PNPLA3 risk allele is associated with risk of hepatocellular carcinoma but not decompensation in compensated cirrhosis.

BACKGROUND: The PNPLA3-rs738409-G, TM6SF2-rs58542926-T, and HSD17B13-rs6834314-A polymorphisms have been associated with cirrhosis, hepatic decompensation, and HCC. However, whether they remain associated with HCC and decompensation in people who already have cirrhosis remains unclear, which limits the clinical utility of genetics in risk stratification as HCC is uncommon in the absence of cirrhosis. We aimed to characterize the effects of PNPLA3, TM6SF2, and HSD17B13 genotype on hepatic decompensation, HCC, and liver-related mortality or liver transplant in patients with baseline compensated cirrhosis. METHODS: We conducted a single-center retrospective study of patients in the Michigan Genomics Initiative who underwent genotyping. The primary predictors were PNPLA3, TM6SF2, and HSD17B13 genotypes. Primary outcomes were either hepatic decompensation, HCC, or liver-related mortality/transplant. We conducted competing risk Fine-Gray analyses on our cohort. RESULTS: We identified 732 patients with baseline compensated cirrhosis. During follow-up, 50% of patients developed decompensation, 13% developed HCC, 24% underwent liver transplant, and 27% died. PNPLA3-rs738409-G genotype was associated with risk of incident HCC: adjusted subhazard hazard ratio 2.42 (1.40-4.17), p=0.0015 for PNPLA3-rs738409-GG vs. PNPLA3-rs738409-CC genotype. The 5-year cumulative incidence of HCC was higher in PNPLA3-rs738409-GG carriers than PNPLA3-rs738409-CC/-CG carriers: 15.6% (9.0%-24.0%) vs. 7.4% (5.2%-10.0%), p<0.001. PNPLA3 genotype was not associated with decompensation or the combined outcome of liver-related mortality or liver transplant. TM6SF2 and HSD17B13 genotypes were not associated with decompensation or HCC. CONCLUSIONS: The PNPLA3-rs738409-G allele is associated with an increased risk of HCC among patients with baseline compensated cirrhosis. People with cirrhosis and PNPLA3-rs738409-GG genotype may warrant more intensive HCC surveillance.

Clinical Outcomes of Patients With Suspicious (LI-RADS 4) Liver Observations.

Hepatocellular cancer (HCC) surveillance is associated with increased curative treatment and improved survival, underscoring its importance in patients with cirrhosis.1 Surveillance is 1 step in a larger HCC screening continuum, and those with abnormal screening results must undergo diagnostic evaluation with multiphase computed tomography (CT) or magnetic resonance imaging (MRI).2 The Liver Imaging Reporting and Data System (LI-RADS) classifies liver observations in at-risk patients based on risk of malignancy and HCC, with LR-5 observations having a positive predictive value exceeding 95% for HCC. However, indeterminate liver nodules (ie, LR-3 or LR-4) are commonly observed in clinical practice, associated with heterogenous HCC risk, and have large variations in practice management.3,4 We previously reported the natural history of LR-3 observations in a multicenter cohort of patients with cirrhosis, demonstrating a high annual incidence for HCC development of 8.4 cases per 100 person-years;5 however, the natural history of LR-4 observations remains uncertain. Herein, we aimed to characterize clinical outcomes in patients with LR-4 observations in a multicenter cohort.

Risk of Hepatocellular Carcinoma in Patients With Indeterminate (LI-RADS 3) Liver Observations.

Early hepatocellular cancer (HCC) detection is associated with curative treatment and improved survival.1 The American Association for the Study of Liver Diseases recommends semiannual ultrasound and α-fetoprotein (AFP) in patients with cirrhosis, and those with abnormal results should undergo diagnostic multiphase computed tomography (CT) or magnetic resonance imaging (MRI).2 The Liver Imaging Reporting and Data System (LI-RADS) was devised to standardize reporting of liver observations in at-risk individuals, ranging from LR-1 ("definitely benign") to LR-5 ("definitely HCC''), with indeterminate observations classified as LR-3 ("intermediate probability of malignancy").3 A study among 999 cirrhosis patients found that indeterminate liver observations are common, being reported on diagnostic CT or MRI in 98 (38.3%) of 256 patients with abnormal ultrasound results.4 Prior studies have reported a wide range in HCC risk, from 4% to 31%, for LR-3 observations, so there is insufficient evidence to recommend a standardized strategy for monitoring LR-3 observations.5,6.

Hepatic decompensation is accelerated in patients with cirrhosis and alpha-1 antitrypsin Pi∗MZ genotype.

