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Scenario 2 Same patient but now the liver biopsy shows changes of steatohepati-
tis, including ballooning without any brosis.
9. What does it take to turn steatosis into steatohepatitis? Are there any
causative factors you can identify, modify, or even prevent?
Multiple pathophysiological processes are now considered to contribute to the
progression of MASLD.Type II diabetes, or insulin resistance, is an important fac-
tor associated with the progression of the disease. An inammatory process second-
ary to lipid accumulation and a dysfunctional oxidative process, called lipotoxicity,
occur. Different chemicals are released because of these inammatory processes.
This creates a subsequent event that results in neutrophil and lymphocyte accumula-
tion, altered cell death, brosis deposition by macrophages, and the progression of
the disease to steatohepatitis. Lifestyle changes that result in a consistent reduction
of metabolic risks, such as excess body weight, insulin resistance, and other modi-
able factors, reduce the progression to steatohepatitis [2, 3, 10].
10. Once you’ve developed steatohepatitis, is this fully reversible? What is
the chance of sampling error on the biopsy?
Fortunately, this patient does not have brosis. It may be easier to reverse the
inammatory process and steatosis in the absence of brosis. Both steatosis and
steatohepatitis reversal are possible with signicant weight loss (possibly 7–10%),
along with metabolic risk reduction. However, complete improvement may not
occur in all patients. A liver biopsy is a reliable way to diagnose MASLD and stage
accurately, although it samples only 1/50,000 or 1/100,000th of the entire liver
organ. It has been suggested that there could be errors due to this. Studies have
shown variations between two samples taken on the same day and from different
lobes of the liver. Despite these variations, liver biopsy is the current gold standard
for the diagnosis of this condition.
11. Do you think you can “save” many of these patients from developing
advanced brosis?
Active research and clinical trials are being conducted to mitigate MASLD and
its progression. As more than one pathophysiological process is involved, a combi-
nation of medications is administered to reduce brosis formation and progression.
Lifestyle changes remain a consistent and valuable component of this disease’s
management. If possible, a combined holistic approach would be the key to improve-
ment for most of these patients.
12. What medications, if any, would you initiate in this particular case based
on the biopsy? Any other secondary measures?
Studies have shown that a sustained weight loss of 7–10% could reverse the
inammatory process. With this weight loss, there is an associated improvement in
metabolic risks, such as insulin resistance, hypertension, and lipid prole, which
contribute to an overall improvement in MASLD patients. This could be achieved
through consistent lifestyle changes, such as dietary and exercise modications.
There are also a few pharmacological agents being considered.
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Vitamin E is used in patients without diabetes and has shown improvement in
steatohepatitis. Incretins, such as GLP-1 agonists (liraglutide and semaglutide), are
benecial for MASLD patients with and without diabetes. Studies have shown
improvement in liver aminotransferase levels, improvement of steatohepatitis, and
weight loss, and lowering of HbA1c among diabetes patients is seen with GLP-1
agonists. Obeticholic acid is another agent that modies bile acid synthesis; it
reduces inammation in the liver and brosis in MASH patients because of this.
These agents are in the nal stages of clinical trials for MASH.Many newer phar-
macological agents are undergoing clinical trials, either alone or in combination;
they modify different metabolic processes involved in MASLD. These agents
include those modifying lipid synthesis, the oxidative process, cell death, and bro-
sis formation. Bariatric surgery is another important and valid consideration in
appropriate patients with MASH [10–12].
Scenario 3 Liver biopsy shows steatohepatitis and stage 3 brosis.
13. How often would you expect to detect patients with fatty liver who are
already in stages of advanced brosis/cirrhosis?
Most patients with MASLD do not have symptoms; hence, many are diagnosed
incidentally on abdominal imaging for other reasons. A portion of this diagnosis can
occur in their late stages of the disease. It is estimated that <5% of patients with
MASLD may progress to cirrhosis; therefore, we can expect that <5% of MASLD
patients may have advanced brosis at the time of detection.
14. How reversible is this stage of liver disease? With what measures?
Fibrosis is less likely to reverse with lifestyle changes and with currently
approved pharmacological agents. A weight loss of >15% may be required for
improvement in brosis. Bariatric surgery is one option, especially for patients with
advanced brosis. A reduction in the brosis stage has been observed many years
after successful bariatric surgery. Newer pharmacological agents that modify col-
lagen synthesis and deposition are being considered. If these agents are successful,
they may also alter the course of this disease [10–12].
