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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_1116_Библиотеки_им_академика_М_И_Перельмана.pdf
Sleeve Gastrectomy in Nonalcoholic Steatohepatitis (NASH)
and Liver Cirrhosis
Mohammad H. Jamal and Rawan El-Abd
1 Definition and Background
Non-Alcoholic Fatty Liver Disease (NAFLD) is a clinic-histopathological spectrum that results from fat accumulation in hepatocytes, that can be present without inflammatory changes (hepatic steatosis) or with concomitant inflammation
(steatohepatitis), resulting in the condition called Non-Alcoholic Steatohepatitis
(NASH). The histopathological finding of NASH is identical to that found in alcoholic steatohepatitis with the biopsy changes showing fat accumulation, lobular
hepatitis, focal necrosis, inflammatory infiltrates, and Mallory bodies [1, 2].
2 Epidemiology
The prevalence of NAFLD is alarmingly increasing worldwide, not only in adults,
where it is reported to be between 6 and 35% [3–5], but also in children and adolescents with the prevalence ranging from 0.7% for ages 2–4 and up to 17.3%
for ages 15–19 years [6]. The highest prevalence of NAFLD is reported to be in
the Middle East and South America [7]. The variable prevalence reported in the
M. H. Jamal (*)
Department of Transplantation, Faculty of Medicine, Health Sciences Centre,
Kuwait University, Kuwait City, Kuwait
e-mail: mohammad.jamal@mail.mcgill.ca
Jaber Al-Ahmad Hospital, Kuwait City, Kuwait
R. El-Abd
Faculty of Medicine, Health Sciences Centre, Kuwait University, Kuwait City, Kuwait
e-mail: rawanela@gmail.com
© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer
Nature Switzerland AG 2021
S. Al-Sabah et al. (eds.), Laparoscopic Sleeve Gastrectomy,
https://doi.org/10.1007/978-3-030-57373-7_15
115
116
literature correlates with the coexistence of higher rates of obesity and other components of the metabolic syndrome in some countries but not others. Specifically,
for NASH, literature review report it to affect 3–5% of the world’s population [8].
The prevalence of NASH in NAFLD patients, however, is reported to be 60% [9].
Of those patients affected with NASH, 20% can progress to cirrhosis [10].
M. H. Jamal and R. El-Abd
3 Risk Factors
Although the pathogenesis of NAFLD is not fully understood, the most accepted
theory implicates insulin resistance as the cause, and this condition is said to be
the hepatic manifestation of the metabolic syndrome [11]. Obesity has the strongest
association with the development of NAFLD, and the risk of developing NAFLD
increases the more obese the individual gets [12, 13]. Other risk factors include
diabetes, hypertriglyceridemia, hypertension, disorders of lipid metabolism, total
parental nutrition, severe weight loss, refeeding syndrome, and drugs [11].
4 Pathophysiology
There is strong evidence today that insulin resistance is the primary pathophysiological condition seen in patients with NAFLD/NASH who might or might not
be obese. Insulin resistance in itself stimulates lipolysis, triglyceride synthesis, hepatic uptake of free fatty acids, and accumulation of hepatic triglyceride,
which potentiates hepatic cell inflammation [14]. In addition, hormones such as
adiponectin, leptin, and resistin, that regulate insulin sensitivity are found to exert
important modulatory action through altered activation of numerous receptors and
cytokines that eventually leads to hepatic cell dysregulation, inflammation, and
apoptosis [15–17]. Several mechanisms are theorized to determine the extent and
progression of necroinflammation in NASH. These include defects in mitochondrial function, impaired free oxygen radical scavenging, and increased hepatic iron
[18–20]. The fibrosis seen in NASH is perisinusoidal (zone 3) and results due to
activation of lobular stellate cells. Portal fibrosis, a feature of advanced disease,
can also occur and is due to activation of a hepatic progenitor cells as a result of
chronic hepatocyte injury. The degree of this fibrotic reaction correlates with the
grade of NASH activity, which in turn correlated with insulin resistance [21].
