Hepatocellular carcinoma (HCC) is changing its face: analysis of the temporal trends in aetiology and clinical patterns of HCC in South Australia.

BACKGROUND: The epidemiology of chronic liver disease is changing with the introduction of potent antiviral therapies for chronic hepatitis C virus (HCV) and the increasing prevalence of non-alcoholic steatohepatitis (NASH). AIM: To establish the impact of this change on the rates and clinical patterns of hepatocellular carcinoma (HCC) in South Australia (SA). METHODS: Newly diagnosed HCC patients from January 2014 until December 2019 from four tertiary centres in SA were included. The overall age-standardised incidence rates (ASIR) of HCC were calculated using 2016 SA population as the standard. To assess the trends, Join-Point regression models were used to calculate the average annual percentage change (AAPC). Forecasting of overall and aetiology-specific HCC from 2020 to 2024 was performed using linear regression. RESULTS: There were 626 new cases of HCC in SA (males 80%; median age 64 years) during the study period. There was a significant increase in NASH-related HCC (AAPC: +7.0%; P < 0.05) from 2014 to 2019. However, there were no significant differences in the ASIR for overall HCC (AAPC: -4.1%), HCV-related HCC (AAPC: -8.0%) and stage of HCC diagnosis (AAPC: +3.0%; P > 0.05). Forecasting analysis projected the decline and increase in the incidence of HCV and NASH-related HCC, respectively, over the next few years. CONCLUSION: Overall ASIR of HCC has plateaued in SA. However, NASH-related HCC has increased significantly and is expected to continue to increase in the near future. Further research and intervention is required to reduce NASH-related HCC, a major contributor to the current and future burden of HCC.

Biliary transporter gene mutations in severe intrahepatic cholestasis of pregnancy: Diagnostic and management implications.

BACKGROUND AND AIMS: Clinical syndromes associated with biallelic mutations of bile acid (BA) transporters usually present in childhood. Subtle mutations may underlie intrahepatic cholestasis of pregnancy (ICP) and oral contraceptive steroid (OCS) induced cholestasis. In five women with identified genetic mutations of such transporters, with eight observed pregnancies complicated by ICP, we examined relationships between transporter mutations, clinical phenotypes, and treatment outcomes. METHODS: Gene mutation analysis for BA transporter deficiencies was performed using Next Generation/Sanger sequencing, with analysis for gene deletions/duplications. RESULTS: Intrahepatic cholestasis of pregnancy was early-onset (9-32 weeks gestation) and severe (peak BA 74-370 µmol/L), with premature delivery (28+1 -370 weeks gestation) in 7/8 pregnancies, in utero passage of meconium in 4/8, but overall good perinatal outcomes, with no stillbirths. There was generally no response to ursodeoxycholic acid and variable responses to rifampicin and chelation therapies; naso-biliary drainage appeared effective in 2/2 episodes persisting post-partum in each of the two sisters. Episodic jaundice occurring spontaneously or provoked by non-specific infections, and OCS-induced cholestasis, had previously occurred in 3/5 women. Two cases showed biallelic heterozygosity for several ABCB11 mutations, one was homozygous for an ABCB4 mutation and a fourth case was heterozygous for another ABCB4 mutation. CONCLUSIONS: Early-onset or recurrent ICP, especially with previous spontaneous or OCS-induced episodes of cholestasis and/or familial cholestasis, may be attributable to transporter mutations, including biallelic mutations of one or more transporters. Response to standard therapies for ICP is often incomplete; BA sequestering therapy or naso-biliary drainage may be effective. Optimized management can produce good outcomes despite premature birth and evidence of fetal compromise.

Wide variation in pre-procedural blood product transfusion practices in cirrhosis: a national multidisciplinary survey.

BACKGROUND AND AIMS: Recent guidelines recognize the limitations of standard coagulation tests in predicting bleeding and guiding pre-procedural blood component prophylaxis in cirrhosis. It is unclear whether these recommendations are reflected in clinical practice. We performed a nationwide survey to investigate pre-procedural transfusion practices and opinions of key health care stakeholders involved in managing cirrhosis. METHODS: We designed a 36-item multiple-choice questionnaire to investigate the international normalized ratio and platelet cutoffs utilized to guide pre-procedural transfusion of fresh frozen plasma and platelets in patients with cirrhosis undergoing a range of low and high-risk invasive procedures. Eighty medical colleagues from all mainland States involved in managing patients with cirrhosis were invited by email to participate. RESULTS: Overall, 48 specialists across Australia completed the questionnaire: 21 gastroenterologists, 22 radiologists, and 5 hepatobiliary surgeons. 50% of respondents reported that their main workplace did not have written guidelines relating to pre-procedural blood component prophylaxis in patients with cirrhosis. There was marked variation in routine prophylactic transfusion practices across institutions for the different procedures and international normalized ratio and platelet cutoffs. This variation was present both within and between specialty groups and held for both low and high-risk procedures. For scenarios where the platelet count was ≤ 50 × 109/L, 61% of respondents stated that prophylactic platelet transfusions would be given before low-risk and 62% before high-risk procedures at their center. For scenarios where the international normalized ratio was ≥2, 46% of respondents stated that prophylactic fresh frozen plasma would be routinely given before low-risk procedures and 74% before high-risk procedures. CONCLUSION: Our survey reveals significant heterogeneity of pre-procedural prophylactic transfusion practices in patients with cirrhosis and discrepancies between guidelines and clinical practice.

