LIVER

DISEASE
Arturo Bautista
Nataly Navarro
Danna García
Rafael Ibarra
Fernando Flores
Carlos Rodriguez
José Eduardo Victorio
Anagaby Litz
CONTENTS

1. Hepatitis in NAFLD.

2. Alcoholic liver disease, disease spectrum,

pathogenesis, and diagnosis.

3. Viral and drug-induced hepatitis.

4. Cirrhosis
1. HEPATITIS IN NAFLD
 NON-ALCOHOLIC FATTY LIVER DISEASE
NAFLD: spectrum of fatty liver disease in people that lack men: <21 glasses/ week
a significant alcohol consumption or some other secondary women: <14 glasses/week
cause

simple steatohepatitis
steatosis

hepatocellular cancer
 Simple steatosis Steatohepatitis (NASH)
Presence of steatosis without Presence of steatosis with evidence of
evidence of hepatocellular damage hepatocellular damage and
or fibrosis inflammation, with/without or fibrosis
EPIDEMIOLOGY
● Most common cause of chronic liver disease
● 20-30% worldwide population have NAFLD
● USA up to 80-100 million people suffer from NAFLD
● NAFLD is the leading indication for liver transplantation in the United States
● 25% of patients with NASH have fibrosis or cirrhosis
● The risk of advanced liver fibrosis is highest in individuals with:
○ NASH > 45 to 50 years of age
● Genetic variations of TM6SF2, MBOAT7 or PNPLA3

related to:

Insulin Overweight/ Metabolic Dyslipidemia

resistance Obesity Syndrome
 PATHOPHYSIOLOGY
“2 hit theory”

1 hit 2 hit
steatosis steatohepatitis
Accumulation Hepatocyte Fibrosis
triglycerides Damage

INNATE
OBESITY IMMUNITY
 PATHOPHYSIOLOGY
1 hit
Interaction between:
- diet
Unbalance between
- metabolic system ingested/used
- host response energy

Accumulation of triglycerides in the cytoplasm of hepatocytes by 5 mechanisms

1. ↑ supply of free fatty acids * (60%)
- visceral/ subcutaneous adipose tissue lipolysis
2. ↑ fat intake in diet
3. ↓ β-oxidation of free fatty acids
4. de novo hepatic lipogenesis intensification *
5. ↓ LDL secretion
* Hyperinsulinemia and insulin resistance ↑↑↑↑
PATHOPHYSIOLOGY
2 hit Hepatocellular damage
Pro-inflammatory signalization

Extrinsic pathway apoptosis

- Free fatty acids activate TLR

β-oxidation fatty acids of long chains in

peroxisomes
ω-oxidation in endoplasmic reticulum
- lipotoxicity and ROS
PATHOPHYSIOLOGY
2 hit

Fibrosis

Due to abnormal cholesterol metabolism

miR-33 & miR-144 → regulate ABCA1

transporter and other genes of:

- cholesterol flow ↑ ↑ ↑ in morbid obesity and NASH

- fatty acid oxidation
- inflammation
EVOLUTION

NAFLD is usually asymptomatic until they are 10-20% NASH

serious complications like:
- ascitis 10-29% 4-29%
cirrhosis hepatocellular
- visceral hemorrhage
carcinoma
- hepatocellular carcinoma

Most common cause of death: cardiovascular disease

CLINICAL MANIFESTATIONS
★ Asymptomatic
❏ Right hypochondriac abdominal pain
❏ Hepatomegaly

Chronic liver disease: Others:

❏ Spider angioma ❏ Chronic fatigue
❏ Palmer erythema ❏ Mood alterations
❏ Splenomegaly ❏ Obstructive sleep apnea
❏ Chronic pain syndrome
Advanced NAFLD:
❏ Jaundice
❏ Ascites
❏ Variceal Hemorrhage
 exclude:

DIAGNOSIS alcohol consumption autoimmune liver disease

1. History and Physical Examination

exposure to drugs Iron/copper overload

Non Invasive Testing viral hepatitis

2. LIVER IMAGING

Ultrasound ! Magnetic Resonance Magnetic Resonance Transient Elastography

Spectroscopy Elastography (FibroScan)

