PNPLA3 Genotype and Diabetes Identify Patients With Nonalcoholic Fatty Liver Disease at High Risk of Incident Cirrhosis.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) can progress to cirrhosis and hepatic decompensation, but whether genetic variants influence the rate of progression to cirrhosis or are useful in risk stratification among patients with NAFLD is uncertain. METHODS: We included participants from 2 independent cohorts, they Michigan Genomics Initiative (MGI) and UK Biobank (UKBB), who had NAFLD defined by elevated alanine aminotransferase (ALT) levels in the absence of alternative chronic liver disease. The primary predictors were genetic variants and metabolic comorbidities associated with cirrhosis. We conducted time-to-event analyses using Fine-Gray competing risk models. RESULTS: We included 7893 and 46,880 participants from MGI and UKBB, respectively. In univariable analysis, PNPLA3-rs738409-GG genotype, diabetes, obesity, and ALT of ≥2× upper limit of normal were associated with higher incidence rate of cirrhosis in both MGI and UKBB. PNPLA3-rs738409-GG had additive effects with clinical risk factors including diabetes, obesity, and ALT elevations. Among patients with indeterminate fibrosis-4 (FIB4) scores (1.3-2.67), those with diabetes and PNPLA3-rs738409-GG genotype had an incidence rate of cirrhosis comparable to that of patients with high-risk FIB4 scores (>2.67) and 2.9-4.8 times that of patients with diabetes but CC/CG genotypes. In contrast, FIB4 <1.3 was associated with an incidence rate of cirrhosis significantly lower than that of FIB4 of >2.67, even in the presence of clinical risk factors and high-risk PNPLA3 genotype. CONCLUSIONS: PNPLA3-rs738409 genotype and diabetes identified patients with NAFLD currently considered indeterminate risk (FIB4 1.3-2.67) who had a similar risk of cirrhosis as those considered high-risk (FIB4 >2.67). PNPLA3 genotyping may improve prognostication and allow for prioritization of intensive intervention.

An Assessment of Comparative Medication Durability in Inflammatory Bowel Disease Patients With and Without Co-morbid Psoriasis, Rheumatoid Arthritis, and/or Enteropathic Arthritis.

BACKGROUND: Patients with inflammatory bowel disease (IBD) are at increased risk for many co-morbid diseases. However, little is known about durability of IBD medications in patients with co-morbid diseases. AIMS: Determine medication durability in IBD patients with and without psoriasis, rheumatoid arthritis, and/or enteropathic arthropathy. METHODS: All patients with at least three ICD-9 or 10 diagnoses for IBD were included in the cohort. The risk factors of interest were a co-morbid diagnosis of psoriasis (IBD-Ps), rheumatoid arthritis (IBD-RA), and/or enteropathic arthritis (IBD-EA). Medication durability was defined as days of medication use, calculated using order start and stop dates from the electronic medical record. Significant differences were tested using the Wilcoxon rank sum test for continuous variables and Fisher's exact test or Pearson's Chi-squared test, as appropriate, for categorical variables. Boxplots were constructed for graphical interpretation of results. RESULTS: In the psoriasis group, there were 481 patients with 831 medication exposures [131 IBS-Ps (16%), 700 IBD only (84%)]. The median days of medication use were numerically higher in the IBD-Ps group for all therapies [anti-TNF: 1109 vs 861 (p = 0.17); anti-IL-12/23: 984 vs 834 (p = 0.33); JAKi: 682 vs 230 (p = 0.13)], anti-TNF/IM: 370 vs 202 (p = 0.57), except anti-integrin therapy [214 vs 470 (p = 0.08)]. When restricting to UC only, patients with co-morbid again Ps had a significantly shorter duration on anti-integrin therapy (84 vs 456 days, p = 0.02). While not reaching statistical significance, there was a distinctly longer medication duration on JAKi therapy (910 vs 317, p = 0.10). When restricting to patients with CD only, no results reached statistical significance though there was a trend towards longer anti-TNF durability in CD-Ps (1340 vs 1000 days, p = 0.098). There were no differences in medication durability in IBD-RA or IBD-EA patients. DISCUSSION: Larger studies investigating medication durability of JAKi and anti-integrin therapy in IBD patients with psoriasis would be beneficial given noteworthy trends towards increased and decreased durability, respectively.