High rates of treatment stage migration for early hepatocellular carcinoma and association with adverse outcomes: An Australian multicenter study.

Background and Aim: The rate of contraindications to percutaneous ablation (PA) for inoperable early hepatocellular carcinoma (HCC) and subsequent outcomes is not well described. We investigated the prevalence and outcomes of inoperable early HCC patients with contraindications to PA, resulting in treatment stage migration (TSM). Methods: Barcelona Clinic Liver Cancer (BCLC) 0/A patients diagnosed between September 2013 and September 2019 across five hospitals were identified. Primary endpoint was proportion of BCLC 0/A HCCs with contraindications to PA. Secondary endpoints included overall survival (OS), local tumor control (LTC), and recurrence-free survival (RFS). The causal effects of PA versus TSM were assessed using a potential outcome means (POM) framework in which the average treatment effects (ATEs) of PA were estimated after accounting for potential selection bias and confounding. Results: Two hundred twenty patients with inoperable BCLC 0/A HCC were identified. One hundred twenty-two patients (55.5%) had contraindications to PA and received TSM therapy, 98 patients (44.5%) received PA. The main contraindication to PA was difficult tumor location (51%). Patients who received TSM therapy had lower median OS (2.4 vs 5.3 years), LTC (1.0 vs 4.8 years), and RFS (0.8 vs 2.9 years); P < 0.001, respectively, compared with PA. The ATE for PA versus TSM yielded an additional 1.11 years (P = 0.019), 2.45 years (P < 0.001), and 1.64 years (P < 0.001) for OS, LTC, and RFS, respectively. Three-year LTC after PA was suboptimal (65%). Conclusion: Our study highlights high rates of contraindication to PA in early HCCs, resulting in TSM and poorer outcomes. The LTC rate for PA appears suboptimal despite being considered as curative therapy. Both findings support the exploration of improved treatment options for early HCCs.

High prevalence of late relapse and reinfection in prisoners treated for chronic hepatitis C.

BACKGROUND AND AIM: Prisoners have a high prevalence of injection drug use (IDU) and chronic hepatitis C (CHC) infection. Treatment of CHC in these patients is effective; however, their long-term outcomes following treatment are unknown. We determined the durability of a sustained virological response (SVR) in prisoners treated for CHC. METHODS: Patients were treated as part of routine clinical practice with interferon (IFN) and ribavirin. A retrospective review of medical records and a computerized pathology system was performed for clinical and laboratory information. RESULTS: Seventy-four prisoners (70 males, mean age 34 years, IDU in 55%) were evaluable for a SVR over a 12-year period to December 2008; the mean follow-up period was 1243 days. Genotype 1, 2, 3, and 6 infection was present in 18, three, 38 and three patients, respectively; the genotype was unknown in 12. Three out of 52 biopsied had cirrhosis. Standard IFN was administered to 25 (34%; 11 with ribavirin), and 49 received pegylated IFN and ribavirin; one did not complete treatment, and two had breakthrough relapses. The end-of-treatment response was achieved in 57 and SVR in 53; 14 were non-responders. Five male patients, four with unknown genotypes and treated with standard IFN alone, relapsed late (following SVR, 9%). Five patients, all treated with pegylated IFN and ribavirin, were reinfected (one prior to and four following SVR). CONCLUSIONS: Prisoners are often successfully treated for CHC. However, this retrospective study indicates that there is a high (17%) prevalence of late recurrence of viremia that is likely a reflection of reinfection due to ongoing risk-taking behavior.

Benefits of breath hydrogen testing after lactulose administration in analysing carbohydrate malabsorption.

BACKGROUND AND AIMS: Breath hydrogen testing after lactulose administration may yield findings of clinical value, but whether it should be a routine part of breath testing has not been evaluated. We examined the contribution of breath testing after lactulose administration to the conduct and interpretation of breath hydrogen responses after fructose and lactose administration. METHODS: Two hundred consecutive patients were given lactulose, fructose or lactose on separate days (at least 2 days apart); breath hydrogen was monitored every 15 min after the administration of each sugar. RESULTS: Peak breath hydrogen levels after lactulose administration correlated with those after fructose (r = 0.26; P = 0.03) and lactose (r = 0.44; P = 0.004). Of the patients with a reduced response to lactulose, 51% had definite or borderline evidence of fructose malabsorption (FM); similarly, 23% of patients had definite or borderline lactose malabsorption. After lactulose administration, an increase in breath hydrogen levels occurred after the same amount of time or longer than after the administration of fructose or lactose (>120 min). The earlier the first rise in breath hydrogen levels after lactulose administration, the more frequently FM occurred, indicating an association between FM and rapid transit and/or small intestinal bacterial overgrowth. CONCLUSION: Routine breath hydrogen testing with lactulose administration before other sugars cannot be used to define non-hydrogen producers, but might, by indicating the vigour of hydrogen production in the individual, allow more rational interpretation of results after testing with other sugars. It permits the duration of testing to be judged and provides information on possible mechanisms of FM.