CT

MRI
 DIAGNOSIS
Invasive Testing

3. Lab Test
● ALT>AST
Serology: Hepatitis B &C Liver Chemistries = ● AST>ALT = fibrosis or cirrhosis
● γ-Glutamyl transferase (GGT) & Alkaline
phosphatase
4. Liver Biopsy Establish severity of liver injury and fibrosis

NAFL NASH NASH cirrhosis

>5% steatosis in hepatocytes ballooning + inflammation + damage fibrosis

TREATMENT
★ Lifestyle Changes:
○ Loss 3-5% body weight → improves steatosis
○ Loss of > 6-10% body weight → improves steatohepatitis and hepatic fibrosis
○ Diet: mediterranean-type
○ Avoid food and beverages high in fructose
○ Increase coffee consumption
○ Aerobic exercise or resistance training (30 min x 5 times per week)

★ Pharmacologic Therapy experimental

○ Orlistat: lipase inhibitor
○ Vitamin E: antioxidant

★ Bariatric Surgery
○ IMC > 35 kg/m2 + cormobolities
2. ALCOHOLIC LIVER DISEASE, DISEASE
SPECTRUM, PATHOGENESIS, AND
DIAGNOSIS.
Alcoholic-Associated liver disease

Alcohol-associated liver diseases (ALD) → comprise a spectrum of diseases associated with

chronic alcohol consumption.

Ranging from alcohol associated fatty-liver disease and steatohepatitis to more advanced liver
disease including fibrosis and cirrhosis.
Epidemiology
5.8% of adults in the USA have an alcohol disorder.
Defined as > 2 drinks per day in women and > 3 drinks per day in men (1 drink equals 14 g of ethanol,
which is 1 beer, 4 oz of wine or 1 oz of 80% spirits).

Prevalence of alcohol associated fatty liver disease: 4.7% of the general population in the USA, 1.5% has
stage 2 or greater fibrosis.

Liver cirrhosis is the 11th cause of mortality worldwide (1.16 millions deaths annually). 48% of cases of
cirrhosis can be attributed to alcohol.

Among patients with alcohol use disorder, 18% had fibrosis, 26% had cirrhosis, and 7% had alcoholic
hepatitis without underlying cirrhosis.

In European: incidence rate for acute alcoholic hepatitis: 24-27: 1 000 000 in women
46-56: 1 000 000 in men
Spectrum of the disease
 Pathogenesis
● Acetate → acetyl-CoA → fatty acids and
triglycerides synthesis.

● Alcohol → ↑ genes involved in lipogenesis and

↓ genes involved in transport and oxidation

● ↑ Ratio NADH/NAD+
○ → DHAP → G3P → combines with fatty
acids to make triglycerides.
○ Decreased TCA → acetyl-CoA used for
ketogenesis or lipogenesis.

● Reduces B-oxidation
● Increase fatty acid mobilization in adipose
tissue and intestines → lead to hepatic
accumulation of fatty acids.
Risk factors
Pathogenesis: Immune and inflammatory Mechanisms

Key points:
• Gut-derived pathogen associated molecular patterns (PAMPs) and LPS
translocate from the gut into the portal vein and to the liver
Mechanisms:
• Alcohol alters gut-barrier function, promoting LPS translocation by:
-Acetaldehyde, increases intestinal permeability to macromolecules like
LPS.
-Decreased tight junctions (ZO-1) protein levels could be observed in the
sigmoid colon
-Increased production of proinflammatory cytokines (TNF-a and IL-6) can
contribute to alcohol-associated endotoxemia.
-Alcohol promotes overgrowth of gram-negative bacteria
Pathogenesis: Immune and inflammatory Mechanisms