Safety and Efficacy of Tumor Necrosis Factor Antagonists in Older Patients With Ulcerative Colitis: Patient-Level Pooled Analysis of Data From Randomized Trials.

BACKGROUND & AIMS: Treatment of older patients (more than 60 years) with ulcerative colitis (UC) can be a challenge, because they might be more vulnerable to adverse events (AEs). We determined the effects of age on the safety and efficacy of anti-tumor necrosis factor (TNF) therapy in a pooled analysis of data from randomized trials. METHODS: We obtained individual patient-level data from 4 trials of anti-TNF therapy for patients with UC from the Yale Open Data Access Project. Participants were assigned to groups of older age (60 years or older) and younger age (younger than 60 years). The primary outcome was difference in serious AEs (SAEs), defined as death, life-threatening event, hospitalization, and/or significant disability. Secondary outcomes were severe infections, non-severe infections, neoplasms, and achievement of clinical remission, defined by trial investigators as Mayo score ≤ 2 with no sub-score >1 at the end of induction or maintenance therapy. A random effects logistic regression model was fitted to estimate the effect of anti-TNF therapy on safety and efficacy by age, adjusting for confounders and trial-level effects. RESULTS: The study cohort included 2257 patients (231 60 years or older). Higher proportions of older patients receiving anti-TNF therapy had SAEs (20%) and hospitalizations (14.4%), compared with younger patients (10.2% had SAEs and 5.2% were hospitalized); there were no significant differences between groups in proportions with severe or non-severe infections. Compared with placebo, there was no significant difference in safety risks associated with anti-TNF therapy (SAEs reduced by 5.4% in older patients vs reduction of 2.4% in younger patients; hospitalizations reduced by 6.7% in older patients vs reduction of 2.5% in younger patients; severe infections reduced by 3.1% vs increase of 0.7% in younger patients). There was no significant difference in between older vs younger patients in efficacy of anti-TNF therapy in inducing remission (odds risk ratio, 1.05, 95% CI, 0.33-3.39) or in maintaining remission (odds risk ratio, 0.49; 95% CI, 0.18-1.33). CONCLUSIONS: In a pooled analysis of data from randomized trials, we found that older patients with UC have an increased baseline increased risk of SAEs, but no increase in risk can be attributed to anti-TNF therapy in older vs younger patients.

Tofacitinib for Biologic-Experienced Hospitalized Patients With Acute Severe Ulcerative Colitis: A Retrospective Case-Control Study.

BACKGROUND & AIMS: Despite rescue therapy, more than 30% of patients with acute severe ulcerative colitis (ASUC) require colectomy. Tofacitinib is a rapidly acting Janus kinase inhibitor with proven efficacy in ulcerative colitis. Tofacitinib may provide additional means for preventing colectomy in patients with ASUC. METHODS: A retrospective case-control study was performed evaluating the efficacy of tofacitinib induction in biologic-experienced patients admitted with ASUC requiring intravenous corticosteroids. Tofacitinib patients were matched 1:3 to controls according to gender and date of admission. Using Cox regression adjusted for disease severity, we estimated the 90-day risk of colectomy. Rates of complications and steroid dependence were examined as secondary outcomes. RESULTS: Forty patients who received tofacitinib were matched 1:3 to controls (n = 113). Tofacitinib was protective against colectomy at 90 days compared with matched controls (hazard ratio [HR], 0.28, 95% confidence interval [CI], 0.10-0.81; P = .018). When stratifying according to treatment dose, 10 mg three times daily (HR, 0.11; 95% CI, 0.02-0.56; P = .008) was protective, whereas 10 mg twice daily was not significantly protective (HR, 0.66; 95% CI, 0.21-2.09; P = .5). Rate of complications and steroid dependence were similar between tofacitinib and controls. CONCLUSIONS: Tofacitinib with concomitant intravenous corticosteroids may be an effective induction strategy in biologic-experienced patients hospitalized with ASUC. Prospective trials are needed to identify the safety, optimal dose, frequency, and duration of tofacitinib for ASUC.

