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303© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2023
W. H. Sobin et al. (eds.), Managing Complex Cases in Gastroenterology,
https://doi.org/10.1007/978-3-031-48949-5_65
Chapter 65
Suspected NAFLD
JamesEsteban
A 35-year-old Latin female is being evaluated for elevated liver enzymes. She has
an ALT of 160, AST of 120, Alk phos of 140 (nL up to 80), bilirubin of 1.2, platelet
count of 180,000, and albumin of 3.8. She has no alcohol and no family history of
liver disease. She is on no medications. Her BMI is 32, and her HbA1C is 6.2.
Hepatitis panel is negative, autoimmune markers are negative, and ceruloplasmin
and alpha-1 antitrypsin phenotype are normal.
How would you approach this patient?
She may have nonalcoholic fatty liver disease, or NAFLD, based on her risk fac-
tors of increased BMI and prediabetes. We need to get an abdominal or right upper
quadrant ultrasound for conrmation that she has hepatic steatosis. It is important to
test and exclude other causes of chronic liver diseases, such as chronic viral hepati-
tis; autoimmune liver diseases, like autoimmune hepatitis and primary biliary chol-
angitis; and inherited metabolic types of liver diseases, such as hemochromatosis,
Wilson’s disease, and alpha-1 antitrypsin deciency. We should check that the
patient is not receiving known steatogenic medications, such as methotrexate, amio-
darone, or certain systemic chemotherapeutic agents.
Recognizing the primacy of metabolic risk factors on the pathogenesis of the
disease and the exclusionary and potentially stigmatizing verbiage of the current
nomenclature, an international expert panel recently published a consensus state-
ment renaming NAFLD to metabolic dysfunction-associated steatotic liver disease,
or MASLD [1].
Ultrasound shows steatosis without obvious signs of cirrhosis or portal
hypertension.
J. Esteban (*)
Division of Gastroenterology and Hepatology, Department of Medicine, Medical College of
Wisconsin, Milwaukee, WI, USA
e-mail: jesteban@mcw.edu
https://t.me/medicina_free
304
What are your next steps?
First, I will stratify the patient’s risk for signicant brosis. Inammation (or
nonalcoholic steatohepatitis, NASH) and brosis are the most important predictors
of hepatic decompensation, hepatocellular carcinoma, and mortality [2]. This can
be done noninvasively through the use of serum biomarkers or through elastography
or invasively with liver biopsy.
Biomarkers from standard lab tests can be used to calculate risk scores, such
as NAFLD fibrosis score (NFS) or the Fibrosis-4 (FIB-4) index. Both are
accessible from various publicly available websites. There are also proprietary
serum biomarkers such as FibroMeter
®
(Echosens) and the Enhanced Liver
Fibrosis or ELF™ score (Siemens). Proprietary biomarkers are slightly more
accurate that nonproprietary biomarkers in diagnosing significant and advanced
liver fibrosis.
On the other hand, elastography measures the stiffness of the liver and uses this
as a surrogate for the stage of liver brosis. In the clinic, vibration-controlled tran-
sient elastography or FibroScan
®
(Echosens) is available and provides real-time
results at the bedside. Radiologists are also able to measure liver stiffness through
ultrasound elastography or magnetic resonance (MR) elastography.
Negative predictive values of these noninvasive markers are generally very good
and, thus, “low” or “low risk” values, in general, excludes advanced liver disease.
However, the positive predictive values of these tests for diagnosing signicant
stages of brosis (i.e., stage 2 and above), and cirrhosis, are not as good (although
still reasonable). Patients with “indeterminate,” “high,” or “high risk” values on
noninvasive testing may be offered a liver biopsy to clarify brosis staging and
determine the presence of steatohepatitis. If the biopsy shows NASH and brosis,
then the patient may benet from off-label use of pharmacotherapies, such as pio-
glitazone and glucagon-like peptide-1 (GLP-1) receptor analogs, or from enroll-
ment in a clinical trial.
Next, all patients with NAFLD/MASLD should be counseled on lifestyle inter-
ventions. We should counsel the patient to lose at least 5–7%, and ideally >10%, of
their body weight. Weight loss of at least 5%, 7%, and 10% is associated with,
respectively, reduction in hepatic steatosis, resolution of NASH, and stabilization
and potential regression of liver brosis [3]. Other lifestyle interventions that can be
recommended include:
• Reduce daily calories by 500–1000kcal/day.