- Alcohol alters microflora decreasing the

numbers of Bifidobacteria spp. and
Lactobacilli spp

Hepatic steatosis and steatohepatitis occurred

at the same time as translocation of life
bacteria into the systemic circulation,
prebiotic therapy attenuated liver injury.
Pathogenesis: Immune and inflammatory Mechanisms

Other inflammatory pathways:

- Inflammasome activation: Activation of caspase-1 leads to piroteolytic cleavage

of pro-IL-1B and IL-18 into bioactive forms.
- Kupffer cell production of protective anti-inflammatory cytokines such as IL-10, is
decreased.
- Autoimmune: Conditions with autoantibodies directed against phospholipids, heat
shock protein and alcohol dehydrogenase
- Genetic factors: People with nucleotide substitution from glutamine to lysine
in alcohol dehydrogenase lead to acetaldehyde accumulation
- Variants in genes (TM6SF2 and MBOAT 7) on chromosome 19 are associated to
alcohol cirrhosis.
Pathogenesis: Immune and inflammatory Mechanisms
Pathogenesis: Fibrosis

• Stellate cells (myofibroblast) are the major source of collagen production in

the liver.
Activation of myofibroblast may happen via:
-TGF-B, PDFG and connective tissue growth factor
-TLR4 signaling
-Oxidative stress
-Inhibition of metalloproteinase-1 levels
Hepatic injury involves dysregulation of the coagulation cascade and fibrinolysis
resulting in the formation of fibrin clots in hepatic sinusoids that could lead to
hypoxia.
Fun fact: CB1 blockade has been
associated to reducing hepatic fibrosis
Clinical Manifestations

Alcoholic fatty liver disease

(reversible):

-Mostly asymptomatic
-Hepatomegaly
-Regress after cessation of
alcohol consumption
Diagnosis

There are three useful tools:

- AUDIT (Alcohol Use Disorders Identification Test) 10-item
- AUDIT-C (Audit-concise) consumption questions
- CAGE (Cut ,Annoyed, Guilty, Eye-opener ) 4-item questionnaire.

Alternative method: “How many times in the past year have you had x or more
drinks a day?”
(Where x = 5 for men and 4 for women)

Measurement of 2 alcohol metabolites: phosphatidyl-ethanol and ethyl

glucuronide could be used in detection of recent alcohol use.
Diagnosis: Biomarkers of alcohol use
● Elevated Gamma-glutamil transferase
● AST>ALT (2x upper limmitand <400 IU/litter) // AST/ALT ratio >1.5
● Serum Bilirubin > 3 mg/dl

(American College of Gastroenterology, 2024)

Histology

Steatohepatitis

Mallory
bodies

Mallory bodies: Hyaline intracytoplasmic

infiltrates
Histology

Inflammation Hepatocyte
ballooning

Cholestasis with
blue canalicular Steatosis and
and hepatocyte fibrosis
plugging

Chicken wire and

pericellular fibrosis Cirrhosis

(American College of Gastroenterology, 2024)

Treatment
Therapy for ALD can be viewed as an inverted pyramid, with patients receiving lifestyle modifications, nutritional
intervention, drug therapy and only a few considered for LT.

Therapy should be directed by disease severity**

Abstinence and Lifestyle Modifications

First steps are to identify excessive drinking, determine the severity of the problem and assess the patient's motivation for
change.

Important to address obesity and smoking (comorbidities associated with progression of ALD).

Three oral medications (disulfiram and acamprosate) & an extended release injectable form of naltrexone have been
approved by the FDA to treat alcohol dependence.
→modestly effective, side effects and underused

Baclofen (gamma aminobutyric acid B-receptor agonist) shows promise in decreasing the relapse of patients with alcohol
associated cirrhosis.

Goal of intervention: sustained abstinence Maintain abstinence is the most important aspect of
a. improves histologic features of alcohol-associated liver injury management because no drugs have been shown to
improve survival.
b. reduces portal pressure
c. slows progression to cirrhosis
(Feldman, M., Friedman, L. S., & Brandt, L. J, 2021).
Treatment
Nutritional Support
Malnutrition is a widespread clinical problem among patients with ALD and it is associated with
higher rates of liver-related complications & mortality.