Management of Crohn Disease: A Review.

IMPORTANCE: Crohn disease, a chronic gastrointestinal inflammatory disease, is increasing in incidence and prevalence in many parts of the world. Uncontrolled inflammation leads to long-term complications, including fibrotic strictures, enteric fistulae, and intestinal neoplasia. Therefore, early and effective control of inflammation is of critical importance. OBSERVATIONS: The optimal management approach for Crohn disease incorporates patient risk stratification, patient preference, and clinical factors in therapeutic decision-making. First-line therapy generally consists of steroids for rapid palliation of symptoms during initiation of anti-tumor necrosis factor α therapy. Other treatments may include monoclonal antibodies to IL-12/23 or integrin α4ß7, immunomodulators, combination therapies, or surgery. Effective control of inflammation reduces the risk of penetrating complications (such as intra-abdominal abscesses and fistulae), although more than half of patients will develop complications that require surgery. Adverse reactions to therapy include antibody formation and infusion reactions, infections, and cancers associated with immune modulators and biologics and toxicity to the bone marrow and the liver. Both Crohn disease and corticosteroid use are associated with osteoporosis. Vaccinations to prevent infections, such as influenza, pneumonia, and herpes zoster, are important components of health maintenance for patients with Crohn disease, although live vaccines are contraindicated for patients receiving immune suppression therapy. CONCLUSIONS AND RELEVANCE: The treatment of patients with Crohn disease depends on disease severity, patient risk stratification, patient preference, and clinical factors, including age of onset and penetrating complications, and includes treatment with steroids, monoclonal antibody therapies, immunomodulators, and surgery. Physicians should be familiar with the advantages and disadvantages of each therapy to best counsel their patients.

CT-Visualized Colonic Mural Stratification Independently Predicts the Need for Medical or Surgical Rescue Therapy in Hospitalized Ulcerative Colitis Patients.

BACKGROUND: Severe ulcerative colitis is associated with significant morbidity. Multidetector computed tomography (MDCT) scans are frequently obtained upon hospital admission, but the ability of radiographic findings to predict steroid failure is unknown. AIM: To identify MDCT features predictive of inpatient rescue in hospitalized UC. METHODS: Patients hospitalized with UC who underwent a CT scan within 48 h of hospitalization were retrospectively identified. Radiologists blinded to the outcome prospectively evaluated CT scans for the presence of bowel wall thickening, stranding, and hyperenhancement as well as mural stratification, mesenteric hyperemia, and proximal dilation. Logistic regression adjusting for potential confounders was used to test the independent association between radiographic findings and need for rescue therapy. RESULTS: The study cohort included 74 patients. The mean age of the group was 45 years, and two-thirds (66%) were male. Twenty-eight (38%) patients required either inpatient medical rescue or colectomy. The mean number of positive radiographic findings was 4.4 (range 2-6) with a higher median number of findings in those who required rescue therapy (5 vs. 4, p = 0.03). Mural stratification was significantly more common among those who required rescue therapy (92% vs. 49%, p = 0.001). No other radiographic findings were independently associated with inpatient rescue. On multivariable analysis, mural stratification (OR 14.9, 95% CI 2.76-80.2) and number of positive findings (OR 2.10, 95% CI 1.06-4.16) remained independently predictive of the need for rescue therapy. CONCLUSIONS: Mural stratification was highly predictive of steroid refractoriness and need for medical or surgical rescue therapy in hospitalized UC.

Depression Is Associated With More Aggressive Inflammatory Bowel Disease.