15. Assuming that you implement screening for esophageal varices and con-
sidering HCC surveillance, are there other measures you would imple-
ment now?
Esophageal varices screening and HCC surveillance are usually considered for
patients with cirrhosis. Liver societies do not recommend routine screening for vari-
ces or HCC in patients without cirrhosis. As this patient has advanced brosis, she
will benet from periodic evaluation for brosis progression and the onset of cir-
rhosis with FibroScan
®
or transient elastography. Elastography, as measured in kilo-
pascals, correlates with portal pressure and decompensated liver disease. If there is
an increase in kilopascals and a signicant reduction in platelets (<180), the above
screenings should be considered. When performing ultrasound-based elastography,
the results may be less reliable if the patient has a high BMI.Due to a similar rea-
son, ultrasound is less reliable in detecting liver lesions in subjects with high
BMI.Some consider an MRI (which is costly) or a CT scan (which could be a con-
cern in patients with renal dysfunction), alternating with ultrasound imaging for
HCC screening [2, 8].
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16. Any medications you would start in this case?
In this patient, with the suggestions of steatohepatitis and the absence of overt
diabetes, adding 800units of vitamin E to her medication regimen is appropriate.
Semaglutide, a GLP-1 agonist, or a similar agent can also be considered after appro-
priately educating the patient about the side effects and how to use it. This can
improve her body weight, insulin sensitivity, and liver aminotransferases. If she has
hyperlipidemia, a statin to reduce it would also be appropriate [10, 11].
17. Do you believe that patients with MASH truly progress to HCC without
developing cirrhosis rst? Why is this, and do you screen any/all of your
patients with MASH for HCC?
About 10% of patients who have HCC with a diagnosis of MASLD do not have
cirrhosis. Many of the risk factors related to MASLD, such as a high BMI and dia-
betes, are also associated with malignancy, including HCC.However, no denitive
pathway has been found in MASH patients. Many of our screening protocols are
based on the costs involved in diagnosing a treatable condition and the quality of
life rendered to society as a result of it. This is based on the prevalence of the disease
and the incidence of HCC in a specic population. The current consensus guidelines
do not recommend screening for patients with MASH without cirrhosis for HCC,
unlike in patients with hemochromatosis or hepatitis B infection, where it is recom-
mended even in the absence of cirrhosis [2].
18. When would you refer this patient for a liver transplant? What would be
the chance of recurrence of MASH post-transplant?
MASH patients should be evaluated for liver transplantation in the appropriate
clinical setting, like any other patient. This would be in patients who have decom-
pensated liver disease or those with a relatively high model for end-stage liver dis-
ease (MELD). The referrals and transplantations for patients with MASLD are
usually no different from those for other chronic liver disorders. Many MASLD
patients also have other comorbidities that could be a concern during the periopera-
tive and postoperative phases. These should be evaluated to reduce morbidity or
mortality posttransplant through a multidisciplinary approach.
Following liver transplantation, the recurrence of hepatic steatosis among
patients with a pretransplant diagnosis of MASH is high. Hepatic steatosis occurs in
patients who have undergone liver transplantation for more than one reason [13].
Immunosuppressive agents required for the maintenance of the transplanted liver
are associated with many metabolic factors and increase the risks for hepatic steato-
sis posttransplantation. However, not all post-liver transplant patients with hepatic
steatosis develop MASH.
General Questions
1. Which patients with MASLD/MASH should consider having bariatric
surgery?
Any patient who could otherwise benet from a bariatric procedure for their
health will also benet if they have MASLD.Patients with MASH with advanced
brosis would benet from signicant weight loss following a bariatric procedure.
A weight loss of >15% occurs frequently following a bariatric procedure. A reduc-
tion or clearance of steatosis and inammation, including ballooning cells, is found
67 Treatment ofMASLD
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following a successful bariatric procedure. Stabilization or even a reduction of
brosis is seen after many years (>5years). Patients with decompensated cirrhosis,
however, do not do well following bariatric surgery and are not generally recom-
mended to undergo this procedure [12].
2. How do patients with MASLD and brosis/cirrhosis compare to patients
with ALD in the same stage of disease? Assuming the alcoholic has stopped
drinking, which has the worse prognosis? Who will have a better outcome after
a liver transplant?
