Underlying steatohepatitis, but not simple hepatic steatosis, increases morbidity after liver resection: A case-control study

Authors


  • Potential conflict of interest: Nothing to report.

  • Abbreviations: AASLD, American Association for the Study of Liver Diseases; ALB, albumin; ASA, American Society of Anesthesiologists; BMI, body mass index; CI, 95% confidence interval; CLD, chronic liver disease; CRCLM, colorectal cancer liver metastases; DM, diabetes mellitus; EBL, estimated blood loss; FLD, fatty liver disease; HCC, hepatocellular carcinoma; HPF, high power field; MetS, metabolic syndrome; NAFLD, nonalcoholic fatty liver disease; NAS, NAFLD activity score; OR, odds ratio; PHI, postoperative hepatic insufficiency; RBC, red blood cell; SH, steatohepatitis; TBIL, total bilirubin.

Abstract

Despite the high prevalence of fatty liver disease, the safety of liver resection in settings of steatohepatitis (SH) or hepatic steatosis is poorly understood. The aim of this study was to determine whether underlying SH or simple hepatic steatosis increases morbidity after liver resection. We compared patients undergoing liver resection with underlying SH or greater than 33% simple hepatic steatosis to controls selected for similar demographics, diagnoses, comorbidities, preoperative chemotherapy treatments, and extent of partial hepatectomy. Primary endpoints included postoperative overall and hepatic-related morbidity. One hundred and two patients with SH and 72 with greater than 33% simple hepatic steatosis who underwent liver resection from 2000 to 2011 were compared to corresponding controls. There were no differences in extent or approach of liver resection, malignant indications, preoperative chemotherapy treatment, elements of metabolic syndrome, alcohol use history, American Society of Anesthesiologists score, age, or gender between patients with SH or simple steatosis and corresponding controls. Ninety-day postoperative overall morbidity (56.9% versus 37.3%; P = 0.008), any hepatic-related morbidity (28.4% versus 15.7%; P = 0.043), surgical hepatic complications (19.6% versus 8.8%; P = 0.046), and hepatic decompensation (16.7% versus 6.9%; P = 0.049) were greater among SH patients, compared to corresponding controls. In contrast, there were no differences in postoperative overall morbidity (34.7% versus 44.4%; P = 0.310), any hepatic-related morbidity (19.4% versus 19.4%; P = 1.000), surgical hepatic complications (13.9% versus 9.7%; P = 0.606), or hepatic decompensation (8.3% versus 9.7%; P = 0.778) between simple hepatic steatosis patients and corresponding controls. Using multivariable logistic regression, SH was independently associated with postoperative overall (odds ratio [OR], 2.316; 95% confidence interval [95% CI]: 1.267-4.241; P = 0.007) and any hepatic-related (OR, 2.722; 95% CI: 1.201-6.168; P = 0.016) morbidity. Conclusion: Underlying SH, but not simple hepatic steatosis, increases overall and hepatic-related morbidity after liver resection. (HEPATOLOGY 2012)

Because of the high prevalence of fatty liver disease (FLD), many patients considered for hepatic resection will have underlying hepatic steatosis or steatohepatitis (SH). Nonalcoholic FLD (NAFLD) is currently the most common chronic liver disease (CLD) in the United States, and nonalcoholic SH (NASH) affects 1%-12% of the population, based on cohort studies.1-4 This rise parallels similar increases in obesity, dyslipidemia, type II diabetes mellitus (DM), and metabolic syndrome (MetS).1 Although hepatocellular carcinoma (HCC) arises less frequently in patients with NASH, compared to other liver diseases (e.g., hepatitis C viral infection), the overall higher prevalence and more rapidly increasing incidence of NASH, relative to other CLDs, mean that the majority of HCCs will arise in the setting of NAFLD in the near future.5-10 Moreover, many of these cases occur without significant fibrosis in the underlying liver and are instead the result of the direct carcinogenic effects of NASH.11, 12 Thus, a substantial portion of HCC amenable to surgical resection will arise in the setting of SH.

Several established risk factors for SH exist. In addition to elements of MetS, extensive alcohol use and chemotherapy treatment may lead to SH. Chemotherapy, particularly irinotecan for colorectal cancer liver metastases (CRCLM), induces steatosis and SH in the non-tumor-bearing liver.13-19 As results of phase III studies showing survival benefits and secondary resectablity of initially unresectable disease from perioperative chemotherapy for CRCLM become widely applied,13, 20-23 rates of underlying hepatic steatosis and SH among those undergoing resection of CRCLM will increase.

