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Chapter 8
Nonalcoholic Steatohepatitis (NASH)
GustavoMarino, IbrahimM.Zeini, andMuhammadGhanem
8.1 Introduction
Nonalcoholic steatohepatitis (NASH) is a more severe form of the spectrum of disease known as nonalcoholic fatty liver disease (NAFLD). Both are characterized by
hepatic steatosis, or abnormal retention of lipids in the liver, in the absence of excessive alcohol use, but NASH is associated with hepatocyte ballooning degeneration,
lobular inammation, and apoptosis that can lead to brosis, scarring, and nally
cirrhosis [1–5]. NASH can be considered a diagnosis of exclusion once testing has
ruled out other causes of elevated liver enzymes and lipid buildup, such as alcoholic
liver disease, hepatitis C, or Wilson disease. Many people have fat deposition in the
liver, and it is still unknown why some show no symptoms while others show signs
of brosis and cirrhosis characterized by inammation and cell death.
8.2 Epidemiology
Prevalence—NAFLD is most commonly identied in patients during their 40s or
50s [4]. NAFLD is evident worldwide but is considered the most common liver
disease in Western industrialized countries, most likely because this is where the
G. Marino
University of Central Florida College of Medicine, Orlando, FL, USA
e-mail: gustavomarino24@knights.ucf.edu
I. M. Zeini · M. Ghanem (*)
Orlando Health Weight Loss and Bariatric Surgery Institute, Orlando Regional Medical
Center, Orlando, FL, USA
e-mail: ibrahim.zeini@orlandohealth.com; Muhammad.ghanem@orlandohealth.com
© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2023
A. Teixeira et al. (eds.), Duodenal Switch and Its Derivatives in Bariatric and
Metabolic Surgery, https://doi.org/10.1007/978-3-031-25828-2_8
95
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major risk factors for NAFLD, central obesity, type 2 diabetes mellitus, dyslipidemia, and metabolic syndrome are most rampant [5, 6]. Studies looking at the
United States population have shown evidence for NAFLD in 10–46% of the population, with most biopsy-based studies suggesting a prevalence of NASH of 3–5%
[7, 8]. Worldwide, NAFLD has a median reported prevalence of 20%.
Patient Demographics—The sex distribution of the disease is debated, with
some suggesting it is more common in women [9] and others suggesting it is more
common in men. Ethnic differences also seem to be characteristic of NASH [10,
11]. Hepatic triglyceride levels were measured in 2287 patients from a multiethnic,
US population-based sample. The ndings showed a higher prevalence of hepatic
steatosis in Hispanics (45%) as opposed to their White (33%) or Black (24%) counterparts. The higher prevalence in Hispanics was explained by a greater prevalence
of obesity [10].
Association with other diseases: Since NASH results from fat deposition in the
liver, this disease commonly affects individuals with metabolic syndrome, characterized by at least 3 of the following 5 symptoms:
1. Obesity
2. Hypertension
3. Diabetes
4. Hypertriglyceridemia
5. Hyperlipidemia
This connection was shown in a study looking at the liver biopsies of 163 patients
diagnosed with NAFLD but without overt diabetes. Of these, 120 (74%) were signicant for NASH [12]. Metabolic syndrome was seen in 67% of those with simple
steatosis (NAFLD) on biopsy, and in 88% of those with NASH on biopsy. It is estimated that in patients with type 2 diabetes, the prevalence of NAFLD and NASH is
76% and 56%, respectively [13].
Other risk factors include [14]:
• Severe weight loss
– Jejunoileal bypass
– Gastric bypass (less common than jejunoileal bypass)
– Severe starvation
• Medication-induced
– Amiodarone
– Diltiazem
– Tamoxifen
– Steroids
8 Nonalcoholic Steatohepatitis (NASH)
97
8.3 Pathogenesis
The leading theory for the development of NAFLD, and later NASH, is the development of a lipotoxic environment in the liver that can damage hepatocytes at the
cellular level [13]. Overabundance of lipids may cause oxidative stress and mitochondrial damage within the cell due to the hazardous peroxidative derivatives from
lipid metabolism. Susceptibility to lipotoxic damage may come from a range of
factors such as those seen in PNPLA3 polymorphisms (a protein associated with
hydrolase activity toward triglycerides and whose dysfunction is linked with steatosis [15]) and metabolic syndrome.
8.4 Clinical Manifestations
While those with NAFLD are often asymptomatic, patients with NASH may present
with nonspecic symptoms like fatigue, malaise, and vague upper right abdominal
discomfort [16]. The diagnosis is typically made in asymptomatic patients during
routine screening or testing for other concerns when test results show abnormal liver
chemistry tests such as elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), abnormal hepatic ultrasonography,
or computed tomography (CT).
