Interactive Clinical Module 7A

Version 1.
1 – NAFLD & NASH ICM 7A

Basic Pathology and Immunology Prof. Marta Cilla 3/12/2020
Interactive Clinical Modules, lecture 7A
NAFLD & NASH

Marta Cilla, MD; Internal Medicine; Università Vita-Salute San Raffaele; IRCCS Ospedale San
Raffaele
Clinical Case
Today we will discuss a clinical case of a 48 y/o male, with a family history type II diabetes and
dyslipidemia. He was a former smoker, drinking a glass of wine per day. His prior medical history
includes appendectomy. The patient decided to have a checkup with bloodwork which showed an
increase of aspartate amino-transferase (value of 42U/L) whereas the normal value is less than
35U/L. He also had an increase of ALT one and a half times higher than the expected limit (83U/L,
whereas normal value is less than 59). GGT (gamma glutamate transferase) was normal, and he
had elevated cholesterol at 236 mg/dl while the limit is 200 mg/dl. HDL was 37 mg/dl and the upper
limit should be 40 mg/dl.
The general practitioner advised an abdominal ultrasound. The ultrasound showed hepatomegaly
and severe hepatic steatosis, so the patient came to our attention in the hepatologic clinic.
Physical Examination
The blood pressure was 135/85 mmHg, the heart rate 80BPM, the weight was 95 kilograms with
BMI at 31 kg/m², indeed class I obesity (please note BMI alone is not a good indicator for obesity,
the more accurate assessment would be a body composition analysis).
The patient was an asymptomatic in the physical examination of heart, chest and limbs: there was
nothing relevant. In the abdomen we note hepatomegaly. At that time, he was not taking any drugs.
So, we have a 48-year-old male, obese patient with hepatic steatosis and liver enzyme
abnormalities, with family history of type II diabetes and dyslipidemia.
Question 1
What will you do?
Tests:
´ A) abdominal CT scan (level II liver assessment)
´ B) Rule out secondary causes of steatosis
´ C) Follow-up blood tests within 6 months
The correct answer is B, because at this moment we haven’t enough tests to decide the causes and
it is important to rule out secondary causes. Option A
is only partially correct but we will see this later.
Secondary causes of hepatic steatosis are listed
in the table.
When we see a patient with hepatic steatosis, we
must collect the patient’s history, for example if he is
taking medications such as glucocorticoids,
amiodarone, methotrexate, antiretroviral agents for
HIV. Other relevant factors may be starvation,
parenteral nutrition and alcohol abuse. Alcoholic
liver diseases are the first cause of hepatic steatosis
Authors: Maria Chiara Rivolta – Nichol Bernardo 1/13

Version 1.1 – NAFLD & NASH ICM 7A
and another very important factor is the history of hepatitis C.
The next step is to exclude secondary causes of hepatic steatosis.
Question 2
In your opinion: What is the amount of alcohol consumption per day that defines the risk of alcoholic
liver disease?
A) >3 beer can or 3 glasses of wine or 3 shots of hard liquor

B) >3 beer can or 2 glasses of wine or 1 shots of hard liquor
C) >3 beer can or 2 glasses of wine or 1/2 shots of hard
liquor what is the amount of alcohol consumption per
day that defines the risk of alcoholic liver disease?
Answer A is correct.
What is a standard drink?

In the US a standard drink is any drink that contains
14g of pure alcohol equivalent to 45ml. We can see
that one small beer can is equivalent to one drink, a
bottle of table wine is equivalent to 5 standard drinks so
one glass is equivalent to one standard drink. One shot
of hard liquor is equivalent to one standard drink.
According to the National Institutes on Alcohol Abuse
and Alcoholism a significant alcohol consumption is
more than 21 standard drinks per week for males
and more than 14 standard drinks per week in
females.
Significant alcohol consumption:
>21 standard drinks per week in men
>14 standard drinks per week in women
Ruling out secondary causes of Steatosis

The amount of increase in amino-transferase and
AST ratio can help to diagnose the patients.
For example, aspartate amino-transverse is higher in
alcohol hepatitis rather than in other conditions for
possible increases in amino-transferases.
It is important to collect a complete history in patients,
especially the drug history, for example medications. It
is also important to exclude chronic viral hepatitis C
and B with antibodies, as well as autoimmune hepatitis.
We can check gamma globulin levels and anti-nuclear
antibodies (ANA), anti-smooth muscle antipodes
(ASMA), and anti-LKM-1 antibodies.