• Minimize saturated fats and rened carbohydrates.
• Avoid sugar-sweetened beverages.
• Mediterranean diet should be considered, although low-carb/low-fat diet and
intermittent fasting both appear to have comparable efcacy.
• Regular physical activity equivalent to 150–300min weekly of moderate inten-
sity aerobic exercise.
• Some resistance and weight training should complement aerobic exercise.
J. Esteban
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305
While weight loss is very important, many of these other interventions can
improve hepatic steatosis and steatohepatitis, even without signicant weight loss,
especially among patients with lean NAFLD/MASLD.
Patients always ask if they should avoid alcohol. Early data suggested that light
alcohol may be protective in NAFLD or MASLD. However, more recent data from
prospective studies indicate that “moderate” alcohol use reduces the likelihood of
clearing NASH while increasing the risk of brosis [4].
You have a FibroScan
®
in your clinic, are you getting a FibroScan
®
on all
patients like this? How accurate is the FibroScan
®
in NAFLD?
I routinely obtain a FibroScan
®
on all of my NAFLD/MASLD patients. FibroScan
has >90% negative predictive value for ruling out advanced brosis in NAFLD/
MASLD [5]. Thus, if liver stiffness on FibroScan
®
is low, or less than 7–8kPa, I feel
comfortable and condent in excluding advanced brosis. I reassure the patient, and
we continue working on lifestyle interventions.
The positive predictive value for FibroScan
®
in diagnosing signicant brosis
and cirrhosis in NAFLD/MASLD patients is modest, ranging from 40 to 70% [6],
especially if the patients are overweight and obese. The positive predictive value is
better in those with lean NAFLD/MASLD. For these patients, I offer liver biopsy
for staging purposes.
How do liver biopsies get done at your institution?
Liver biopsies can be done percutaneously, by a hepatologist or by a diagnostic
radiologist, or transvenously, by an interventional radiologist. In percutaneous biop-
sies, the proceduralist may elect to do the procedure under direct ultrasound guid-
ance (usually the radiologists) or “blindly” after identifying and marking suitable
intercostal areas via bedside ultrasound (usually the hepatologists).
In transvenous or transjugular liver biopsy, the interventional radiologist passes
a wire and needle through the internal jugular vein, down the vena cava, and into a
hepatic vein (usually the right), from where they collect cores of liver tissue. The
interventional radiologist can also measure free and wedged hepatic venous pres-
sures during the same procedure, which provides valuable information in diagnos-
ing portal hypertension.
References
1. Rinella ME, Lazarus JV, Ratziu V, Francque SM, Sanyal AJ, Kanwal F, et al. A multi-
society Delphi consensus statement on new fatty liver disease nomenclature. Hepatology.
2023;29(1):101133.
2. Sanyal AJ, Van Natta ML, Clark J, Neuschwander-Tetri BA, Diehl A, Dasarathy S, et al.
Prospective study of outcomes in adults with nonalcoholic fatty liver disease. N Engl J Med.
2021;385(17):1559–69.
3. Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B,
Gonzalez-Fabian L, etal. Weight loss through lifestyle modication signicantly reduces fea-
tures of nonalcoholic steatohepatitis. Gastroenterology. 2015;149(2):367–78.
65 Suspected NAFLD
https://t.me/medicina_free
306
4. Ajmera V, Belt P, Wilson LA, Gill RM, Loomba R, Kleiner DE, et al. Among patients with
nonalcoholic fatty liver disease, modest alcohol use is associated with less improvement in
histologic steatosis and steatohepatitis. Clin Gastroenterol Hepatol. 2018;16(9):1511–20.
5. Mózes FE, Lee JA, Selvaraj EA, Jayaswal ANA, Trauner M, Boursier J, etal. Diagnostic accu-
racy of non-invasive tests for advanced brosis in patients with NAFLD: an individual patient
data meta-analysis. Gut. 2022;71(5):1006–19.
6. Xiao G, Zhu S, Xiao X, Yan L, Yang J, Wu G.Comparison of laboratory tests, ultrasound, or
magnetic resonance elastography to detect brosis in patients with nonalcoholic fatty liver
disease: a meta-analysis. Hepatology. 2017;66(5):1486–501.