5 Clinical Presentation
The clinical manifestations range from being asymptomatic with incidental discovery of the disease during imaging for unrelated conditions to biochemical
finding of a persistently elevated liver enzymes and/or non-specific symptoms of
fatigue, edema, pruritis, gastrointestinal bleeding, or ascites. Patients might have
a normal physical examination (19–30%) or hepatomegaly (up to 53%), jaundice,
splenomegaly, ascites, and/or stigmata of liver disease (5–16%).
Sleeve Gastrectomy in Non-alcoholic Steatohepatitis …
117
6 Diagnosis
The diagnosis of NAFLD requires the presence of hepatic steatosis as identified by
imaging or biopsy and exclusion of:
1. Significant alcohol consumption
2. Co-existing chronic liver disease
3. Other causes of hepatic steatosis (hepatitis C, medications, TPN, chronic liver
diseases)
The amount of alcohol consumption considered to be significant defers according
to different guidelines:
• EASL, NICE, and AISF Guidelines:
>30 g/d in men and >20 g/d in women.
a. AASLD guidance:
>21 standard drink on average per week in men and >14 in women.
b. Asia–Pacific Guidelines:
>7 standard alcoholic drinks/week (70 g ethanol) in women and >14 (140 g) in
men.
The diagnosis of NASH, to date, relies on histologic examination showing hepatocyte ballooning degeneration, diffused lobular inflammation and fibrosis [11].
Fibrosis staging is an important factor to consider in all NAFLD patients as it was
found to be the strongest predictor of all-cause and disease-specific mortality [22].
Actually, the severity of any chronic liver disease, in general, relies on the degree
of fibrosis. By identifying patients with advanced fibrosis, physicians can plan
more aggressive follow-up, investigations, and therapeutic measures. Although
liver biopsy is the gold standard for evaluation of liver fibrosis, non-invasive investigations could substitute for invasive procedures in some patients. Table 1 presents a comprehensive list of the non-invasive methods used to detect fibrosis and
assess the severity of liver disease listed by Trautwein et al. [23].
7 Non-invasive Tests
7.1 Laboratory Investigations
Laboratory abnormalities includes elevated AST and ALT (up to fivefold elevation), ALP (up to twofold), and AST:ALT ratio <1 unless cirrhosis develops.
Bilirubin, albumin, and prothrombin time can be affected in late stages. However,
normal liver function tests cannot exclude NAFLD and laboratory alterations may
be due to a concomitant liver disease. Detection of laboratory abnormalities of elevated ferritin or low autoantibody titers (anti-nuclear antibodies and anti-smooth
118
Table 1 Non-invasive measures to assess liver fibrosis
Serum tests
• Enhanced Liver Fibrosis test
• FibroTest
• Fibrosis-4 test
• HepaScore
• FibroIndex
• Aspartate aminotransferase-to-platelet ratio
Liver Stiffness Measurement tests
• Transient Elastography
• Shear Wave Elastography
• Acoustic Radiation Force Impulse Imaging
• Magnetic Resonance Elastography
Magnetic Resonance-/Positron Emission Tomography-Based Imaging
• Liver inflammation score
• Proton density fat fraction
Functional Tests
• Cholate clearance test
• 13C-methacetin breath test
Clinical Scores
• Model for End-stage Liver Disease
• Child–Pugh
• Lille
M. H. Jamal and R. El-Abd
muscle antibodies) may not be due to other liver disease but instead can be a sole
manifestation of NALFD [24]. Kowdley et al. reported that serum ferritin >1.5
times the upper limit of normal was associated with advanced cirrhosis in 628
NAFLD patients [25]. For detecting and stages liver fibrosis, other investigations
have been developed, including the Enhanced Liver Fibrosis (ELF) Panel, which
tests for tissue inhibitor of metalloproteinases 1 (TIMP-1), amino-terminal propeptide of type III procollagen (PIIINP), and hyaluronic acid (HA) and was found to
predict moderate fibrosis and cirrhosis in patients with chronic liver disease [26].
In fact, Kim et al. studied the use of ELF in the clinical setting on 170 patients
chronic hepatitis B patients and reported it to predict liver related decompensation
as good as TE with an AUROC of 0.8 [27].