Another thing that we must exclude is hemochromatosis using plasma iron, ferritin and total iron
binding capacity. There are a lot of other causes for mild or moderately elevated serum amino-
transferase but the first time we must exclude these above characteristics, that in our patient are
indeed normal.
• Drug history
• Ab anti-HCV, HBsAg, HBsAb, Ab antiHbc
• Serum gammaglobulin level, ANA, ASMA, anti-LKM-1
• Plasma iron, ferritin, and total iron binding capacity → Normal
6 months later
We plan blood tests within six months and six months later the blood tests are the same as the
previous ones. We have an increase in amino-transferase, GGT are normal, platelets are normal
and we have low HDL cholesterol.
Blood test: AST 37 U/L (v.n. <35), ALT 80 U/L (v.n. <59), GGT 38 U/L (v.n. <68),
PLT 248.000, col 236 mg/dl (HDL 37 mg/dl).
So, at this point we may exclude other causes for the increase of amino-transferase (like Wilson’s
disease). We check ceruloplasmin levels, alpha-1 antitrypsin. We check for celiac disease with
anti-tissue transglutaminase antibodies. We also check for thyroid disease with TSH, which in
our patient resulted to be 4.4, higher than normal values which is less than 4.
fT4 0.69 ng/dL (vn 0.70-1.48)
Furthermore, antibodies anti-Tg and anti-TPO are negative.
A thyroid ultrasound was ordered and showed a thyroid of normal size and eco structure with no
evident nodules.
So, the endocrinologist prescribed L-Thyroxin 50mcg/day to correct the patient TSH levels.
Patient risk factors
Our patient is at risk of cardiovascular diseases,
due to the fact that he is obese, he has a family
history of type II diabetes and he has dyslipidemia.
With fat conventional ultrasound of the abdomen
and the increase of amino-transferase we can
exclude secondary causes of steatosis.
We can consider Non-alcoholic fatty liver
disease (NAFDL), which is the presence of
hepatic steatosis with at least 5% of
hepatocytes showing fat accumulation in
individuals who consume little or no alcohol and
do not have any other secondary cause of
hepatic steatosis.
NAFLD is a spectrum of liver diseases, the first step
is NAFL, or hepatic steatosis where we have
steatosis in more than 5% of hepatocytes as
previously stated, this first step is still reversible.
The second step is non-alcoholic steatohepatitis
or NASH where histological features include

steatosis in more than 5% of hepatocytes,
hepatocyte ballooning and lobular inflammation.
End stage liver disease is the last step and is
known as cirrhosis. In cirrhosis there is fibrotic
degeneration of the liver and this is an
irreversible condition.
NAFLD is the most common liver disease in the
world.
We can see that in the US 25% of those with
NAFLD, will have NASH and 25% of this
subgroup will undergo end stage liver disease
(cirrhosis). We don’t know how many of these
individuals will develop hepatocarcinoma or HCC,
but NAFLD is the top reason for liver
transplantation in the US as of 2020.
It is a major public health problem afflicting
approximately one billion individuals Worldwide.
Epidemiological features
An analysis form 22 countries showed that more
than 80% of patients with NASH are overweight or obese, 72% have dyslipidemia and 55.5% have
received a diagnosis of type II diabetes mellitus.
We can see that there is a lower prevalence in poorer countries.
Younossi ZM et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes:
A systematic review and meta-analysis. J Hepatol Oct 2019
NASH is the hepatic correlate of metabolic syndrome

Together with diabetes, dyslipidemia, hyper tension and visceral adipose accumulation, NASH is
the hepatic correlate.
What is metabolic syndrome?

What is metabolic syndrome?
A) three any of the following 5 characteristics
B) Points 1 and 2 any of the following
C) Points 2 and 2 any of the following
Adult Treatment Panel III criteria (ATP III)
1. Obesity, defined as waist ≥102 cm (men) or ≥88 cm (women)
2. Triglycerides ≥ 150 mg/dL or drug treatment for elevated triglycerides
3. HDL cholesterol < 40 mg/dL (men) and <50 mg/dL (women) or drug treatment for low HDL
cholesterol
4. Hypertension, defined as ≥130/85 mmHg or drug treatment for hypertension
5. Fasting glucose ≥ 100 mg/dL or drug treatment for elevated blood glucose
The correct answer is A: any three of the above listed 5 characteristics.