The safety of liver resection in the setting of FLD is poorly understood. Several studies, reviews, and meta-analyses have examined the role of FLD on postoperative outcomes after liver resection.18, 24-32 However, results of these studies are difficult to interpret because of (1) inclusion of patients with advanced fibrosis and other underlying liver pathologies along with FLD, (2) inclusion of patients who underwent concomitant major extrahepatic procedures at the time of liver resection, (3) different and arbitrarily defined standards for the presence of and severity of steatosis, and (4) failure to differentiate between steatosis and SH.33 Importantly, no previous report has distinguished between possible etiologies of FLD or ascertained whether poor postoperative outcomes were the result of the histopathologic changes in the underlying liver or other side effects from the factors (e.g., chemotherapy treatment, MetS, and so on) predisposing to liver injury. The aim of this report is to determine whether SH or greater than 33% simple steatosis in the underlying liver increases morbidity after liver resection.

Patients and Methods

Inclusion Criteria, Definitions, and Underlying Liver Histopathology.

After obtaining institutional board review approval, demographics, comorbid conditions, clinicopathologic data, surgical treatments, and postoperative outcomes for patients who underwent liver resection at the University of Pittsburgh Liver Cancer Center (Pittsburgh, PA) from 2000 to 2011 were reviewed. Patients with a diagnosis of SH or simple steatosis greater than 33% in the underlying liver on examination of the resection specimen by an experienced hepatobiliary pathologist were included in this study. These patients were identified from a previously established hepatobiliary database. Exclusion criteria were (1) bridging fibrosis or cirrhosis in the non-tumor-bearing liver, (2) presence of other chronic diseases of the underlying liver, such as hepatitis B or C viral infection, primary sclerosing cholangitis, and so on, (3) concomitant major extrahepatic procedures, including bile duct resection with subsequent biliary-enteric anastomosis, colorectal resection, and so on, and (4) preoperative cholestasis defined as total bilirubin (TBIL) greater than 1.5 mg/dL or history of biliary stent placement. Steatosis grade, lobular inflammation, hepatocyte ballooning, and extent of fibrosis are reported as described by Kleiner et al.34 Instead of the precise number of foci per high power field (HPF), lobular inflammation was reported as “none,” “rare/spotty,” “mild,” or “moderate/heavy.” Each of these terms were then coded in increasing severity from 0 to 3 in calculating the NAFLD activity score (NAS).34 Pathologist determination of NASH was reported independently of NAS. Grades of SH, as defined by consensus guidelines,35 were not differentiated in this study. The underlying liver pathology reported in this study was identified on postoperative examination of each resection specimen by the hepatobiliary pathologist—suspicions of FLD on preoperative imaging or on intraoperative examination were not recorded thus and not used to assign underlying liver pathology.

Per American Association for Study of Liver Diseases (AASLD) consensus statements, the alcohol consumption threshold to distinguish nonalcoholic from alcoholic SH included less than 21 drinks per week for men and less than 14 drinks per week for women at the height of maximal intake before liver resection.35 Extent of alcohol use was determined from retrospective chart review. Criteria for MetS were extrapolated from international guidelines36, 37 and included any three of the following: body mass index (BMI) greater than 28.8 kg/m2 (validated as a replacement for elevated waist circumference in men and women)8 and documentation of, or medical treatment for, dyslipidemia, hypercholesterolemia, hypertension, and/or DM. Liver resections were defined according to Brisbane's terminology.38 Minimally invasive liver resection included pure laparoscopic, hand-assisted laparoscopic, robotically assisted laparoscopic, and hybrid laparoscopic/open liver resections.

Control Selection Criteria and Endpoints.