7.2 Imaging
1. Transient Elastography (TE)/Fibro scan
Fibro scan is a sensitive imaging modality to measure hepatic steatosis and stiffness. This imaging modality incorporates ultrasonography and relies on the
principle that velocity of a wave through a homogenous tissue is proportional
to its elasticity/stiffness, expressed in kilopascals (kPa). It utilizes the use of a
Sleeve Gastrectomy in Non-alcoholic Steatohepatitis …
119
transducer probe, which emits low-frequency (50 Hz) vibrations into the liver.
Those vibrations are then detected through pulse-echo acquisition, and by using an
equation, the velocity of the wave is calculated. The stiffer the liver, the faster the
velocity. TE is non-invasive, accessible for the outpatient setting, less expensive
than a liver biopsy, free of side-effects, and requires 5–7 minutes to be performed.
It also gives a more representable view of the hepatic parenchyma, as it evaluates a
larger area compared to liver biopsy. In addition, the results are instantaneous enabling physicians to make quick decisions, all of which make TE useful for screening NAFLD patients and for follow-up of chronic liver diseases [28, 29].
Patients with an elastography value <6 kPa were repeatedly found to have no
or minimal fibrosis and thus can be monitored with repeat TE instead of undergoing liver biopsy [30]. Eddowes et al. have studied 450 adults suspected to have
NAFLD in a prospective analysis where they underwent both a diagnostic liver
biopsy and Fibro scan, and they reported that Fibro scan was able to accurately
identify patients with steatosis and fibrosis while using CAP and liver stiffness
measurement (LSM) with an area under the receiver operating curve (AUROC) of
0.7–0.89 [31]. Also, a meta-analysis lead by Musso et al. on 32 articles evaluating
the diagnostic accuracy of non-invasive tests against liver biopsy showed TE to
have a sensitivity and specificity of ≥94% and an AUROC of 0.94 when diagnosing NAFLD and differentiating its histological subtypes [32].
When used to detect significant fibrosis and severe fibrosis, TE was found to
have an AUROC of 0.84 (0.82–0.86) and 0.89 (0.88–0.91), respectively [33].
Tamano et al. investigated the sensitivity of TE in detecting hepatic stiffness and
fibrosis in 32 NAFLD compared to 32 chronic viral liver disease patients and
found that TE is more sensitive in NAFLD than the later with its ability to differentiate between F 0 and F 1/F 2/F 3, F 1 and F 3/F 4, and F2 and F4 in NAFLD,
while in chronic viral disease it differentiates F1/F2/F3 and F4 [34].
When it comes to its utility for diagnosing liver cirrhosis, a meta-analysis done
by Shi et al. on 3644 patients reported TE to have a sensitivity and specificity of
up to 90% in detecting portal hypertension for patients with cirrhosis [35], other
meta-analysis also showed TE to be a sensitive method in detecting liver cirrhosis
with an AUROC of 0.90 to 0.95 ranging from 0.90 to 0.95 [33, 36].
The main limitations of TE are faced when dealing with patients with ascites or
those who are morbidly obese [29] but recent advances in creating XL probes is
targeting this problem [37]. Garg et al. have tested the accuracy of Fibro scan in correctly diagnosing 76 morbidly obese individuals and found the imaging modality to
have a success rate in diagnosing hepatic steatosis and fibrosis of 88% with AUROC
for CAP and LSM ranging from 0.65 to 0.83 [38]. A Canadian study of 251 patients
studied found that 14% had discordance between liver biopsy and TE results, with
mild fibrosis, higher body mass index (BMI), alanine aminotransferase elevation,
and variability in liver stiffness measurement being the main determinants of the
discordant results [39]. Another study on 210 chronic liver disease patients with a
2
BMI ≥28 kg/m
assessed the use of transient elastography XL probe and found that
discordance in measurement of liver fibrosis by biopsy versus TE to be infrequent
but a BMI greater than 40 led to a 4- to 5-fold increase in discordance [40].