J. Esteban
https://t.me/medicina_free
307© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2023
W. H. Sobin et al. (eds.), Managing Complex Cases in Gastroenterology,
https://doi.org/10.1007/978-3-031-48949-5_66
Chapter 66
Treatment ofNAFLD
FranciscoDurazo
An obese nondiabetic male, age 39 with a BMI of 34, is referred with an ultrasound
showing steatosis. He has one or two drinks each weekend. His platelet count is
170K.His ALT is 75, AST is 48, and alk phos is 150. His hepatitis panel, ANA,
ASMA, alpha-1-antitrypsin, ceruloplasmin, and celiac panel are all normal.
How would you manage this patient?
We explain that this is not purely a liver disease but rather a systemic inamma-
tory condition. Many people with fatty liver and normal glucose have insulin resis-
tance. Therefore, just having a fatty liver should be a red ag for insulin resistance,
present in as many as 95% of people with fatty liver.
Treatment is not aimed specically at the liver but rather at the entire body. The
rst thing we recommend is exercise. Studies have shown that consistent exercise
over a 2-year period signicantly improves steatosis and brosis on liver biopsy. We
recommend a Mediterranean diet, avoiding fructose and avoiding alcohol. We rec-
ommend drinking 2–3 cups of regular coffee daily.
We recommend weight loss. Evidence shows that weight loss of 10% of total
weight leads to dramatic improvement in liver histology. In a patient who weighs
240, a 10% loss in weight requires only losing 1 pound a week over 6months.
For patients who are diabetic, pioglitazone is benecial. It is certainly a far better
choice than insulin for patients with NAFLD.We offer vitamin E to patients with
biopsy proven NASH.We prefer to use it in women because vitamin E may increase
the rate of prostate cancer.
F. Durazo (*)
Division of Gastroenterology and Hepatology, Department of Medicine,
Medical College of Wisconsin, Milwaukee, WI, USA
e-mail: fdurazo@mcw.edu
https://t.me/medicina_free
308
We recommend bariatric surgery for those patients with NAFLD and a BMI >40,
who can’t lose weight by other means, or in patients with a BMI >35, who have
other comorbidities, like obstructive sleep apnea, diabetes that is hard to control, or
severe hyperlipidemia.
Can you predict which patients with NAFLD will have a more ominous clin-
ical course?
Yes, we think the NAFLD brosis score is a good noninvasive predictor.
F. D u r a z o
https://t.me/medicina_free
309© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2023
W. H. Sobin et al. (eds.), Managing Complex Cases in Gastroenterology,
https://doi.org/10.1007/978-3-031-48949-5_67
Chapter 67
Treatment ofMASLD
AchutanSourianarayanane
A 43-year-old female with a BMI of 31 is seen by her primary care doctor and found
to have an AST of 60 and an ALT of 90. She is prediabetic and has one or two drinks
on weekends. Alkaline phosphatase and bilirubin are normal. Other labs are sent
off, including hepatitis panel, autoimmune panel, ceruloplasmin, A1AT, and Fe/
TIBC, which return normal. Ultrasound shows steatosis. The doctor tells her to
abstain completely from alcohol and try to lose 20 lbs. over the next 3months. If her
liver enzymes don’t improve, he says, he will refer her to a hepatologist, and she
might end up needing a liver biopsy.
1. Is this initial strategy of weight loss and abstention and then waiting and
seeing reasonable?
Her imaging suggests the presence of hepatic steatosis. Based on the pattern of
liver chemistry, along with the presence of metabolic risks and the absence of excess
alcohol intake, her fatty liver is secondary to metabolic dysfunction-associated stea-
totic liver disease (MASLD). MASLD is the current terminology for nonalcoholic
fatty liver disease (NAFLD), which is an encompassing diagnosis of those with fatty
liver with metabolic risks. Similarly, metabolic dysfunction-associated steatohepa-
titis (MASH) is the replacement term for prior nonalcoholic steatohepatitis (NASH).