Pathogenesis
NASH often develops in the context of hepatic
steatosis but isolated steatosis is three to four
times as prevalent as NASH.
NASH does not correlate with the severity of
steatosis. Insulin resistance plays a key role in
the pathogenesis of NASH, because there is an
excess in the availability of lipids that can be
either triglycerides or free fatty acids.
In the first case (e.g., excess triglycerides) we can
speak about steatosis, because there is a safer
lipid storage. In the second case (e.g., excess
free fatty acids) we can speak about NASH,
because free fatty acids can give rise to lipo-
toxicity in hepatocytes. The hepatocytes thus
send cell signals to neighboring cells such as
Kupffer cells, the endothelial cells, the HSCs and
inflammatory cells. This eventually leads to a
wound healing response, with inflammation,
vascular remodeling, fibrogenesis and
accumulation of immature liver epithelial cells.
Finally, the liver will undergo apoptosis of
hepatocytes.
Fibrosis Progression in NASH
When we have a single injury there is complete resolution of inflammation without fibrosis. When
instead we have repetitive injuries in a limited time then we must prevent an excessive
accumulation of scar tissue and finally favor fibrosis regression.
Instead, when the injury and inflammation are repetitive and continuous then there is
accumulation of scar tissue which culminates in cirrhosis which is the end stage of liver disease.
(see image for clarification).
Three scenarios are shown: (A) a single

inflammatory stimulus, with complete resolution
and no fibrosis; (B) repetitive inflammation which
terminates early enough, to prevent excessive
accumulation of scar tissue and finally fibrosis
regression;
(C) repetitive inflammation, with continuous
accumulation of scar tissue and progression
towards cirrhosis.
Schuppan D. et al. Determinants of fibrosis
progression and regression in NASH.
J Hepatol 2018

NASH: a Complex Phenotype

We can say that NASH is a complex phenotype in that genetic, epigenetic and
environmental factors are all involved. The patatin-like phospholipase
domain-containing 3 (PNPLA3) polymorphism is the major commonly
inherited determinant of NAFLD. This gene encodes adiponutrin and regulates
both triglycerides and retinoid metabolism.
Is the major common inherited determinant of NAFLD.
Another polymorphism is the Transmembrane 6 superfamily, member 2 or TM6SF2. This gene
instead encodes for a protein that regulates VLDL secretion from the hepatocyte.
The number of discovered genes harboring risk variants and their effect
size is compared to that of loci associated with circulating TG levels.
Epigenetic Factors
Some studies have identified that epigenetic alterations in mice and in
humans can dysregulate metabolic pathways, controlling adipose tissue
accumulation, insulin sensitivity and tissue generation and regeneration.
Whether this mechanism can influence susceptibility to non-alcoholic
steatohepatitis (NASH) is still under investigation.
• In mice, both overeating and undereating during pregnancy induce epigenetic mechanisms that
disrupt the insulin-like growth factor axis during fetal development, increasing the susceptibility of
offspring to obesity and the metabolic syndrome later in life.
• Studies of families with adult-onset obesity have identified genome-wide epigenetic alterations
that dysregulate metabolic pathways controlling adiposity, insulin
sensitivity, and tissue generation or regeneration.
• Whether such epigenetic mechanisms influence susceptibility to nonalcoholic steatohepatitis is
being investigated.
Environmental Factors
Environmental factors are the modifiable risk factors that challenge systemic and hepatic energy
homeostasis and homeostasis.
Environmental factors include diet-composition, feeding frequency, adipose tissue amounts, sleep-
wake cycle and alterations in commensal microbiota. We can see that in dysbiosis (a condition in
which the gut bacteria become imbalanced as a result of a wide range of digestive disturbances)
there is an alteration of tight junctions so there will be translocation of bacteria from the gut lumen
to the underlying tissues.
In this case there is an alteration in commensal microbiota with higher proportions of Bacteroidetes
and lower proportions of Prevotella spp. in
patients with NASH as compared to the
healthy controls.
This is relevant because it is central to an
accurate development of microbiota targeted
therapies, for instance fecal microbiota
transplant.