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M. H. Jamal and R. El-Abd
2. Shear Wave Elastography (SWE)
This is an imaging modality that utilizes shear waves produced by ultrasound
to detect liver stiffness. It was able to accurately stage fibrosis and differentiate
fibrosis stages of F 0–1 from F 2–4 with high probability. It is reported to be as
accurate or more accurate than TE [41]. Actually, Cassinotto et al. who have studied different imaging modalities for diagnosing 291 NAFLD patients found that
both SWE and TE to have similar cutoff values for staging fibrosis: 6.3/6.2 kPa
for ≥F2, 8.3/8.2 kPa for ≥F3, and 10.5/9.5 kPa for F4 [37].
3. Acoustic Radiation Force Impulse (ARFI)
ARFI performance is reported to be similar to transient elastography with the
added benefits of the ability of using it on patients with ascites or those who are
obese. Palmeri et al. conducted a study on 172 patients with NAFLD and found
that ARFI imaging could differentiate between low (F0–2) and high (F3–4) stages
of fibrosis with an AUROC, sensitivity, and specificity of 0.90. They also stated
that a BMI greater than 40 did not affect results of this imaging technique [42].
Additionally, Freiedrich-Rust et al. published a meta-analysis of 518 patients supporting the diagnostic accuracy of ARFI imaging in diagnosing liver fibrosis, with
AUROC curves of 0.87, 0.91, and 0.93 for significant fibrosis, severe fibrosis, and
cirrhosis, respectively [43].
4. Magnetic Resonance Imaging (MRI)
MRI (proton density fat fraction or spectroscopy) is the most sensitive imaging
modality to detect hepatic steatosis with a liver fat content as low as 5 – 10%. Its
use, however, is limited to clinical studies due to its high cost, long time of execution, and limited availability [44]. Magnetic Resonance Elastography (MRE)
combines MRI imaging with low-frequency vibrations to create visual images that
reflect liver stiffness and can detect fibrosis, making it useful in the imaging of
chronic liver disease. It is, however, costly, and labor intensive, making it a less
favorable method over TE.
8 Scoring Systems
1. Fatty Liver Index (FLI)
The fatty liver index is an algorithm that predicts the presence of hepatic steatosis
based on patient’s waist circumference, body mass index (BMI, serum triglycerides, and gamma-glutamyl transferase (GGT). It’s a score from 0 to 100, a FLI
<30 rules out fatty liver, while a score ≥60 rules in the diagnosis [45].
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121
2. NAFLD liver fat score
This score integrates hepatic transaminases and fasting insulin levels with the
presence of the metabolic syndrome to predict the present or absence of hepatic
steatosis. It is shown to be as effective as FLI [46].
3. Fibrosis Scoring systems
The scores used to date are the Fibrosis 4 calculator score [47] and NAFLD fibrosis score [48]. The former uses patient’s age, AST, platelet count, and ALT to predict the presence of absence of fibrosis, while the later uses the same in addition to
albumin, BMI, and the presence of absence of diabetes. By applying these scores,
a significant proportion of NAFLD patients can avoid undergoing an invasive
biopsy to diagnose their condition, with accurate prediction reaching up to 90%.
4. Biomarker Cytokeratin-18
Biomarkers of inflammation or fibrosis can predict prognosis of NAFLD patients
although the presence of multiple co-morbidities is the most important predictor
of progressing inflammation and fibrosis in NAFLD patients as per the AASLD
guidelines. Cytokeratin-18 fragment is the most studied marker of inflammation and liver cell apoptosis and can be used to monitor NASH patients [49].
A meta-analysis found that the pooled AUROC, sensitivity, and specificity of
cytokeratin-18 for diagnosing NASH to be 0.82 (0.78–0.88), 0.78 (0.64–0.92), and
0.87 (0.77–0.98), respectively [32].