Patients with SH or simple hepatic steatosis were individually matched to control patients based on extent of liver resection and resection approach. Control patients were identified from an established hepatobiliary database and had no underlying liver pathology—including any degree of hepatic steatosis. Controls were then further selected for each individual SH or simple hepatic steatosis patient based on the following criteria in descending priority: malignant versus benign indication for liver resection, treatment with preoperative chemotherapy, preoperative alcohol use predisposing to alcoholic SH, diagnosis of MetS and individual elements of MetS (e.g., BMI within 3.0 kg/m2), American Society of Anesthesiologists (ASA) score (within 1), age at liver resection (within 5 years), specific indication for liver resection, and gender. Using these selection criteria, 1 control patient was paired with only 1 SH or simple hepatic steatosis patient. Patients with SH or simple steatosis were compared to corresponding controls. Endpoints included postoperative mortality and morbidity within 90 days after liver resection, intraoperative blood loss, and red blood cell (RBC) transfusion within 30 days after liver resection. Postoperative complications were further classified into severe morbidity (defined as Dindo-Clavien39 grade III or IV complications) and any hepatic-related morbidity. The latter included the following: postoperative hepatic insufficiency (PHI), defined as peak postoperative TBIL greater than 7 mg/dL40; right-sided pleural effusion requiring thoracentesis; ascites requiring diuretic treatment and/or prolonged intraoperative drainage; intra-abdominal abscess requiring percutaneous drainage; hepatic encephalopathy; bile leak requiring prolonged intraoperative drainage, percutaneous drainage, and/or endoscopic retrograde cholangiography with sphincterotomy and stent placement; and bleeding requiring packing and/or reoperative intervention. We further distinguished surgical hepatic complications from hepatic decompensation, defined to include PHI, ascites, and/or hepatic encephalopathy. Surgical hepatic complications included the following: right-sided pleural effusion requiring thoracentesis; intra-abdominal abscess requiring percutaneous drainage; bile leak requiring prolonged intraoperative drainage, percutaneous drainage, and/or endoscopic retrograde cholangiography with sphincterotomy and stent placement; and bleeding requiring packing and/or reoperative intervention. Thus, three types of liver complications were reported: any hepatic-related morbidity; surgical hepatic complications; and postoperative hepatic decompensation.

Statistical Analyses.

MedCalc software (version 12.1.4.0) was used to perform statistical analyses. Normality of continuous variables was examined, and all between-group differences of non-normally distributed continuous variables were tested using nonparametric statistics. Baseline characteristics of the sample were characterized by numbers and corresponding percentages for categorical variables and median and interquartile range (25th-75th percentiles) for continuous variables. Between-group univariable analyses were performed using chi-square tests, Fisher's exact test, and Mann-Whitney's U tests. All tests were two-tailed, with a significant P value defined as less than 0.05. Multivariable logistic regression analyses were performed to test potential predictors of overall and hepatic-related morbidity after liver resection. Between-group differences in demographics, comorbid conditions, diagnoses, medical or surgical treatments, or underlying liver pathology that resulted in a P value less than or equal to 0.05 on univariable analyses were included in the logistic regression models. Overall models as well as independent predictors of outcome were characterized using a P value of less than 0.05. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were reported.

Results

From 2000 to 2011, 2,347 patients underwent liver resection at the University of Pittsburgh Liver Cancer Center. One hundred and two patients with SH and 72 patients with simple hepatic steatosis met study inclusion criteria. Thirty-four of one hundred and two (33.3%) of SH patients did not have MetS, a history of alcohol abuse, and were not treated with chemotherapy before liver resection. However, most of these patients did have at least one element of MetS, including diabetes (4 of 34; 11.8%), hypertension (15 of 34; 44.1%), dyslipidemia (8 of 34; 23.5%), and BMI greater than 28.8 kg/m2 (18 of 34; 52.9%). Nine (26.4%) patients had no elements of MetS. Twenty-three of seventy-two (31.9%) patients with simple hepatic steatosis did not have MetS, a history of alcohol abuse, and were not treated with chemotherapy before liver resection. However, most of these patients did have at least one element of MetS, including diabetes (6 of 23; 26.1%), hypertension (7 if 23; 30.4%), dyslipidemia (2 of 23; 8.7%), and BMI greater than 28.8 kg/m2 (16 of 23; 69.6%). Only 1 patient (4.3%) had no elements of MetS.

Comparisons of Preoperative Variables Between Patients With SH or Simple Hepatic Steatosis and Corresponding Controls.

Rates of malignant diagnoses, preoperative chemotherapy treatment, alcohol use, elements of MetS, and ASA score were very similar between SH patients and corresponding controls (Table 1). There were no significant differences in BMI, gender, or age at liver resection between these groups. Similarly, rates of malignant diagnoses, female gender, preoperative chemotherapy treatment, alcohol use, and elements of MetS were similar among patients with simple hepatic steatosis and corresponding controls (Table 1). There were no significant differences in age, BMI, or gender between patients with simple hepatic steatosis and corresponding controls. Patients with simple hepatic steatosis did have higher ASA scores, compared to corresponding controls (median 3 versus 2; P = 0.010). Although albumin (ALB) levels were slightly higher among control patients, there were no substantial differences in preoperative laboratory levels between SH patients and corresponding controls. There were no significant differences in any preoperative laboratory level between patients with simple hepatic steatosis and corresponding controls.