A direct comparison of outcomes between patients with ALD and MASLD is not
easy. Patients with MASLD may continue to have metabolic risks and may have
gradual MASLD progression over time. However, many patients with ALD may
improve or may not progress if their consumption of alcohol is discontinued entirely.
The patient outcomes in these two groups could also be affected by their age and
comorbidity, in addition to their liver disease-related outcomes. Many patients with
MASLD are older and have comorbidities due to the presence of metabolic risk
(i.e., high BMI, diabetes, and hyperlipidemia), such as cardiovascular, cerebrovas-
cular, and renal disorders. These could contribute to reduced overall outcomes fol-
lowing liver transplantation.
3. Is liver transplant restricted for any of the MASLD patients?
It is possible that MASLD patients have signicant cardiovascular or other
comorbidities. As in any other patient, these risk factors have a bearing on periop-
erative and postoperative complications and may restrict those undergoing liver
transplantation. The body habitus of the patient may also cause some restrictions on
undergoing liver transplantations. Retrospective and large database studies suggest
that patients with a BMI >50 do not do as well as those with a BMI <50 following
liver transplantation. With the increasing technology and training of surgeons, many
patients with a higher BMI are undergoing liver transplantation with a good out-
come [14].
4. In which MASLD patients do you like to use vitamin E, pioglitazone, and
GLP-1 agonists?
Currently, the FDA recommends pharmacological intervention for patients with
a histological diagnosis of MASH. Vitamin E has been found to be benecial in
MASH patients with improvement of inammation and balloon cells on histology
among patients without diabetes. In patients with diabetes, vitamin E has not proven
to be benecial. Some researchers recommend a combination of pioglitazone and
vitamin E for patients with diabetes and MASH.Others feel that the benet observed
with this combination therapy is from pioglitazone alone and that the use of vitamin
E may not be required. Pioglitazone causes a reduction in hepatic steatosis. They
also have an increase in subcutaneous fat and overall weight gain. Hence, it is not
considered a preferred treatment for most patients. GLP-1 agonists can be used in
all patients with MASH, especially those with type II diabetes. They have also been
considered for the management of obesity. These patients should be educated about
potential hypoglycemic episodes when a GLP-1 agonist is used [10, 11].
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5. Are any other drugs you like to use today in MASLD patients?
Statins have been found to benet patients across the spectrum of MASLD.They
have been associated with a reduction in the progression of the disease. Statins also
benet patients with hyperlipidemia, which is an important metabolic risk factor
in MASLD.
6. Are there any other drugs that are promising that you anticipate being
available in the next 5years?
There are many drugs undergoing clinical trials in various phases that could be
used for the treatment of MASH.Obeticholic acid, an FXR agonist, has been prom-
ising. It reduces the inammatory process in addition to brosis reduction in MASH
patients. A variation of this agent (Cilofexor) with fewer side effects is also being
considered. Cenicriviroc, a chemokine antagonist, reduced brosis in MASH
patients. Aramchol, an acetyl-co A inhibitor, and resmetirom, a thyroid hormone
receptor (ꞵ) agonist, reduced hepatic steatosis among MASLD patients. Elabranor,
lanibranor, and other peroxisome proliferator-activated receptor agonists reduce
inammation in MASH. Agents that directly act on collagen and elastin cross-
linkage (e.g., simtuzumab), reduce cell death and apoptosis (e.g., selonsertib), and
reduce brosis may also be available. These drugs could be used either alone or in
combination for an overall effective management of MASH in the future [10, 11].
References
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fatty liver disease nomenclature. Hepatology. 2023;29(1):101133. https://doi.org/10.1097/
HEP.0000000000000520.
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fatty liver disease: practice guidance from the American Association for the Study of Liver
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ease. Minerva Gastroenterol Dietol. 2013;59(1):69–87.
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relation to vibration controlled transient elastography: an NHANES analysis. Clin Res Hepatol
Gastroenterol. 2022;46(7):101997.
6. Sumida Y, Yoneda M, Tokushige K, Kawanaka M, Fujii H, Yoneda M, Imajo K, Takahashi
H, Eguchi Y, Ono M, Nozaki Y, Hyogo H, Koseki M, Yoshida Y, Kawaguchi T, Kamada Y,
Okanoue T, Nakajima A, Japan Study Group Of Nad Jsg-Nad. FIB-4 rst in the diagnostic
algorithm of metabolic-dysfunction-associated fatty liver disease in the era of the global meta-
bodemic. Life (Basel). 2021;11(2):143.