The Gut-Liver Axis
• The gut-liver axis is essential for regulation of systemic metabolism, for gut hormone release and
for the immune response. The communication in this axis is mediated by bile acids, which are
essential for the absorption of dietary fats and vitamins.
We can see that in NASH there is an alteration of some receptors and this leads to lipid accumulation
in the liver. This is important because therapeutic targeting of these receptors is currently being
studied in clinical trials.
[-]: Farnesoid X receptor (FXR) activation, mediated by BAs, can limit lipid accumulation in the liver
(↑ TG clearance and ↓ TG hepatic synthesis).
[+]: Constitutive androstane receptor (CAR) inhibits FXR.
[+]: β-adrenergic receptors activate CAR.
• Therapeutic targeting of nuclear receptors, for example the FXR system, is currently being
investigated in several clinical trials.
Clinical Manifestation
Generally, patients with NASH are asymptomatic, some will complain of fatigue or right upper
abdominal discomfort.
Physical examination findings are generally normal but there may be notable hepatomegaly due to
fat infiltration in the liver.
Laboratory findings
Laboratory finding may be normal. In a lot of cases liver enzymes are normal, but there may be mild
to moderate elevation in amino-transferase levels (2 to 5 times the upper normal level ULN), and
generally AST alteration is less than 1.
The degree of amino-transferase alteration does not predict the degree of inflammation or hepatic
steatosis, because we can have normal enzymes in NASH.
Serum ferritin concentration may be elevated. If it is 1.5x the normal level it is correlated to higher
activity scores and with advanced hepatic fibrosis.
´ May be mild or moderate elevations in the AST e ALT levels (X2-5 ULN, AST/ALT < 1). The
degree of aminotransferase elevation does not predict the degree of hepatic inflammation or
fibrosis
´ May be an elevated serum ferritin concentration (if > 1.5x is associated with a higher activity
score and with advanced hepatic fibrosis).
Our Patient
Coming back to our patient, we have a diagnosis of NAFLD so we can now evaluate the metabolic
risk factors.
We have measured that the patient has a waist of 120cm, has triglycerides at 120ml/dL and total
cholesterol at 236mg/dL with HDL cholesterol at 37mg/dL. Blood pressure is 135/85 mmHg, and
fasting glucose is 90mg/dL.
After the diagnosis of NAFLD, we evaluate the metabolic risk factors:
1. Waist 120 cm
2. Triglycerides 120 mg/dl
3. Total cholesterol 236 mg/dl (HDL cholesterol 37 mg/dl)
4. B.P. 135 / 85 mmHg

5. Fasting glucose 90 mg / dL
Does our patient have metabolic syndrome?
A) Yes
B) No
C) Insufficient data
Yes, our patient has a metabolic syndrome because his waist circumference is 120 cm and the
upper limit for males is 102cm. Also, the patient falls into the hypertensive range since the threshold
is 130/85mmHg, and his HDL is 37mg/dL whereas the minimum HDL for men should be at 40mg/dL.
Thus at least 3 of the 5 points to consider for metabolic syndrome are met.
So, our patient is a 48-year-old male diagnosed with NAFLD, metabolic syndrome and
hypothyroidism.
What’s our next move?
A) Set up drug therapy
B) RMN abdomen
C) Rule out NASH
The correct answer is C.
Diagnosis
Liver biopsy is the gold standard for diagnosis of NASH. We can see 4 characteristics that should
be present in the biopsy in order for definitive diagnosis:
1. At least 5% of hepatocyte showing fat accumulation.
2. Hepatocyte ballooning degeneration.
3. Inflammation.
4. Fibrosis.
The fibrosis can be divided into sub categories: F0 stands for no fibrosis, F1 for portal fibrosis without
septa, F2 for portal fibrosis with few septa, F3 for bridging septa between central and portal veins
and F4 is for cirrhosis.
It is very important to stage fibrosis because once the F2 stage is reached the liver specific mortality
rate increases.
Liver biopsy has a number of limitations because it is rather invasive and costly. It may be further
complicated by morbidity, and it is not practical for screening or monitoring patients.
Both all-cause and liver-specific mortality increase once F2 fibrosis has developed.
Non-Invasive Assessment
Before biopsy it is better to do a non-
invasive assessment of NASH. After
diagnosis of NAFLD we can rule out
advanced fibrosis because we can see
that in this stage all causes of mortality
increase.
We have two scores NAFLD fibrosis
score or NFS and FIB-4 index. The first
score includes: age, BMI, presence of
diabetes, amino-transferase ratio, platelet and albumin measurements.