Table 1. Univariable Comparisons of Demographics, Diagnoses, Comorbidities, and Preoperative Laboratory Values Between (1) Patients With SH and Corresponding Controls and (2) Patients With Simple Steatosis and Corresponding Controls
 SH (n = 102)Controls (n = 102)P ValueSteatosis (n = 72)Controls (n = 72)P Value
  • *

    Alcohol consumption defined per AASLD consensus statement.35

  • Refers to any two of the following: MetS, preoperative chemotherapy treatment, or alcohol use.

Female (%)52 (51.0)64 (62.7)0.12042 (58.3)42 (58.3)1.000
Age, years (range)58 (50-66)62 (51-71)0.13456 (49-66)61 (51-72)0.111
Malignant diagnosis (%)77 (75.5)78 (76.5)1.00058 (80.6)58 (80.6)1.000
 Cholangiocarcinoma5 (4.9)11 (10.8) 2 (2.8)3 (4.2) 
 Gallbladder cancer1 (1.0)4 (3.9) 1 (1.4)1 (1.4) 
 Hepatocellular cancer17 (16.7)9 (8.8) 3 (4.2)5 (6.9) 
 Other metastases13 (12.7)12 (11.8) 7 (9.7)14 (19.4) 
 Metastatic colorectal41 (40.2)42 (41.2) 45 (62.5)35 (48.6) 
Benign diagnosis (%)25 (24.5)24 (23.5)1.00014 (19.4)14 (19.4)1.000
 Focal nodular hyperplasia8 (7.8)6 (5.9) 5 (6.9)5 (6.9) 
 Giant cavernous hemangioma5 (4.9)10 (9.8) 3 (4.2)4 (5.6) 
 Hepatocellular adenoma5 (4.9)3 (2.9) 5 (6.9)1 (1.4%) 
 Miscellaneous7 (6.9)5 (4.9) 1 (1.4)4 (5.6%) 
Alcohol use* (%)13 (12.7)14 (13.7)1.0009 (12.5)10 (13.9)1.000
MetS (%)36 (35.3)37 (36.3)1.00017 (23.6)16 (22.2)1.000
Hypertension (%)62 (60.8)60 (58.8)0.88636 (50.0)40 (55.6)0.617
DM (%)31 (30.4)29 (28.4)0.88016 (22.2)15 (20.8)1.000
Dyslipidemia (%)38 (37.3)41 (40.2)0.73124 (33.3)22 (30.6)0.813
BMI, kg/m2 (range)30.9 (27.1-35.2)29.9 (26.6-33.2)0.17130.6 (27.2-36.4)29.9 (26.6-33.4)0.110
Preoperative chemotherapy (%)35 (34.3)34 (33.3)0.96039 (54.2)36 (50.0)0.673
“Two-hit” (%)13 (12.7)11 (10.8)0.82811 (15.3)11 (15.3)1.000
ASA score (range)3 (2-3)3 (2-3)0.9623 (2-3)2 (2-3)0.010
Preoperative laboratory values (range)      
 Aspartate aminotransferase, U/L29 (23-36)26 (21-34)0.17128 (23-33)27 (22-34)0.616
 Alanine aminotransferase, U/L32 (23-50)27 (21-39)0.09834 (26-41)30 (23-39)0.229
 TBIL, mg/dL0.5 (0.4-0.7)0.5 (0.3-0.7)0.1290.5 (0.4-0.7)0.4 (0.3-0.7)0.536
 ALB, mg/dL4.0 (3.9-4.3)3.9 (3.5-4.2)0.0024.0 (3.7-4.3)4.0 (3.7-4.3)0.572
 International normalized ratio1.0 (1.0-1.1)1.0 (1.0-1.1)0.0531.0 (1.0-1.1)1.0 (1.0-1.1)0.288

Surgical Treatments and Underlying Liver Histopathology.

The extent of liver resection for patients with SH and simple hepatic steatosis is summarized in Table 2. The most common liver resections in each group were right hepatectomy followed by nonanatomic resections, left lateral sectionectomy, and left hepatectomy. A total of 23.5% and 22.2% of patients with SH and simple hepatic steatosis underwent a minimally invasive liver resection, respectively. For the entire study cohort, Pringle's maneuver was applied in 97 of 348 (27.9%) patients. There were no significant differences in the frequency of Pringle's application between patients with SH and corresponding controls (26 of 102 [25.5%] versus 29 of 102 [28.4%]; P = 0.752) or between patients with simple hepatic steatosis and corresponding controls (18 of 72 [25.0%] versus 24 of 72 [33.3%]; P = 0.359).