8.1 Invasive Measure
8.1.1 Liver Biopsy
Biopsy remains the gold standard method to diagnose patients with the NAFLD spectrum. It can correctly differentiate Non- Alcoholic Fatty Liver (NAFL) from NASH
and stage liver fibrosis, providing prognostic information regarding the risk of progression to cirrhosis [7]. NAFL is diagnosed when hepatic steatosis is >5% in liver
biopsy in the absence of alcohol consumption [50]. Contrary to NASH, NAFL patients
have <1% chance of developing cirrhosis or dying due to liver disease [30, 48].
Characteristically, NASH is defined by histologic examination showing zone 3,
centrilobular macro vesicular steatosis with hepatocyte ballooning and inflammatory infiltrates [51]. It is important to detect these histological differences to guide
management as the prognosis of NALF and NASH hugely differ. Although fibrosis
tends to progress over the years in both NAFL and NASH patients as reported by
a meta-analysis of 11 cohorts with a sample size of 411 biopsy-proven NAFLD
patients, the progression is much faster for NASH [52].
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M. H. Jamal and R. El-Abd
For example, Matteoni et al., who have studied 137 NAFLD liver biopsies found that the development of cirrhosis and later liver-related mortality
is not the same across all patients with the NAFLD spectrum, and that poor
outcomes are higher in patient’s whom biopsy showed Mallory hyaline or
fibrosis, as features of NASH [10]. This was also replicated by Ekstedt et al.
who studied 229 biopsy-proven NAFLD patients for up to 33 years of follow
up and found those with fibrosis stage of 3–4 had increased mortality with
a Hazard Ratio (HR) of 3.3 (CI 2.27–4.76, P <0.001). In addition, a recent
meta-analysis by Dulai et al. on 1,495 NAFLD patients with a person years
follow-up of 17,452 showed that NAFLD patients who had fibrosis had an
increased risk of all-cause and liver-related mortality with a dose response
relationship. All-cause mortality of fibrosis stage 1 was Mortality Rate Ratio
(MRR) = 1.58 (95% CI 1.19–2.11) while that of stage 4 was MRR = 6.40
(95% CI 4.11–9.95) and liver-related mortality was MRR = 1.41 (95% CI
0.17–11.95) for stage 1 and MRR = 42.30 (95% CI 3.51–510.34) for stage 4,
concluding that the risk of mortality increases exponentially as fibrosis stage
increases [53]. Even more, a study conducted by Angulo et al. included 619
multinational NAFLD patients with a median follow up of 13 years reported
that fibrosis stage was independently associated with long-term overall mortality and liver transplantation.
Performing a liver biopsy, however, has several limitations that include high
cost, its invasive nature, pathologist variability, and sampling error [51, 54].
Thus, not all NAFLD patients should undergo liver biopsy [7, 55]. The AASLD
guidelines advice to perform a liver biopsy for patients with the metabolic syndrome, or when other non-invasive modalities classify the patient as high risk,
as their disease status is more likely to be rapidly progressive, which necessities accurate prognostic information. Actually, Bazick et al. have reported their
results under the NASH Clinical Research Network assessing a new model to
predict advanced fibrosis in diabetic patients with NAFLD on 435 patients, in
which 69% were found to have NASH and 41% had advanced fibrosis, reconfirming that diabetes makes NAFLD patients a high-risk group instantly. Their
model predicted fibrosis better than the NAFLD fibrosis score and can be used
to assess the need for liver biopsy in diabetic patients [56]. Also, Simeone et al.
have also studied the effect of diabetes on NAFLD progression in a cohort of
18,754 patients and found that diabetes was associated with 2 times the risk of
disease progression and mortality [57].
The AASLD guidelines, in addition, advices a biopsy in the setting of high ferritin and high iron saturation levels or low titers of serum antinuclear antibody/
antismooth muscle antibody to rule out hemochromatosis, or autoimmune liver
disease, respectively [7]. In addition, based on the EASL 2009 special conference,
Ratziu et al. published that patients with thrombocytopenia, hypoalbuminemia and
AST > ALT as signs of cirrhosis, or those undergoing bariatric surgery should be
offered a liver biopsy for diagnosis and staging as NASH is highly prevalent in the
bariatric patient population [55].