→NG feeding tube is placed is the patient cannot voluntarily ingest at least 2500 kcal/day (even when esophageal varices
are present) Patients with severe alcohol associated hepatitis should receive enteral feedings to ensure adequate calorie and protein intake.

→Glucocorticoid therapy can increase voluntary dietary intake (provides same benefit as NG tube)

Hepatic glycogen stores are depleted in patients with cirrhosis

As a result patients go into early starvation mode after 12 hours of fasting.
→Short periods of inadequate nutrition can lead to peripheral muscle proteolysis
→Patients with severe alcohol-associated hepatitis or cirrhosis should be given nighttime (9 pm) snacks to prevent
starvation

Vitamin and mineral deficiencies

-Folate, vitamin B,
-Fat soluble vitamins: A,D,E
-Minerals: magnesium, selenium and zinc
Zinc deficiency: skin lesions, night blindness, hepatic encephalopathy, altered taste and altered wound healing (common).

(Feldman, M., Friedman, L. S., & Brandt, L. J, 2021).

Treatment
Specific therapy for alcohol-associated hepatitis:
Glucocorticoids
32 mg of methylprednisolone daily for 28 days followed by a 2 week taper.

MOA
a.Glucocorticoids work by binding to glucocorticoid receptors (GRs) into the cytoplasm
b.Grs translocate to the nucleus and bind to GR elements in the promoter regions of glucocorticoid responsive genes ro
switch on expression of certain anti inflammatory genes and reduce inflammation
Patients with severe alcohol associated
Unfortunately many patients are glucocorticoid resistant*** hepatitis who do not have a systemic infection
or GI bleeding a short course of glucocorticoid
therapy should be considered.
Pentoxifylline (PTX)
Non selective phosphodiesterase (PDE) inhibitor used as an alternative to glucocorticoids.

MOA
a.PTX increase intracellular concentrations of cyclic adenosine monophosphate and cyclic guanosine monophosphate
b.Increase cyclic adenosine monophosphate modulates the cytokine inflammatory response:
limits pro-inflammatory effect of leukotrienes and TNF-a

Studies did not confirm beneficial survival effects of PTX in patients with severe alcohol associated hepatitis***
PTX needed to be taken 3 times a day- associated GI distress.
(Feldman, M., Friedman, L. S., & Brandt, L. J, 2021).
Treatment
LT (Liver Transplant)
Alcohol associated cirrhosis is the second most common indication for LT in the USA.

The outcome following LT is favorable.

Factors that reduce survival after transplantation: concurrent HCV infection, smoking related cancer, cardiovascular
disease and return to destructive patterns of drinking.

A multidisciplinary approach both before and after operation appears to offer the best opportunity for patients with ALD.

→”Six month rule”

Traditional 6-month abstinence period required by many transplant center and insurance companies to help ensure
maximal hepatic recovery off alcohol and document sobriety.

Patients with severe alcohol-associated hepatitis traditionally have not been considered to be appropriate candidates for
LT because of recent drinking (fear of return to drinking)***

(Feldman, M., Friedman, L. S., & Brandt, L. J, 2021).

Prognosis
The prognosis for individuals patients with ALD depends on:
a. Degree of pathological injury
b. Nutritional status
c. Occurrence of complications of advanced liver disease
d. Comorbid conditions: obesity & HCV infection
e. Ability to discontinue destructure patterns of drinking

Patients with fatty liver disease have the best outcome.

Patients with alcohol-associated hepatitis or cirrhosis have intermediate outcome.

Patients with combined cirrhosis and alcohol-associate hepatitis have the worst outcome.

(Feldman, M., Friedman, L. S., & Brandt, L. J, 2021).

Prognosis
Alcohol associated Hepatitis
Represents 1% of hospital admissions in the US

Clinical features:
● hepatic encephalopathy
● elevation of serum bilirubin above 25 mg/dL
● development of renal insufficiency

(1)Madderey and Boitnott

Discriminant function (DF)
Objective: Identify patients with poor short-term survival rates who should be considered for specific therapy.
Greater than >32: encephalopathy and development of acute kidney injury.