Table 2. Surgical Treatments and Background Liver Histopathology for Patients With SH and Simple Steatosis
 SH (n = 102)Simple Steatosis (n = 72)
  1. The largest component of each resection is reported.

Type of liver resection (%)  
 Extended right hepatectomy1 (1.0)0
 Right hepatectomy35 (34.3)25 (34.7)
 Right posterior sectionectomy8 (7.8)6 (8.3)
 Extended left hepatectomy03 (4.2)
 Left hepatectomy15 (14.7)9 (12.5)
 Left lateral sectionectomy16 (15.7)10 (13.9)
 Nonanatomic resection27 (26.5)19 (26.4)
Minimally invasive approach24 (23.5)16 (22.2)
Background liver histopathology  
 Steatosis (%)  
  <500
  5-3339 (38.2)0
  34-6642 (41.2)60 (83.3)
  >6621 (20.6)12 (16.7)
 Lobular inflammation (%)  
  None8 (7.8)60 (83.8)
  Rare/spotty58 (56.9)8 (11.1)
  Mild29 (28.4)4 (5.6)
  Moderate/heavy7 (6.9)0
 Hepatocyte ballooning (%)  
  None10 (9.8)64 (88.9)
  Few69 (67.6)8 (11.1)
  Many23 (22.5)0
 NAS (range)4 (3-5)2 (2-3)
 NAS ≥4 (%)73 (71.6)11 (15.3)
 Perisinusoidal and/or portal/periportal fibrosis (%)80 (78.4)21 (29.2)

Histopathology of the underlying liver for patients with SH and simple hepatic steatosis is summarized in Table 2. Severe hepatocellular damage (as measured by moderate/heavy lobular inflammation and/or many ballooned hepatocytes per HPF) occurred in a minority of SH patients. Median NAS among SH patients was 4 (range, 3-5). Similarly, only 16.7% of patients with simple hepatic steatosis had severe steatosis. Perisinusoidal and/or portal/periportal fibrosis was present in 78.4% and 29.2% of patients with SH and simple steatosis, respectively.

Intra- and Postoperative Outcomes.

For the entire study cohort (n = 348), postoperative mortality, overall morbidity, severe morbidity, and any hepatic-related morbidity occurred in 9 (2.6%), 153 (44.0%), 58 (16.7%), and 73 (21.0%) patients, respectively. Postoperative hepatic decompensation, surgical hepatic complications, and hepatic insufficiency occurred in 37 (10.6%), 46 (13.2%), and 16 (4.6%) patients, respectively. Median intraoperative estimated blood loss (EBL) was 250 mL (range, 150-450), and 19.5% (68 of 348) patients received an RBC transfusion within 30 days after liver resection. SH patients had higher 90-day overall (56.9% versus 37.3%; P = 0.008) and any hepatic-related (28.4% versus 15.7%; P = 0.043) morbidity, compared to corresponding controls (Table 3). Rates of postoperative hepatic decompensation (16.7% versus 6.9%; P = 0.049), surgical hepatic complications (19.6% versus 8.8%; P = 0.046), and PHI (6.9% versus 2.0%; P = 0.170) were also higher among SH patients, although the latter difference was not statistically significant. Peak postoperative TBIL levels for SH patients with PHI were 34.7, 24.9, 18.9, 17.2, 13.3, 9.0, and 7.0 mg/dL. Corresponding levels for control patients with PHI were 9.7 and 9.0 mg/dL. There were no differences in 90-day postoperative mortality or severe morbidity, EBL, or 30-day RBC transfusion rates between SH patients and corresponding controls (Table 3). There was no significant difference in any endpoint between patients with simple hepatic steatosis and corresponding controls (Table 3). Peak postoperative TBIL levels for patients with simple hepatic steatosis and PHI were 19.4, 10.7, 10.7, and 10.4 mg/dL, whereas corresponding levels for controls with PHI were 21.0, 14.8, and 11.6 mg/dL. Specific postoperative complications are summarized in Table 4. Gender, patient age, malignant diagnosis, hypertension, MetS, ASA score ≥3, liver resection approach, extent of liver resection, and underlying SH were associated with overall morbidity on univariable analysis among SH and corresponding control patients (Table 5). Factors independently associated with overall morbidity on multivariable logistic regression were resection of four or more liver segments (OR, 4.228; 95% CI: 2.215-8.072; P < 0.001), MetS (OR, 2.929; 95% CI: 1.530-5.607; P = 0.001), and SH (OR, 2.316; 95% CI: 1.267-4.241; P = 0.007). Among patients with SH and corresponding controls, gender, preoperative chemotherapy treatment, liver resection approach, extent of liver resection, and underlying SH were associated with any hepatic-related morbidity on univariable analysis (Table 5). On multivariable logistic regression, resection of four or more segments (OR, 9.493; 95% CI: 4.177-21.577; P < 0.001), male gender (OR, 3.252; 95% CI: 1.448-7.303; P = 0.004), and SH (OR, 2.722; 95% CI: 1.201-6.168; P = 0.016) were independently associated with any hepatic-related morbidity. The relative low numbers of PHI, postoperative hepatic decompensation, and surgical hepatic complication events precluded corresponding multivariable analyses.