Lifestyle changes are the most important components for the management of this
condition and should be incorporated in every patient with MASLD.Although she
does not consume excess alcohol, reduction or abstinence from alcohol will facili-
tate improvement in her liver disorder. Hence, the recommendation for abstinence is
appropriate within the current guidelines. Studies recommend lifestyle changes that
result in sustained weight loss of 5–7%, which has been found to be benecial to
patients with MASLD.It also helps many patients with prediabetes improve their
A. Sourianarayanane (*)
Division of Gastroenterology and Hepatology, Department of Medicine, Medical College of
Wisconsin, Milwaukee, WI, USA
e-mail: asourianar@mcw.edu
https://t.me/medicina_free
310
overall health and the metabolic risk associated with MASLD.Although a target
weight loss of 5–7% is considered appropriate, it may be difcult for most patients
to achieve consistently. Improvement in metabolic risks has been noticed, with con-
sistent lifestyle changes, including diet and exercise, even in the absence of weight
loss. This may need to be considered in subsequent clinical visits and recommenda-
tions [1–3].
2. If the numbers were reversed and the AST was 90 and ALT 60, would that
raise any alarm bells?
A liver chemistry pattern with an AST higher than ALT can suggest more than
one clinical possibility in this patient. The occurrence of AST higher than ALT in
patients with MASLD could raise concerns about advanced brosis or even the
presence of cirrhosis. However, her AST was 1.5 higher than her ALT.This could
also raise concerns about other causes, such as a relatively higher level of alcohol
consumption than could be safely metabolized by her liver. Her alcohol usage is
well within liver societies’ and the American Dietary Association’s recommenda-
tions. It is possible a person’s perception of the standard unit of alcohol measure
differs from those recommendations; besides, the effect of a given amount of alco-
hol may vary in an individual [2, 4].
She is only able to lose 5 lbs., and her repeat LFTs 3months later are essentially
unchanged. She is referred to you, the hepatologist.
3. Is there any role for FibroScan
®
? Would you order one? What would be
the considerations in deciding on this or using any other noninvasive measure
for the presence of brosis or potentially classifying her as having steatohepa-
titis versus simple fatty liver?
Liver chemistries, commonly called liver function tests, do not reect the sever-
ity of liver disease. She could have hepatic steatosis with an ongoing inammatory
process and brosis. The MASLD brosis score and FIB-4 are commonly used
noninvasive biomarkers based on clinical and biochemical parameters. These bio-
markers stratify patients into a low, intermediate, or advanced stage of MASLD.These
tests are easily available and less costly to administer. Although these biomarkers
are sensitive enough to detect an advanced stage of the disease, they are less specic
in diagnosing them. Hence, a second test, such as FibroScan
®
, should be used to
conrm the diagnosis, when available [5, 6].
The duration of the disease was not known in this patient. She also has a meta-
bolic risk and elevated aminotransferases. As MASLD is a “silent disease” with
minimal or no symptoms until the onset of decompensated cirrhosis, assessing the
severity of the disease is appropriate. An evaluation by FibroScan
®
is appropriate.
4. How accurate is FibroScan
®
when evaluating fatty liver? Do you rely on
the CAP score?
FibroScan
®
can diagnose the presence of fat in the liver if it is more than 11%.
Following a FibroScan
®
(also called vibration-controlled transient elastography
®
),
two sets of results are obtained. One is a controlled attenuation parameter (CAP),
which correlates with the presence of hepatic steatosis or a fatty liver. It requires the
presence of hepatic steatosis of >11% to be detected and quantied by this method.
A. Sourianarayanane
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311
Studies have shown that the CAP value correlates with the histological grade of
steatosis. The cutoff ranges used to differentiate various histological grades of ste-
atosis may vary due to patient characteristics, such as BMI.The other value obtained
from FibroScan
®
is transient elastography measured in kilopascals, which indicates
the brosis stage of liver disease in MASLD.The elastography results may be less
reliable in patients with a BMI of >35 [7, 8].
The SAF score (steatosis, activity, and brosis) is a histological scoring system
for patients with MASH.It is used mostly in Europe and in MASLD research. A
similar histological scoring system called NAFLD activity score (NAS) proposed
by the NASH Clinical Research Network (CRN), which is often referred to as the
NASH-CRN, is used commonly in the United States.
5. Would you do a liver biopsy? Which patients do you think should have a
liver biopsy?