7. Sasso M, Miette V, Sandrin L, Beaugrand M.The controlled attenuation parameter (CAP):
a novel tool for the non-invasive evaluation of steatosis using Fibroscan. Clin Res Hepatol
Gastroenterol. 2012;36(1):13–20.
8. Caussy C, Chen J, Alquiraish MH, Cepin S, Nguyen P, Hernandez C, Yin M, Bettencourt
R, Cachay ER, Jayakumar S, Fortney L, Hooker J, Sy E, Valasek MA, Rizo E, Richards L,
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Brenner DA, Sirlin CB, Ehman RL, Loomba R.Association between obesity and discordance
in brosis stage determination by magnetic resonance vs transient elastography in patients
with nonalcoholic liver disease. Clin Gastroenterol Hepatol. 2018;16(12):1974–1982.e7.
9. Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P,
Mills PR, Keach JC, Lafferty HD, Stahler A, Haidadottir S, Bendtsen F.Liver brosis, but no
other histologic features, is associated with long-term outcomes of patients with nonalcoholic
fatty liver disease. Gastroenterology. 2015;149(2):389–97.
10. Sourianarayanane A, Challa SR.Non-alcoholic fatty liver: current management and future
trends. Gut Gastroenterol. 2020;3:001–17.
11. Oseini AM, Sanyal AJ. Therapies in non-alcoholic steatohepatitis (NASH). Liver Int.
2017;37(Suppl 1):97–103. https://doi.org/10.1111/liv.13302.
12. Sasaki A, Nitta H, Otsuka K, Umemura A, Baba S, Obuchi T, Wakabayashi G. Bariatric
surgery and non-alcoholic fatty liver disease: current and potential future treatments. Front
Endocrinol (Lausanne). 2014;5:164.
13. Sourianarayanane A, Arikapudi S, McCullough AJ, Humar A. Nonalcoholic steatohepatitis
recurrence and rate of brosis progression following liver transplantation. Eur J Gastroenterol
Hepatol. 2017;29(4):481–7.
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A. Sourianarayanane
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319© 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_68
Chapter 68
Alcohol andLiver Disease inWomen
VeronicaLoy
A 60-year-old female is referred for elevated liver enzymes. She and her husband
enjoy drinking wine with dinner and have it most evenings. They generally each
have two glasses of wine, nishing off about 2/3 of the bottle.
Her physical exam is unremarkable. Her BMI is 20. Her AST is 90, ALT is 70, Alk
phos is 80, and bilirubin is 1.0. Hepatitis panel, autoimmune panel, ceruloplasmin,
and alpha-1 antitrypsin are all unremarkable. An US of the liver shows mild steato-
sis and no nodularity.
She is surprised because her husband recently had his annual physical exam and
his liver enzymes were normal.
What is your interpretation of these ndings, and can you describe the
increased susceptibility women have to alcoholic liver disease?
It looks to me like this woman has some mild alcohol-related steatohepatitis.
Thankfully, her synthetic function is intact with that normal bilirubin. Her ultra-
sound does not show nodularity, so there is no obvious cirrhosis, but that doesn’t
necessarily mean that she doesn’t have some brosis, because that is difcult to
assess by ultrasound alone. She does appear to have some mild alcohol-related
steatohepatitis.
Why would she have this and her husband doesn’t? I think that in every indi-
vidual, their own risk for developing steatohepatitis and ultimately cirrhosis of the
liver is multifactorial. One of those factors is gender. There are certainly a lot of
other factors. I don’t know other health differences between her and her husband,
but gender alone is a driving factor in the risk of developing brosis, cirrhosis, or
just alcohol-related steatohepatitis.
V. Loy (*)
Division Gastroenterology and Hepatology, Department of Medicine, Medical College of
Wisconsin, Milwaukee, WI, USA
e-mail: vloy@mcw.edu
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There are many reasons for gender differences in liver disease. First, we know
that female patients metabolize alcohol differently than males. As a result, females
have a higher rate of steatosis and inammation and cytokine release at a much
lower level of alcohol intake than males. Over the years, two to three glasses of wine
a night, for a decade, for a female, is enough to put someone at risk for cirrhosis.