Table 3. Univariable Comparisons of Intra- and Postoperative Outcomes Between (1) Patients With SH and Corresponding Controls and (2) Patients With Simple Steatosis and Corresponding Controls
 SH (n = 102)Controls (n = 102)P ValueSteatosis (n = 72)Controls (n = 72)P Value
  • *

    Some patients had both hepatic decompensation and surgical hepatic complications after liver resection.

EBL, mL (range)250 (110-500)250 (100-450)0.488275 (150-400)250 (150-525)0.769
30-day postoperative RBC transfusion (%)19 (18.6)25 (24.5)0.3959 (12.5)15 (20.8)0.264
Peak postoperative TBIL, mg/dL (range)1.3 (0.9-2.0)1.3 (0.7-2.1)0.1711.2 (0.9-1.9)1.3 (0.9-2.7)0.307
Postoperative hepatic insufficiency (%)7 (6.9)2 (2.0)0.1704 (5.6)3 (4.2)1.000
90-day postoperative mortality (%)4 (3.9)1 (1.0)0.3703 (4.2)1 (1.4)0.620
90-day postoperative morbidity (%)      
 Overall complications58 (56.9)38 (37.3)0.00825 (34.7)32 (44.4)0.310
 Severe complications20 (19.6)17 (16.7)0.71610 (13.9)11 (15.3)0.833
 Any hepatic-related complications29 (28.4)16 (15.7)0.04314 (19.4)14 (19.4)1.000
 Hepatic decompensation*17 (16.7)7 (6.9)0.0496 (8.3)7 (9.7)0.778
 Surgical hepatic complications*20 (19.6)9 (8.8)0.04610 (13.9)7 (9.7)0.606
Table 4. Postoperative Complications Stratified by Background Liver Histopathology
 SH (%) (n = 102)Controls (%) (n = 102)Steatosis (%) (n = 72)Controls (%) (n = 72)
  1. Patients may have incurred more than one complication.

Hepatic related    
 Bile leak10 (9.8)4 (3.9)8 (11.1)2 (2.8)
 Postoperative hepatic insufficiency7 (6.9)2 (2.0)4 (5.6)3 (4.2)
 Ascites13 (12.7)5 (4.9)4 (5.6)6 (8.3)
 Intra-abdominal abscess6 (5.9)2 (2.0)3 (4.2)2 (2.8)
 Bleeding3 (2.9)001 (1.4)
 Pleural effusion5 (4.9)2 (2.0)3 (4.2)3 (4.2)
 Hepatic encephalopathy2 (2.0)1 (1.0)1 (1.4)1 (1.4)
Other    
 Multisystem organ failure5 (4.9)1 (1.0)3 (4.2)1 (1.4)
 Pneumonia5 (4.9)02 (2.8)4 (5.6)
 Delirium4 (3.9)3 (2.9)1 (1.4)3 (4.2)
 Respiratory insufficiency/failure12 (11.8)9 (8.8)3 (4.2)2 (2.8)
 Venous thromboembolism3 (2.9)2 (2.0)1 (1.4)2 (2.8)
 Urinary tract infection3 (2.9)3 (2.9)03 (4.2)
 Gastrointestinal bleeding1 (1.0)2 (2.0)02 (2.8)
 Renal insufficiency/failure4 (3.9)4 (3.9)03 (4.2)
 Clostridium difficle colitis1 (1.0)1 (1.0)02 (2.8)
 Wound infection6 (5.9)4 (3.9)1 (1.4)4 (5.6)
 Paralytic ileus5 (4.9)3 (2.9)4 (5.6)1 (1.4)
 Myocardial infection or cardiac arrythmia5 (4.9)3 (2.9)3 (4.2)4 (5.6)
 Cerebrovascular accident3 (2.9)1 (1.0)01 (1.4)
Table 5. Univariable Analysis for Overall and Any Hepatic-Related Postoperative Morbidity Among Patients With SH and Corresponding Controls (n = 204)
 Overall Morbidity (%)P ValueHepatic Morbidity (%)P Value
  • *

    Not used in subsequent multivariable analysis for overall morbidity in lieu of MetS.