A liver biopsy to diagnose or stratify a patient with MASLD is becoming less
common. The use of liver biopsy is usually considered for patients in whom there is
a concern for an advanced stage of brosis. Noninvasive tests are recommended to
stratify MASLD patients initially as a screening test. These tests, such as the
MASLD brosis score, FIB-4, etc., are based on clinical and biochemical parame-
ters. These tests have a high sensitivity for detecting patients with an advanced stage
of MASLD. Individuals who are found to have a low probability of advanced
MASLD do not require further testing. A second test with higher specicity, such as
elastography (FibroScan
®
), is performed on patients with an intermediate or
advanced stage on initial screening tests. Patients who cannot be categorized and are
considered to have intermediate risk will benet from liver biopsy staging. A liver
biopsy is also required if the patient is considered for a clinical trial [5].
If this patient has a BMI of less than 35, the FibroScan
®
test results could be
considered reliable. If FibroScan
®
elastography does not suggest advanced brosis
(<10kPa), a liver biopsy is not recommended. A liver biopsy could be considered
otherwise [8].
6. Other than avoiding alcohol and weight loss, are there any other second-
ary, behavioral, or dietary measures that can be helpful? Would you have done
any other serologic or other testing at this point? Do you routinely check all
your patients for alcohol use even if they claim to drink minimally, such as in
this patient?
Signicant sustained weight loss has been shown to improve many histological
parameters seen in MASLD.A 5–7% weight loss has been associated with a reduc-
tion in steatosis. With additional weight loss, other histological features, such as
inammation and brosis reduction, have been documented. A weight loss of >15%
has been shown to improve brosis stages on histology. Avoidance of alcohol is an
important factor among those who have histological improvements with weight
loss. Signicant and sustained weight loss is not easily achievable by most patients.
Other lifestyle changes, such as regular exercise outside work, improve the overall
health of the liver. Some of the biochemical parameters and insulin sensitivity have
improved with this measure, even in the absence of weight loss [2, 3].
67 Treatment ofMASLD
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312
Different diets have been suggested for the management of patients with
MASLD.These include diet modication based on the reduction of macronutrients,
such as fat, and carbohydrates, including fructose, either individually or in combi-
nation and along with a variation in the time of meal consumption. These modica-
tions have resulted in weight loss and an improvement in their body weight,
metabolic risks, and liver aminotransferases. Many of these modications are dif-
cult to maintain, and a long-term benet is less often achieved. A portion- and
calorie- controlled Mediterranean diet (without alcohol use) is benecial in MASLD
and is also easier to adhere to in the long term. Studies have also found that caffeine
intake is associated with a reduced progression of MASH.
Some providers routinely recommend tests such as phosphatidylethanol (PEth)
to measure alcohol in patients with a presumed diagnosis of MASLD to corroborate
the role of alcohol in their disease. This is considered, because an individual’s per-
ception of the standard unit of alcohol measure may differ from the guidelines of
liver societies and the American Dietary Association. Additionally, many people
underestimate their alcohol use. Patients with MAFLD can include those with alco-
hol usage or viral infection. This is a move away from the use of MASLD, which is
a diagnosis of exclusion in those with an absence of other causes.
Scenario 1 Liver biopsy shows steatosis without any changes of steatohepatitis or
any brosis.
7. Is steatosis without steatohepatitis a benign entity? Is the prognosis that
much better? Do you have thoughts on what proportion of these patients prog-
ress to more severe liver injury? Does this depend on the risk factors?
Our initial understanding of the minimal or nonprogressive form of MASLD
patients with simple steatosis was mainly from retrospective studies. These studies
found that patients with hepatic steatosis without MASH had a benign course and
did not progress to MASH.Newer studies suggest that a portion of patients with
steatosis alone without MASH on initial biopsy had ndings of MASH on subse-
quent histological evaluation. The proportion of patients with initial simple steatosis
who progress to advanced disease is unknown. Some studies suggest that nearly
25% of these patients may progress to MASH or may even have brosis later.
Insulin resistance plays a signicant role in progressive disease. Among all the fac-
tors, the presence of brosis is signicant and associated with poor outcomes in
patients with MASLD [9].
8. In this scenario, are there any medications that you would consider or
would initiate at this point?
Currently, there are no FDA-approved medications for patients with simple ste-
atosis. The only approved medication is vitamin E, which is considered for patients
with biopsy-proven MASH without type II diabetes. This patient has diabetes and
does not have MASH; hence, lifestyle changes without additional pharmacological
agents is appropriate for her [10, 11].
A. Sourianarayanane
https://t.me/medicina_free
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