FIB-4 index instead includes age, amino-transferase, and platelet measurement.
Using these scores, we can divide patients into three categories: low risk, intermediate risk, high
risk. In case of low risk, we can consider repeating NFS/FIB-4 assessment every 2 years. In case
of intermediate risk, we consider imaging methods. Instead in case of high risk it is worth doing a
liver biopsy.
In the case of our patient, we have chosen the following course of action:
the amino-transverse platelet ratio determines significant fibrosis, so we
choose imaging since he is at intermediate risk.
We must assess the presence of steatosis and fibrosis, we do so with
ultrasound.
APRI (AST/PLT ratio) ≤0.3 or ≤0.5 rule out advanced fibrosis and cirrhosis
respectively, APRI ≥ 1.5 predict significant fibrosis
Role of Imaging - Assessment of steatosis

Looking at the image, through conventional ultrasound, we see
first in the normal panel that the echogenicity of the liver relative
to the adjacent right kidney is the same so it is a normal liver.
In the second panel there is a middle steatosis because the liver
is more “brilliant” than the adjacent kidney. In the moderate
degree we can see the liver that is more brilliant than the kidney,
but there is an area of dark which repress the moderate stage of
liver steatosis.
In the severe degree we can see the line of the diaphragm.
Conventional ultrasound is not highly sensitive but when it is
positive it has a high specificity for moderate to severe hepatic steatosis.
Ultrasound does have a number of limitations especially in obese individuals because it is difficult
to see the liver through the thick layer of adipose.
Magnetic resonance spectroscopy MRS is the

gold standard to quantify liver fat, because we can
quantify water and fat, and the fat signal fraction
can be calculated. We can see accumulating fat in
the liver in the following images.
The sensitivity of this technique is almost 100% for
the diagnosis of steatosis when the accumulation
of fat is greater than 5.56%.
The limitations of this technique are the cost and lack of availability of the machinery, also there is
limited spatial coverage and it is not useful for longitudinal monitoring.

For the assessment of fibrosis (which is important to identify
since fibrosis leads to many causes of death) we can use
elastography method such as Fibroscan. This method is the
most commonly used imaging modality to diagnose and grade
hepatic fibrosis. We can use a probe that sends a vibration to
the liver and we can measure the waves that come back, so we can
provide and estimation of the liver stiffness measurement.
Liver stiffness is a marker of the stage of fibrosis.
The limitations of this method are high failure rates in obese
patients.
We can use shear wave elastography SWE, which

allows the evaluation of hepatic stiffness in a given
area. This method is useful because in the same
exam we can do ultrasound elevation and shear-
wave elastography with the same wavelength, this
allows a simultaneous evaluation of steatosis and
stiffness.
Then we have magnetic resonance elastography in 3D, which provides the highest diagnostic
accuracy for assessment of fibrosis. Its limitations are that it is not practical to use in routine care.
In clinical practice we use convertible ultrasound for steatosis, and shear wave elastography for the
assessment of fibrosis.
Conventional ultrasound is the most commonly used imaging modality to diagnose and grade hepatic
steatosis.
• ↑‘‘echogenicity” of the liver relative to adjacent right kidney and the obscuration of liver structures.
• It is not sensitive but when it is positive it has a high specificity for detection of moderate to severe hepatic
steatosis.
• It is limited in accuracy, repeatability and reproducibility for both diagnosis and grading of hepatic
steatosis, particularly in obese individuals.
Magnetic resonance spectroscopy (MRS) is the gold standard to quantify liver fat.
• The signal intensity at frequencies corresponding to water or fat can be quantified and the fat signal
fraction can be calculated.
• Sensitivity of almost 100% for the diagnosis of steatosis when the accumulation of fat is greater than
5.56%
• Limitations: cost, not readily available, limited spatial coverage and not useful for longitudinal monitoring.
Elastography-based method (Fibroscan)
• It is the most commonly used imaging modality to diagnose and grade hepatic fibrosis.
• It provides estimation of liver stiffness measurement, acting as a surrogate marker of liver fibrosis stage.
• Limitations: high failure rates in obese patients (BMI ≥35 kg/m2).
Shear wave elastography:
It allows to evaluate the hepatic stiffness in a specific area of interest.
Magnetic Resonance Elastography 3D (MRE)
• Provides the highest diagnostic accuracy for the assessment of fibrosis.