Gender 0.045 0.002
 Male (n = 88)49 (55.7) 29 (33.0) 
 Female (n = 116)47 (40.5) 16 (13.8) 
Age, years 0.050 0.707
 ≥70 (n = 52)31 (59.6) 10 (19.2) 
 <70 (n = 152)65 (42.7) 35 (23.0) 
Malignant diagnosis 0.013 0.191
 Yes (n = 155)81 (52.3) 38 (24.5) 
 No (n = 49)15 (30.6) 7 (14.3) 
Alcohol use history 0.458 0.786
 Yes (n = 27)15 (55.6) 7 (25.9) 
 No (n = 177)81 (45.8) 38 (21.5) 
Hypertension* 0.043 0.887
 Yes (n = 122)65 (53.3) 26 (21.3) 
 No (n = 82)31 (37.8) 19 (23.2) 
DM 0.105 0.1663
 Yes (n = 60)34 (50.0) 9 (15.0) 
 No (n = 144)62 (43.1) 36 (25.0) 
MetS 0.017 0.359
 Yes (n = 73)43 (58.9) 13 (17.8) 
 No (n = 131)53 (40.5) 32 (24.4) 
BMI, kg/m2 0.569 0.287
 >28.8 (n = 125)54 (43.2) 24 (19.2) 
 ≤28.8 (n = 79)32 (40.5) 21 (26.6) 
Dyslipidemia 0.093 0.486
 Yes (n = 79)44 (55.7) 15 (19.0) 
 No (n = 124)52 (41.9) 30 (24.2) 
ASA score 0.031 0.913
 ≥3 (n = 108)59 (54.6) 23 (21.3) 
 <3 (n = 96)37 (38.5) 22 (22.9) 
Preoperative chemotherapy 0.720 0.046
 Yes (n = 69)34 (49.3) 21 (30.4) 
 No (n = 135)61 (45.5) 23 (17.0) 
Liver resection approach 0.002 0.003
 Minimally invasive (n = 48)11 (22.9) 2 (4.2) 
 Open (n = 156)85 (54.5) 43 (27.6) 
Extent of liver resection, segments <0.001 <0.001
 ≥4 (n = 76)50 (65.8) 35 (46.0) 
 <4 (n = 128)46 (35.9) 10 (7.8) 
Microsteatosis 0.069 0.287
 Yes (n = 79)44 (55.7) 21 (26.6) 
 No (n = 125)52 (41.6) 24 (19.2) 
SH 0.008 0.042
 Yes (n = 102)58 (56.9) 29 (28.4) 
 No (n = 102)38 (37.3) 16 (15.7) 

Discussion

The aim of this retrospective study was to determine whether simple hepatic steatosis or SH worsens outcomes after liver resection. To achieve this aim, we individually matched patients with either underlying histopathology to control patients based upon extent and approach of liver resection. Controls were then further selected based upon similar diagnoses and potential etiologies of SH or simple steatosis—including alcohol use, MetS, and preoperative chemotherapy (Table 1). Moreover, the incidence of patients with “two-hits” predisposing to SH (e.g., preoperative chemotherapy treatment and MetS) was similar between SH patients and corresponding controls. Thus, our study accounts for the morbidity derived from factors, such as DM, morbid obesity, and preoperative chemotherapy treatment, separate from underlying liver injury.41-43 We excluded patients with bridging fibrosis, cirrhosis, cholestasis, or other CLDs in the underlying liver and those who underwent concomitant major extrahepatic procedures (including bile duct resection and bilioenteric anastomosis) to eliminate potential confounding variables that may influence postoperative outcomes. This study design thus avoids the flaws present in other reports that cloud conclusions regarding the association of underlying liver pathology and postoperative outcomes.18, 24-32 Only those with at least moderate underlying steatosis (defined by greater than 33% of liver parenchymal involvement by the NAS)34 were included in the group of patients with simple hepatic steatosis. This relatively high threshold for simple steatosis was selected to maximize the likelihood of detecting differences in postoperative morbidity, when compared to corresponding controls with no underlying liver pathology.