Background & Aims: Alpha-1 antitrypsin deficiency is caused by mutations in SERPINA1, most commonly homozygosity for the Pi∗Z variant, and can present as liver disease. While heterozygosity for Pi∗Z (Pi∗MZ) is linked to increased risk of cirrhosis, whether the Pi∗MZ genotype is associated with an increased rate of decompensation among patients who already have compensated cirrhosis is not known. Methods: This was a retrospective study of Michigan Genomics Initiative participants with baseline compensated cirrhosis. The primary predictors were Pi∗MZ or Pi∗MS genotype (vs. Pi∗MM). The primary outcomes were hepatic decompensation with ascites, hepatic encephalopathy, or variceal bleeding, or the combined endpoint of liver-related death or liver transplant, both modeled with Fine-Gray competing risk models. Results: We included 576 patients with baseline compensated cirrhosis who had undergone genotyping, of whom 474 had Pi∗MM, 49 had Pi∗MZ, and 52 had Pi∗MS genotypes. Compared to Pi∗MM genotype, Pi∗MZ was associated with increased rates of hepatic decompensation (hazard ratio 1.81; 95% CI 1.22-2.69; p = 0.003) and liver transplant or liver-related death (hazard ratio 2.07; 95% CI 1.21-3.52; p = 0.078). These associations remained significant after adjustment for severity of underlying liver disease, and were robust across subgroup analyses based on etiology, sex, obesity, and diabetes status. Pi∗MS was not associated with decompensation or death/transplantation. Conclusions: The SERPINA1 Pi∗MZ genotype is associated with an increased rate of hepatic decompensation and decreased transplant-free survival among patients with baseline compensated cirrhosis. Lay summary: There is a mutation in the gene SERPINA1 called Pi∗MZ which increases risk of liver scarring (cirrhosis); however, it is not known what effect Pi∗MZ has if someone already has cirrhosis. In this study, we found that people who had cirrhosis and Pi∗MZ developed complications from cirrhosis faster than those who did not have the mutation.

Accuracy of Non-invasive Indices for Diagnosing Hepatic Steatosis Compared to Imaging in a Real-World Cohort.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease is common and under-diagnosed. This study evaluated the accuracy of several previously reported indices, including hepatic steatosis index, alanine aminotransferase (ALT) method, Framingham steatosis index, and Dallas steatosis index, to diagnose hepatic steatosis in a real-world cohort. METHODS: This study included 701 randomly selected adult patients seen in our integrated healthcare system between 2015 and 2020 with appropriate abdominal imaging and routine outpatient laboratory studies. Information on demographics, comorbidities and existing liver disease, anthropometrics, laboratory studies, and abdominal imaging was collected. The sensitivity, specificity, and C-statistic of each method in detecting hepatic steatosis based on abdominal imaging were determined. RESULTS: 202/701 patients (28.8%) had hepatic steatosis on abdominal imaging. These patients were more likely to have metabolic syndrome components and higher body mass index. All indices performed similarly with moderate accuracy in detecting hepatic steatosis based on the C-statistic (95% confidence interval): Hepatic steatosis index 0.76 (0.72-0.79), Framingham steatosis index 0.78 (0.74-0.82), and Dallas steatosis index 0.80 (0.76-0.83). ALT method had sensitivity 44.7% (36.9-52.7%) and specificity 88.6% (85.0-91.7%). Several sensitivity analyses were performed, which did not significantly alter the performance of any index. CONCLUSION: The findings support both the clinical utility of these indices in diagnosing hepatic steatosis in the absence of imaging in real-world settings and the research utility of these indices in generating reliable electronic medical record-based nonalcoholic fatty liver disease cohorts.

Accuracy of International Classification of Diseases-10 Codes for Cirrhosis and Portal Hypertensive Complications.

BACKGROUND AND AIMS: International Classification of Diseases (ICD)-10 codes may correspond to cirrhosis diagnosis. However, these codes have not been as well studied as ICD-9 codes. We aimed to evaluate the positive predictive value (PPV) and specificity of ICD-10 codes for cirrhosis. METHODS: We conducted a single-center retrospective study of patients in Michigan Medicine (Ann Arbor, MI, USA). We evaluated patients with at least one of 28 ICD-10 codes for cirrhosis and randomly selected controls for the presence of cirrhosis and/or portal hypertensive complications. RESULTS: Among 1317 patients with at least one ICD-10 code consistent with cirrhosis and/or portal hypertension, 796 had confirmed cirrhosis. After excluding ICD-10 codes found in < 10 patients, we evaluated the PPV of the 19 remaining codes. Of these, 15 had a high PPV for cirrhosis (> 80%), including codes for cirrhosis itself, gastroesophageal varices, hepatic encephalopathy, and other portal hypertensive complications. Specificity of ICD codes for cirrhosis for these 15 codes was high (> 94% for all). PPV and specificity were high across liver disease etiologies. Among patients without portal hypertension, PPVs of ICD-10 codes for cirrhosis were lower but still > 80% for the most common codes. PPVs of most codes for portal hypertensive complications were > 70%. Defining cirrhosis based on the presence of any of the 15 codes resulted in a PPV of 86% and by two different codes, a PPV 94%. CONCLUSIONS: ICD-10 codes for cirrhosis can accurately identify patients with cirrhosis with or without portal hypertensive complications.