OBJECTIVES: Depression is prevalent in inflammatory bowel disease (IBD) patients. The impact of depression on IBD is not well-studied. It is unknown how providers should assess depression. METHODS: We used data from the Sinai-Helmsley Alliance for Research Excellence cohort, to assess methods of diagnosing depression and effects of baseline depression on disease activity at follow-up. A patient health questionnaire (PHQ-8) score ≥5 was consistent with mild depression. Relapse was defined as a modified Harvey-Bradshaw Index ≥5 or Simple Clinical Colitis Activity Index >2. We performed binomial regression to calculate adjusted risk ratios (RRs). RESULTS: We included 2,798 Crohn's disease (CD) patients with 22-month mean follow-up and 1,516 ulcerative colitis (UC) patients with 24-month mean follow-up. A total of 64% of CD patients and 45% of UC patients were in remission at baseline. By self-report, 20% of CD and 14% of UC patients were depressed. By PHQ-8, 38% of CD and 32% of UC patients were depressed (P<0.01). Adjusted for sex, remission, and disease activity, CD patients with baseline depression were at an increased risk for relapse (RR: 2.3; 95% confidence interval (CI): 1.9-2.8), surgery, or hospitalization (RR: 1.3 95% CI: 1.1-1.6) at follow-up. UC patients with baseline depression were also at increased risk for relapse (RR: 1.3; 95% CI: 0.9-1.7), surgery, or hospitalization (RR: 1.3; 95% CI: 1.1-1.5) at follow-up. CONCLUSIONS: Baseline depression is associated with a higher risk for aggressive IBD at follow-up. A single question is not a sensitive method of assessing depression. Providers should consider administering the PHQ-8 to capture those at greater risk for aggressive disease.

Gastrointestinal Bleeding Following LVAD Placement from Top to Bottom.

BACKGROUND: Left ventricular assist devices (LVADs) are an increasingly prevalent form of mechanical support for patients with end-stage heart failure. These devices can be implanted both as a bridge to transplant and as definitive/destination therapy. Gastrointestinal (GI) bleeding is one of the most common and recalcitrant long-term complications following LVAD implantation, with an incidence approaching 30 %. AIMS: This review will discuss what is known about the pathophysiology of GI bleeding in LVADs and the currently available options for medical and/or endoscopic management. RESULTS: The pathophysiology of bleeding is multifactorial, with hemodynamic alterations, acquired von Willebrand factor deficiency, and coagulopathy being most often implicated. The majority of bleeding events in this population result from angioectasias and gastroduodenal erosive disease. While these bleeding events are significant and often require transfusion therapy, they are rarely life threatening. Endoscopy remains the standard of care with upper endoscopy offering the highest diagnostic yield in these patients. However, the effectiveness of endoscopic hemostasis in this population is not well established. A small number of studies have evaluated medical therapy and alterations in LVAD settings as a means of preventing or treating bleeding with variable results. CONCLUSIONS: In summary, GI bleeding with LVADs is a common occurrence and will continue to be as more LVADs are being performed for destination therapy.

Breath Methane Levels Are Increased Among Patients with Diverticulosis.

BACKGROUND: Diverticulosis and its complications are important healthcare problems in the USA and throughout the Western world. While mechanisms as to how diverticulosis occurs have partially been explored, few studies examined the relationship between colonic gases such as methane and diverticulosis in humans. AIM: This study aimed to demonstrate a significant relationship between methanogenic Archaea and development of diverticulosis. METHODS: Subjects who consecutively underwent hydrogen breath test at Rush University Medical Center between 2003 and 2010 were identified retrospectively through a database. Medical records were reviewed for presence of a colonoscopy report. Two hundred and sixty-four subjects were identified who had both a breath methane level measurement and a colonoscopy result. Additional demographic and clinical data were obtained with chart review. RESULTS: Mean breath methane levels were higher in subjects with diverticulosis compared to those without diverticulosis (7.89 vs. 4.94 ppm, p = 0.04). Methane producers (defined as those with baseline fasting breath methane level >5 ppm) were more frequent among subjects with diverticulosis compared to those without diverticulosis (50.9 vs. 34 %, p = 0.0025). When adjusted for confounders, breath methane levels and age were the two independent predictors of diverticulosis on colonoscopy with logistic regression modeling. CONCLUSIONS: Methanogenesis is associated with the presence of diverticulosis. Further studies are needed to confirm our findings and prospectively evaluate a possible etiological role of methanogenesis and methanogenic archaea in diverticulosis.