• It can image shear wave fields in three dimensions of the entire liver, rather than a smaller area of interest.
• Limitations: it is not practical to beSWE: shear-wave elastography.
• MRE: Magnetic Resonance Elastography
Back to Our Patient

As we said our patient is at intermediate risk for advanced fibrosis so we offer him an RMN abdomen
showing hepatomegaly and severe hepatic steatosis and a Fibroscan showing the values of 22.5
kilo pascals which corresponds to fibrosis stage 4, so the higher stage.
• Fibroscan: KPa 22.5, IQR 5.1 -> F4
In his case after imaging, we see a high risk of fibrosis so we may consider moving to the more
invasive test of biopsy.
The liver biopsy of our patient shows the following: 70% steatosis which is predominantly
macrovascular, it presents aspects of ballooning and degeneration and focal necro inflammatory
outbreaks.
The liver biopsy presents aspects of centrilobular peri-cellular fibrosis, fibrous thickening of the portal
spaces and occasional port-portal fibrous shoots.
The conclusion is that he has mild NASH with initial formation of fibrous septa, and the stage of
fibrosis is stage 2.
There are two scores for NASH, NAS an SAF.

The first is for steatosis lobular inflammation and ballooning, and then we can evaluate fibrosis
in different stages. The second is steatosis, activity (lobular inflammation and ballooning) and
fibrosis. We speak of NASH when NAS is equal or greater than 5 and activity is more than 2.
SAF score: S (3) A(1) F(2).
NAS score : steatosis (3) + ballooning degeneration (1) + lobular inflammation
(1); fibrosis 2.
NASH
DIAGNOSIS: NASH F2
NAS 5
ACTIVITY 2

Therapy
The therapy is a big problem, since we have no direct therapy for NASH. Weight loss and lifestyle
alteration are the best current therapies in such patients as ours. Bariatric surgery may be a
consideration, but only after the patient’s psychological evaluation is carried out to guarantee the
success. The patient must also be able to adhere to a diet plan for a period of 6 moths un order to
be considered for the surgery.
When patients come to the hepatology clinic, they want the doctor to solve their problem, but in this
case, there isn’t a therapy. We look to reduce the risk for cardiovascular diseases and cancer
which are the leading causes of death in these patients.
The key point in the therapy is weight loss.
There are many pharmacotherapies currently being used in clinical trials.
In this table is a list of potential NASH therapies being
evaluated in phase 2 or 3 of clinical trials.
We can see that therapeutic targets are metabolic stress,
inflammation and fibrosis, because these are the chief
factors of pathogenesis of NASH and Steatosis. If you
consider how vast the problem is it is rather important to
identify a successful therapy.
• Presently, there are no medications approved by
the Federal Drug Administration (FDA) or European
Medicines Agency (EMA) for the treatment of NAFLD or
NASH.
Diehl A.M. et al. Cause, Pathogenesis, and Treatment of
Nonalcoholic Steatohepatitis. N Engl J Med 2017
* This agent was superior to placebo in a randomized clinical trial.
PPAR denotes peroxisome proliferator–activated receptor, FXR farnesoid X receptor, GLP-1
glucagon-like peptide-1, FGF fibroblast growth factor.
Question
What is the major cause of death in patients with NASH?
A) HCC (hepato-cellular carcinoma)
B) Cardiovascular disease
C) Gastro-esophageal variceal hemorrhages
The answer is B because NASH is essentially a part of metabolic syndrome.
In the end stages of cirrhosis, we may instead have fissures due to portal hypertension and variceal
hemorrhages are a complication of this situation.
Early identification and treatment of risk factors for cardiovascular disease
Back to Our Patient
We send our patient to a nutrition specialist for a low-calorie diet and exercise.
6 months later our patient weight dropped to 83kg, his BMI is of 27.8 so he is overweight but no
longer considered in the obesity range, his abdominal ultrasound showed hepatomegaly and
severe hepatic steatosis, biochemistry values was better than previously with normal liver
cytolysis and cholestasis indices, and with normal cholesterolemia, blood sugar and
triglycerides.