Physical ndings—NASH patients often show evidence of hepatomegaly on
physical examination due to fatty deposition on the liver [17] though the extent can
be highly variable. In one study looking at 12 patients with NASH, 11 had hepatomegaly (dened as a liver span of >18cm on CT), with a mean liver span of 21cm.
However, in a different study looking at the CT scans and ultrasounds of 144 patients
with NASH, 18% were noted to have hepatomegaly, and there was a positive correlation between increased levels of hepatomegaly and those with more advanced
stages of brosis (28%) [18]. Since NASH can progress to cirrhosis in its later
stages, if left untreated, the patient may have symptoms of chronic liver disease like
ascites, palmar erythema, and spider angiomata.
8.4.1 Diagnosis
The diagnosis of NASH requires both physical exam, patient history, and imaging
to rule out any other possibilities. The patient must not have any history of signicant alcohol consumption, nor any indication of existing diagnoses for chronic liver
disease including chronic viral hepatitis, Wilson disease, lipodystrophy, abetalipoproteinemia, hemochromatosis, autoimmune liver disease [19], etc. A magnetic
resonance imaging (MRI) or computed tomography (CT) must show evidence of
hepatic steatosis.
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CT and MRI are both utilized to identify features common to both NAFLD and
NASH such as steatosis, but they are often not sensitive to inammation or brosis
characteristic solely of NASH.However, it is difcult to study the accuracy and
specicity of CT and MRI in diagnosing NASH because not everyone is sent for
liver biopsy, which is the only conrmatory test for NASH.There are studies that
have looked at the efcacy of CT and MRI in diagnosing NASH via conrmatory
liver biopsy. One study that used conrmatory liver biopsy to nd evidence of
hepatic steatosis found that CT lacked sensitivity while MRI lacked specicity. The
study looked at 131 individuals undergoing both liver biopsy and radiologic evaluation with non-contrast CT, contrast-enhanced CT, or MRI.The sensitivities were
33, 50, and 88%, and the specicities were 100, 83, and 63%, respectively. Therefore,
the sensitivity and specicity of liver biopsy (95 and 88%, respectively) is higher for
liver biopsy, making it the gold standard for diagnosis [20].
NASH is also associated with advanced liver brosis. While liver biopsy remains
invasive and expensive, the enhanced liver brosis (ELF) score is an extracellular
matrix marker set consisting of metalloproteinases, amino-terminal propeptide of
type III procollagen, and hyaluronic acid that has shown goo correlation with brosis stages in chronic liver disease. Individuals with an ELF score of 10.51 or higher
are diagnosed with advanced liver brosis and a higher correlation with NASH [21].
A liver biopsy is the only way to denitively conrm the presence of steatosis
and distinguish it from NAFLD. Biopsy is also necessary in order to grade and stage
the disease [22, 23]. A biopsy is obtained if there is:
• Evidence of chronic liver disease, splenomegaly, or cytopenias (evidence of
cirrhosis)
• A serum ferritin greater than 1.5× the normal limit (NASH and advanced brosis)
• Age over 45 with obesity or diabetes as comorbidities (NASH and advanced
brosis)
• Concern from the patient regarding the presence of inammation or brosis
Biopsy helps to assess for NAFLD, which requires a minimum of greater than
5% steatotic hepatocytes in a liver tissue section [24–26]. NASH can be distinguished from NAFLD with this minimum criterion in addition to hepatic lobular
inammation (typically in acinar zone 3) and hepatocyte ballooning degeneration.
Evidence of brosis is not necessary but is frequently encountered. The appearance
of NASH may be histologically identical to that of alcoholic steatohepatitis, but the
patient’s social history should rule this possibility out. Other histological ndings
specic for NASH may include:
• Apoptotic bodies
• Collagen deposits around the sinusoid that may make acinar zone 3 have a char-
acteristic “chicken wire pattern”
• Mallory bodies
NASH may exist alongside other liver diseases, which can make the diagnosis of
NASH difcult. Patients with NASH may also have co-morbidities like alcoholic
liver disease, but the means to distinguish the contributions of each to the disease’s
8 Nonalcoholic Steatohepatitis (NASH)
99
progression does not exist at this time. In a study analyzing 3581 liver biopsies from
patients with some type of chronic liver disease, the prevalence of steatohepatitis
ranged from 1.6% (autoimmune hepatitis) to 7.9% (alpha-1 antitrypsin deciency),
none of which had signicant alcohol consumption in the patient history [25].
After enough hepatocellular damage, NASH can progress to cirrhosis and may
make the inammation and steatosis less evident in the liver. The progression to
cirrhosis also causes the risk for hepatocellular carcinoma (HCC) to increase. The
increased association between NASH and HCC comes from studies examining the
risk for HCC and diseases strongly connected to NASH, like metabolic syndrome
and diabetes. Studies looking at the connection between these diseases have found
that the features commonly linked to NASH are more frequent in patients who had
HCC than in age- and sex-matched patients who had HCC due to a well-dened
viral or alcoholic origin [27].