Whereas in a male, it would be more like four to six a night. There is a very big dif-
ference in the way the body metabolizes alcohol at a lower level, which presents a
higher risk to these people. It also relates to body size and body mass. A smaller
stature person is going to have a lower threshold for damage from alcohol and gen-
erally women are smaller than men.
Most women are not aware of this distinction. Most of the women I see say that
they’re not drinking any more than their peers and they’re not drinking more than
their husband. They are astonished to end up in this situation. I really don’t think
there is enough awareness of the increased risk females have with alcohol
consumption.
We also know that in the primary care setting and the ER setting, women are far
less likely to be screened for alcohol use disorder. Even if female patients are
screened, they are far less likely to be referred for counseling or medical therapies.
We are really just not doing a good job of awareness in the medical community to
help these people prevent alcohol related liver damage.
What do you make of the AST>ALT?
Briey, the AST, being greater than the ALT, is thought to be predictive of
alcohol- related liver disease. The one caveat to that is once someone is cirrhotic,
regardless of the cause of cirrhosis, typically the AST is going to be higher than
the ALT.
I often see patients where their medical team is grilling them and accusing them
of drinking, because their AST is higher than their ALT.And they’re not drinking,
but they’re cirrhotic and that’s just what happens once someone is cirrhotic.
Would you simply advise the patient to stop drinking and follow the enzyme
levels over the next 3–6months, or would you do further investigations (i.e.,
FibroScan
®
, biopsy, etc.).
As far as what to do next, I would probably advise her to work on minimizing or
stopping alcohol and repeat the enzymes in 3–6months. The reason that I would not
advocate for a FibroScan
®
or a biopsy is that, rst of all, FibroScan
®
is not validated
in people who are actively using alcohol. We tend to see an overestimate of the level
of brosis on FibroScan
®
in someone who’s using alcohol. It’s just not accurate in
my opinion. Similarly, with biopsy, if a biopsy is obtained on someone when there
is a lot of active inammation, it’s very challenging for the pathologist to estimate
the amount of brosis. Finally, there is a really good chance in this woman that with
complete abstinence from alcohol the liver has a great chance to heal and regener-
ate. Therefore, what you see on a biopsy today may be very different from what you
see after 6months of abstinence, during which you give the body the tools it needs
V. L o y
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to repair itself. If she’s willing to stop, I think you’ll get a more accurate assessment
after waiting 6months. Unfortunately, many people aren’t willing to stop. Without
alcohol cessation, I would move on to a biopsy, not a FibroScan
®
. If they’re not
going to stop alcohol, the FibroScan
®
isn’t something I offer them.
68 Alcohol andLiver Disease inWomen
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323© 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_69
Chapter 69
Alcoholic Hepatitis
FranciscoDurazo
A 52-year-old executive is red from his job. Prior to that he would have two hard
drinks a day after work. After being red, he goes on a drinking binge for a month.
He nally gets dragged in to see the doctor by his wife when he becomes jaundiced.
His PT is 17, INR is 2.1, bilirubin is 12, AST is 80, ALT is 50, Alk phos is 120, creati-
nine is 1.2, Hgb is 11.8, and Maddrey score is 34.
How would you manage this patient with presumed acute alcoholic hepatitis?
These days, acute alcoholic hepatitis is overdiagnosed. It seems like everyone
who is drinking and presents with jaundice is immediately diagnosed with alcoholic
hepatitis. As a result, we see many patients placed on steroids and getting infections,
where steroids weren’t needed in the rst place.
So, the rst thing is to make sure this really is acute alcoholic hepatitis. On physi-
cal exam, we need to see an enlarged liver with a bruit. If we examine the patient
and there is not an enlarged liver, then it is probably alcoholic cirrhosis we are deal-
ing with.
The benet of steroids is limited. Even in the studies where acute alcoholic hepa-
titis was appropriately diagnosed and steroids given according to protocol, there
were a lot of complications, and the benet of steroids was quite modest. Therefore,
we refrain from using steroids, unless a patient presents with orid alcoholic hepa-
titis, where the diagnosis is obvious. Steroids are approved if the Maddrey score is
>32 (I prefer to hold out for an even higher Maddrey score). In that case, we will
give prednisolone for up to 28days.
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
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