We also repeated NFS scores which showed low fibrosis risk, differently from the previous one
which showed intermediate risk.
We plan another 6 months follow up with continuation of the diet.
NFS: -3.259; FIB-4: 0.74; APRI: 0.29
Low fibrosis risk, Follow up to 6 months and continuation of diet therapy.
Conclusion
We can conclude that NASH is the hepatic correlate of metabolic syndrome, and it has become a
major cause of cirrhosis and liver cancer. It is a big problem with elevated medical costs, in the
US it contributes to over 100 billion in spending. Accurate diagnosis and staging of NASH are
essential for the management.
The pathogenic mechanism is unclear, but metabolic stress, inflammation and fibrosis are the key
processes.
Pharmacological agents that target this mechanism are not currently available but are being
investigated in clinical trials.
Q&A
Question: In the very early stages what would be the management of these patients (a patient with
a small alteration in liver enzyme)?
Answer: When there are mild liver test alterations in this case it is very important to collect a
complete history of the patient which includes drug history (toxic intake), physical examination to
see potential features of chronic hepatitis. So, collect patient history and a full physical examination
would be the key things that a general practitioner could do with a patient upon discovery of mild
liver enzyme alterations. Then if there is an alteration in liver it is helpful to also do imaging such as
and abdominal ultrasound. This can help visualize the margins of the liver and if there is steatosis,
if there are other potential liver problems. Then if there are abnormalities in the ultrasound then the
general practitioner should refer the patient to a hepatic specialist. The hepatic specialist will try to
exude chronic hepatitis D and C, toxic hepato-lysis and if these are normal, we may exclude other
causes of liver disease.
Question: If the patient has a mild alteration of hepatic enzymes but no sign of steatosis or any
visible damage detectable via ultrasound, what should the general practitioner do?
Answer: After collecting patient history and carrying out the physical, if there isn’t a discernible
cause for these alterations then the patient can plan a follow up within 6 months. The follow up
should consist of a blood test. It the test is normal then within 6 months we can do another check
up with the addition of the ultrasound. If the test results are unclear then the patient should be
referred to a hepatic specialist.

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Version 1.

1 – NAFLD & NASH ICM 7A

NAFLD & NASH

Authors: Maria Chiara Rivolta – Nichol Bernardo 1/13

A) >3 beer can or 3 glasses of wine or 3 shots of hard liquor

What is a standard drink?

Ruling out secondary causes of Steatosis

Authors: Maria Chiara Rivolta – Nichol Bernardo 2/13

Authors: Maria Chiara Rivolta – Nichol Bernardo 3/13

NASH is the hepatic correlate of metabolic syndrome

What is metabolic syndrome?

Authors: Maria Chiara Rivolta – Nichol Bernardo 4/13

Three scenarios are shown: (A) a single

Authors: Maria Chiara Rivolta – Nichol Bernardo 5/13

NASH: a Complex Phenotype

Authors: Maria Chiara Rivolta – Nichol Bernardo 6/13

Authors: Maria Chiara Rivolta – Nichol Bernardo 7/13

Authors: Maria Chiara Rivolta – Nichol Bernardo 8/13

Role of Imaging - Assessment of steatosis

Magnetic resonance spectroscopy MRS is the

Authors: Maria Chiara Rivolta – Nichol Bernardo 9/13

We can use shear wave elastography SWE, which

Authors: Maria Chiara Rivolta – Nichol Bernardo 10/13

Back to Our Patient

There are two scores for NASH, NAS an SAF.

Authors: Maria Chiara Rivolta – Nichol Bernardo 11/13

Authors: Maria Chiara Rivolta – Nichol Bernardo 12/13

Authors: Maria Chiara Rivolta – Nichol Bernardo 13/13

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