The NAFLD activity score (NAS) is used to grade the severity of NAFLD [25].
The NAS is the sum of the biopsy’s scores for steatosis and lobular inammation
(on a scale from 0 to 3) and hepatocellular ballooning (0–2). Fibrosis is not graded.
Scores ranging between 5–8 are largely considered diagnostic of NASH.Other histologic scoring systems for NASH exist but are not discussed here.
8.5 Treatment
Certain general measures are applied to a patient’s lifestyle in order to manage disease progression and lower the chances of developing other co-morbidities.
Alcohol use—Heavy alcohol use is associated with advanced disease progression so all patients with NASH are advised to abstain from alcohol, but in particular
avoid an episode of heavy drinking (dened as more than 14 drinks per week or
more than 4 drinks on a single day for men and more than 7 drinks per week or more
than 3 drinks on a single day for women) [28].
Vaccines—With a damaged liver, a patient may be more susceptible to developing certain infections. Vaccination for available hepatitis serotypes should be given
to patients without serologic evidence of immunity. Other vaccines recommended
for patients with chronic liver disease include pneumococcal, inuence, tetanus, and
other vaccines given to the general population.
Weight loss—Lifestyle interventions can help to improve fat deposition on the
liver, liver biochemical tests, serum insulin levels, and overall quality of life. This is
especially important for overweight and obese patients with NASH.Patients are
advised to adhere to a diet and exercise plan tailored to their goals. If these goals
have not been met within 6months, bariatric surgery or drug therapy may be considered. For suspected NASH, patients are advised to lose 1–2lbs per week with
their plan with the overall goal of losing 5–7% of their body weight. For biopsy
conrmed NASH patients, the treatment is more intensive, with an overall goal of
7–10% body weight drop within 6months [29, 30]. Several studies suggest that a
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minimum drop of 5% body weight is needed to see improvement in hepatic steatosis, while greater than a 7% drop has been associated with a reduction in the patient’s
NAS score [31].
8.6 Medication
• Metformin—evidence for the use metformin in treating NAFLD and NASH has
shown little benet in both children and adults. It may be more effective than no
treatment at all in reducing metabolic parameters to a normal level, but it does
little to improve the inammation and brosis seen in NASH [14].
• Glitazones, peroxisome proliferator activated receptor stimulators that reduce
insulin resistance, are recommended for individuals with advanced liver brosis
to help reduce the progression. Adding vitamin E to this treatment has also been
shown to further reduce brosis progression. The patient’s other comorbidities
should be considered before administering this treat (i.e., glitazones are contra-
indicated in heart failure, current or previous history of bladder cancer, etc.).
Long-term outcomes of this treatment have not been identied [14].
• New therapies like NGM282, a recombinant broblast growth factor 19 ana-
logue, have been associated with greater than 30% decrease in liver fat content
across 12weeks in patients with NASH, and one study looking at 43 patients
with NASH, and the effect on the stage of brosis, showed improvement in liver
histology and stage of brosis in 50–68% of patients. These therapies are still
undergoing long-term testing and adverse effects are still being evaluated. Due to
its limited availability, this drug is also very expensive.
• Other options used for NAFLD, like statins and orlistat, are not recommended
for treating NASH, specically.
Bariatric surgery—If patients do not meet their goals after 6months, they may
be referred for a bariatric surgery evaluation. Bariatric surgery has been shown to
improve quality of life and demonstrate improvements on histological evaluation.
Bariatric surgery, in patients with obesity, reduces liver fat and progression of
NASH.Several retrospective studies, and one study monitoring patients for a 5-year
period after surgery, have shown that bariatric surgery can improve or even reverse
NAFLD, NASH, and brosis [32, 33]. However, there is some evidence that suggests that bariatric surgery is associated with worsening liver enzyme levels and
they need to be monitored over a 3-month period post-operatively [22]. Foregut
bariatric surgery is not recommended yet specically for treating NASH.
Liver transplantation—Liver transplant has been shown to be an efcacious
therapy for decompensated liver disease caused by NASH.The European Association
for the Study of the Liver has guidelines for when patients with NASH with
8 Nonalcoholic Steatohepatitis (NASH)
101
concurrent HCC or liver failure can be considered for liver transplant. A few of the
indications for assessment for transplant include:
• Acute liver failure
• Ascites
• HCC
• Encephalopathy
Some of the contraindications for liver transplant are the following:
• AIDS
• Liver cancer with metastases
• Continuous alcohol or illicit substance abuse
• Sepsis
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