Patients with SH in the underlying liver had higher overall (56.9% versus 37.3%; P = 0.008) and any hepatic-related (28.4% versus 15.7%; P = 0.043) morbidity after liver resection, compared to corresponding controls. SH was associated with both outcomes on multivariable logistic regression—indicating that SH leads to higher morbidity after liver resection independent of etiology. Hepatic-related postoperative morbidity in SH patients is the result of pathologic damage in the underlying liver and not from other side effects derived from factors, such as MetS and preoperative chemotherapy treatment, predisposing to this liver injury. Importantly, both postoperative hepatic decompensation (including ascites, PHI, and hepatic encephalopathy) and surgical hepatic complications were higher among SH patients, compared to corresponding controls. In contrast, there was no difference in postoperative outcomes between patients with simple hepatic steatosis in greater than 33% of the underlying liver, compared to corresponding controls (Table 3). These results stress the importance of distinguishing between simple steatosis and SH in assessing the influence of FLD on outcomes after liver resection and may explain the inconsistency on the severity of steatosis in association with postoperative outcomes observed in other reports.33 Consistent with our previous study, resection of four or more liver segments was also independently associated with overall and any hepatic-related morbidity.44

Results of our study regarding the deleterious effects of SH have broad implications for the multidisciplinary care of patients undergoing liver resection, which comprises surgeons, radiologists, medical oncologists, and hepatologists. Preoperative identification of SH, either by liver biopsy or the continued development of noninvasive imaging techniques, in “at risk” patients should be considered in planning liver resection. Administration of chemotherapy for initially resectable malignant disease should be considered cautiously, especially in patients with MetS or a history of alcohol use. Medications shown to reverse histologic features of SH45, 46 should be evaluated in randomized trials for improving postoperative outcomes for patients with SH undergoing liver resection. Similar to cirrhosis, studies assessing the overall safety profile of liver resection and/or evaluating the effect of new techniques or devices on postoperative outcomes should account for underlying SH.

Several limitations to this retrospective study should be considered. Occult alcohol use and potential inaccuracies in degrees of alcohol consumption obtained from retrospective chart reviews may have clouded the differentiation between alcoholic and nonalcoholic SH.47 Because preoperative serum triglyceride, high-density lipoprotein, and/or fasting glucose levels, waist circumference, and blood-pressure measurements were not available for most patients, we used surrogates for each parameter, including medication treatment and BMI. Thus, there were likely some patients with unrecognized elements of MetS in this study. Although this is the largest series in the literature evaluating the effects of SH on surgical outcomes after liver resection, relatively small patient numbers precluded subgroup analysis of those patients undergoing major hepatic resection, multivariable analysis for PHI, postoperative hepatic decompensation, and surgical hepatic complications in particular, and comparisons of patients with definite or borderline SH.34, 35 Of note, a minority of patients had severe SH (measured by many ballooned hepatocytes and/or moderate/heavy lobular inflammation per HPF) or severe hepatic steatosis. A multicenter study comprising several well-experienced hepatobiliary centers would not only overcome these cohort size limitations, but also account for differences among individual and institutional pathologists in distinguishing between simple hepatic steatosis and SH. Despite extensive criteria for control patient selection, there were some characteristics that were not accounted for that may have influenced postoperative outcomes. These include specific preoperative chemotherapy regimens, time interval from discontinuation of chemotherapy to liver resection, extent and date of discontinuation of alcohol use relative to liver resection, and preoperative nutritional status. Because of the rigid exclusion criteria, the number of patients with FLD in this study represents a small fraction of the total number of patients who underwent resection at our center. Thus, more studies are needed to determine the effects of FLD on postoperative outcomes when in conjunction with other CLDs and with simultaneous major nonhepatic procedures. We examined postoperative morbidities and hepatic insufficiency as the main endpoints. Other important markers of heathcare utilization, such as length of hospital and/or intensive care unit stay and duration of respiratory failure, are also key endpoints that should be examined in future studies.

In conclusion, underlying SH, but not simple hepatic steatosis, increases overall and hepatic related morbidity after liver resection. These findings prompt the need for reliable noninvasive detection techniques for SH, increased consideration of the deleterious effects of SH when planning preoperative chemotherapy treatments and liver resection, and studies evaluating benefits from medical treatment of SH before partial hepatectomy.

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