Comprehensive genetic study of the insulin resistance marker TG:HDL-C in the UK Biobank.

Insulin resistance (IR) is a well-established risk factor for metabolic disease. The ratio of triglycerides to high-density lipoprotein cholesterol (TG:HDL-C) is a surrogate marker of IR. We conducted a genome-wide association study of the TG:HDL-C ratio in 402,398 Europeans within the UK Biobank. We identified 369 independent SNPs, of which 114 had a false discovery rate-adjusted P value < 0.05 in other genome-wide studies of IR making them high-confidence IR-associated loci. Seventy-two of these 114 loci have not been previously associated with IR. These 114 loci cluster into five groups upon phenome-wide analysis and are enriched for candidate genes important in insulin signaling, adipocyte physiology and protein metabolism. We created a polygenic-risk score from the high-confidence IR-associated loci using 51,550 European individuals in the Michigan Genomics Initiative. We identified associations with diabetes, hyperglyceridemia, hypertension, nonalcoholic fatty liver disease and ischemic heart disease. Collectively, this study provides insight into the genes, pathways, tissues and subtypes critical in IR.

Genetic Defects in Early-Onset Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) represents a spectrum of disease, which is characterized by chronic gastrointestinal inflammation. Monogenic mutations driving IBD pathogenesis are more highly represented in early-onset compared to adult-onset disease. The pathogenic genes which dysregulate host immune responses in monogenic IBD affect both the innate (ie, intestinal barrier, phagocytes) and adaptive immune systems (ie, T cells, B cells). Advanced genomic and targeted functional testing can improve clinical decision making and present increased opportunities for precision medicine approaches in this important patient population.

Risk Variants in or Near ZBTB40 AND NFATC1 Increase the Risk of Both IBD and Adverse Bone Health Outcomes Highlighting Common Genetic Underpinnings Across Both Diseases.

BACKGROUND: Inflammatory bowel disease (IBD) is associated with an increased risk of osteoporosis and bone fracture. The aims of this study were to (1) confirm the association between IBD and low bone density and (2) test for shared risk variants across diseases. METHODS: The study cohort included patients from the Michigan Genomics Initiative. Student's t tests (continuous) and chi-square tests (categorical) were used for univariate analyses. Multivariable logistic regression was performed to test the effect of IBD on osteoporosis or osteopenia. Publicly available genome-wide association summary statistics were used to identify variants that alter the risk of IBD and bone density, and Mendelian randomization (MR) was used to identify causal effects of genetically predicted IBD on bone density. RESULTS: There were 51 405 individuals in the Michigan Genomics Initiative cohort including 10 378 (20.2%) cases of osteoporosis or osteopenia and 1404 (2.7%) cases of IBD. Patients with osteoporosis or osteopenia were more likely to be older (64 years of age vs 56 years of age; P < .001), female (67% vs 49%; P < .001), and have a lower body mass index (29 kg/m2 vs 30 kg/m2; P < .001). IBD patients with (odds ratio, 4.60; 95% confidence interval, 3.93-5.37) and without (odds ratio, 1.77; 95% confidence interval, 1.42-2.21) steroid use had a significantly higher risk of osteoporosis or osteopenia. Twenty-one IBD variants associated with reduced bone mineral density at P ≤ .05 and 3 IBD risk variants associated with reduced bone mineral density at P ≤ 5 × 10-8. Of the 3 genome-wide significant variants, 2 increased risk of IBD (rs12568930-T: MIR4418;ZBTB40; rs7236492-C: NFATC1). MR did not reveal a causal effect of genetically predicted IBD on bone density (MR Egger, P = .30; inverse variance weighted, P = .63). CONCLUSIONS: Patients with IBD are at increased risk for low bone density, independent of steroid use. Variants in or near ZBTB40 and NFATC1 are associated with an increased risk of IBD and low bone density.