In summary of the above references, a liver biopsy is offered for patients who:
Sleeve Gastrectomy in Non-alcoholic Steatohepatitis …
123
1. Have indicators of cirrhosis (stigmata of chronic liver disease, splenomegaly, or
cytopenias)
2. Have a serum ferritin >1.5 times the upper limit of normal (NASH)
3. Are >45 years old or are obese + features of metabolic syndrome (high risk of
fibrosis).
4. Have type 2 diabetes and elevated liver enzymes
5. Have low titers of serum antinuclear antibody/antismooth muscle antibody
6. Have an elevated value with a fibrosis scoring system
7. Have an elastography value >6 kPa or reliable value cannot be obtained due to
obesity
8. Are undergoing bariatric surgery
Through biopsy, the NAFLD Activity Score (NAS) and Steatosis Activity Fibrosis
scoring system (SAF) are used to assess disease activity.
1. NAFLD Activity Score (NAS)
The total NAS score (0–8) depends on 5 features on the biopsy specimens found
to be independently associated with the diagnosis of NASH. These were steatosis (P = 0.009), lobular inflammation (P = 0.0001), hepatocellular ballooning
(P = 0.0001), fibrosis (P = 0.0001), and absence of lipogranulomas (P = 0.001).
The characteristic histologic feature of NAS found to be the most significant to
diagnose NASH is ballooning. The score is the sum of steatosis, lobular inflammation, and hepatocellular ballooning scores and was found to have good reproducibility across pathologists. A score of ≥5 is diagnostic of NASH and a score
of <3 excludes the condition [58]. A meta-analysis reported the pooled AUROC,
sensitivity, and specificity of this score to be 0.85 (0.80–0.93), 0.90 (0.82–0.99),
and 0.97 (0.94–0.99), respectively, in detecting NASH with advanced fibrosis [32].
2. Steatosis Activity Fibrosis scoring system (SAF)
SAF was developed in a study of a cohort of 679 obese patients undergoing bariatric surgery with intraoperative liver biopsy. This score also measures steatosis,
lobular inflammation, and hepatocellular ballooning but reports a score for steatosis (S), activity (A), and fibrosis (F) to categorize patients as NASH, NALFD
without NASH, and no NAFLD. The activity score (A) incorporates ballooning +
lobular inflammation and can discriminate NASH if A >2 because all of the NASH
patients in the study had A score ≥2 and no patients with A <2 had NASH [59].
9 Clinical Scores
1. Child–Pugh score:
This is a clinical score used to assess severity of liver disease to prioritize patients
who would benefit from liver decompression or transplant allocation. It groups
patients in to one of 3 categories:
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M. H. Jamal and R. El-Abd
• Child–Pugh A: 5 to 6 points - good hepatic function
• Child–Pugh B: 7 to 9 points - moderately impaired hepatic function
• Child–Pugh C: 10 to 15 points - advanced hepatic dysfunction
Five criterions are used to calculate the score:
1. Encephalopathy:
• None = 1 point
• Grade 1 and 2 = 2 points
• Grade 3 and 4 = 3 points
2. Ascites:
• None = 1 point
• slight = 2 points
• moderate = 3 points
3. Bilirubin:
• <2 mg/ml = 1 point
• 2 to 3 mg/ml = 2 points
• >3 mg/ml = 3 points
4. Albumin:
• >3.5 mg/ml = 1 point
• 2.8 to 3.5 mg/ml = 2 points
• <2.8 mg/ml = 3 points
5. INR:
• <1.7 = 1 point
• 1.7 to 2.2 = 2 points
• >2.2 = 3 points
This score was found to help predict all-cause mortality and risk of development
of liver-related complications, such as variceal bleeding. Infante-Rivard et al. studied the use of this score in 177 cirrhotic patients and found overall mortality for
these patients to be 0% at one year for Child class A, 20% for Child class B, and
55% for Child class C [60]. Limitations of this score include the requirement of
subjective assessment for grading ascites and encephalopathy and that it does not
account for renal function.
2. MELD Score
MELD score stands for Model for end-stage liver disease (MELD) and was
created to predict survival of patients undergoing transjugular intrahepatic