 25% (IQR, 0-17, 0-33%, respectively) of the pressure waves were retrograde in this period. After the end of antral phase III--that is, in late duodenal phase III--the proportion of retrograde pressure waves increased successively to 91.5% (IQR, 66-100%) in DS2, 74.5% (IQR, 50-100%) in DS3, and 66% (IQR, 8.2-95.8%) in DS4, respectively, before the onset of duodenal motor quiescence. In phase II antegrade pressure waves predominated (63-76%, medians) in all four duodenal subsegments examined. CONCLUSIONS: During the interdigestive phase III the antral perstalsis is antegrade, but most juxtapyloric duodenal pressure waves are retrograde; that is, antral and duodenal contractions are on a collision course. In the proximal part of the descending duodenum the end of duodenal phase III shows retroperistalsis after the onset of phase I in the gastric antrum. These motor patterns may be important for regulation of the chemical milieu in the juxtapyloric area.