Patients with inflammatory bowel disease (IBD) are at an increased risk of osteopenia, osteoporosis, and bone fracture. Herein, we identify risk variants in or near ZBTB40 and NFATC1 which associate with risk of both IBD and low bone density. Therefore, a subset of patients with IBD may be at risk for osteopenia and osteoporosis regardless of steroid use.

A founder mutation in LEPRE1 carried by 1.5% of West Africans and 0.4% of African Americans causes lethal recessive osteogenesis imperfecta.

PURPOSE: Deficiency of prolyl 3-hydroxylase 1, encoded by LEPRE1, causes recessive osteogenesis imperfecta (OI). We previously identified a LEPRE1 mutation exclusively in African Americans and contemporary West Africans. We hypothesized that this allele originated in West Africa and was introduced to the Americas with the Atlantic slave trade. We aimed to determine the frequency of carriers for this mutation among African Americans and West Africans, and the mutation origin and age. METHODS: Genomic DNA was screened for the mutation using PCR and restriction digestion, and a custom TaqMan genomic single-nucleotide polymorphism assay. The mutation age was estimated using microsatellites and short tandem repeats spanning 4.2 Mb surrounding LEPRE1 in probands and carriers. RESULTS: Approximately 0.4% (95% confidence interval: 0.22-0.68%) of Mid-Atlantic African Americans carry this mutation, estimating recessive OI in 1/260,000 births in this population. In Nigeria and Ghana, 1.48% (95% confidence interval: 0.95-2.30%) of unrelated individuals are heterozygous carriers, predicting that 1/18,260 births will be affected with recessive OI, equal to the incidence of de novo dominant OI. The mutation was not detected in Africans from surrounding countries. All carriers shared a haplotype of 63-770 Kb, consistent with a single founder for this mutation. Using linkage disequilibrium analysis, the mutation was estimated to have originated between 650 and 900 years before present (1100-1350 CE). CONCLUSION: We identified a West African founder mutation for recessive OI in LEPRE1. Nearly 1.5% of Ghanians and Nigerians are carriers. The estimated age of this allele is consistent with introduction to North America via the Atlantic slave trade (1501-1867 CE).

Efficacy of Ustekinumab in Crohn's Disease With and Without Concurrent Autoimmune Skin Disease.

BACKGROUND: Approximately 33% of Crohn's disease (CD) patients have associated autoimmune skin disease. The pathophysiology of the latter frequently involves interleukin-12/interleukin-23 signaling pathways that may also impact gut inflammation. Ustekinumab is an anti-IL-12/23 FDA-approved biologic for psoriasis and inflammatory bowel disease. However, its relative efficacy has never been studied in CD with autoimmune skin disease (CD-ASD) vs CD without autoimmune skin disease (CD-none). METHODS: This is a retrospective, single-center, case-control study comparing markers of disease activity between CD-ASD and CD-none. Biomarkers (fecal calprotectin [FCP], C-reactive protein [CRP]) prior to drug initiation and after at least 5 months of standard IBD dose ustekinumab therapy were extracted from the medical record. In addition, 2 blinded observers performed 5-point Likert scoring before and after endoscopic, pathologic, and imaging reports. RESULTS: In all, 395 CD patients received ustekinumab therapy (79 CD-ASD, 316 CD-none). Patients were similar in age; gender; ethnicity; CD severity, phenotype, and duration; tobacco, immunomodulator, and steroid use. Ustekinumab had greater efficacy in CD-ASD when evaluated by FCP (P = .0337) and CRP (P = .078). The CD-ASD group also showed better outcomes in Likert scores of endoscopy (P = .016), histopathology (P = .074), and imaging (P = .094). In all Likert parameters, CD-ASD had more patients with complete resolution of moderate/severe disease (P < .05). Additional subanalyses for surgeries, ulcers, abscesses, fistulas, and colitis were conducted, with colitis reaching statistical significance (P = .0011). CONCLUSIONS: Concurrent autoimmune skin disease in CD is associated with greater ustekinumab effectiveness in controlling intestinal inflammation.

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.