(2)MELD score

(3)Glasgow alcohol-associated hepatitis score

(4)ABIC score
Objective: Predict survival in patients with severe alcohol-associated hepatitis.
3 groups with predicted 3 month survival rates of 25%, 70% and 100% based on the age, bilirubin, INR/PT and creatinine.

(Feldman, M., Friedman, L. S., & Brandt, L. J, 2021).

(Feldman, M., Friedman, L. S., & Brandt, L. J, 2021).
Prognosis
Alcohol-associated Cirrhosis
Within 15 years, 90% of patients can be expected to die if they do not undergo LT (liver transplant)

(1)Child Turcotte Pugh (CTP) Score

Clinical tool used mostly to determine prognosis in patients with alcohol-associated cirrhosis.
Adopted widely for risk-stratifying patients with cirrhosis because of its simplicity and ease of use.

(2)MELD Score
Useful to predict short term survival in groups of patients with various liver diseases.
System used for allocation of donor organs in the USA***

Acute on chronic liver failure

Patients with stable, compensated cirrhosis can gradually develop complications: jaundice & coagulopathy.

The 3 most common precipitating factors:

→ Increase in alcohol intake

→ Viral infection
Hepatotropic viruses: HAV (hepatitis A), HBV(hepatitis B) & HEV (hepatitis E)
Non-hepatotropic viruses: influenza A

→ Drug toxicity
Drinkers are susceptible to acetaminophen hepatotoxicity due to the induction of CYP2E1

Alcoholics who take excessive doses of acetaminophen over a prolonged period to relief minor pain can experience a sudden
deterioration of their clinical condition. (Feldman, M., Friedman, L. S., & Brandt, L. J, 2021).
Approach algorithm

(American College of Gastroenterology, 2024)

3. VIRAL AND DRUG-INDUCED HEPATITIS.
(Harrison et al, 2022)

Viral Hepatitis
- Acute viral hepatitis is a systemic infection affecting the liver predominantly.
Cases of acute viral hepatitis are caused by one of five viral agents:

The only DNA,

but replicates
as a retrovirus

Although these agents can be distinguished by their molecular and antigenic properties, all types of viral hepatitis
produce clinically similar illnesses.
● Inflammation of the lobules and portal tracts → CD8+ T-cell mediated hepatocyte apoptosis
● Periportal zone of liver is first affected (Zone I)
● ↑↑ Liver enzymes (ALT>AST), ↓ Urine urobilinogen, ↑ Conjugated and unconjugated bilirubin
● Viral prodrome of fever, anorexia, nausea, vomiting → Jaundice, pruritus, pale stool, dark urine
(Harrison et al, 2022)

Hepatitis A
HAV is a nonenveloped 27-nm, heat-, acid-, and ether-resistant, single-stranded,
positive-sense RNA virus in the Hepatovirus genus of the picornavirus family.

The virion contains four structural capsid polypeptides, designated VP1–VP4

Its replication is limited to the liver, but the virus is present in the liver, bile, stools, and blood
during the late incubation period and acute preicteric/presymptomatic phase of illness.

Despite slightly longer persistence of virus in the liver, fecal shedding, viremia, and infectivity
diminish rapidly once jaundice becomes apparent.

Detection of HAV RNA by sensitive reverse transcription polymerase chain reaction assays has
been reported to persist at low levels in stool, the liver, and serum for up to several
months after acute illness; however, this does not correlate with persistent infectivity.

Councilman bodies on histology (Eosinophilic globule of apoptotic hepatocytes)

(Harrison et al, 2022)

Hepatitis A
(Harrison et al, 2022)

Hepatitis A
Early antibody response is
predominantly of the IgM class and
persists for several (~3) months,
rarely for 6–12 months.

During convalescence, however,

anti-HAV of the IgG class becomes the
predominant antibody.

Therefore, the diagnosis of hepatitis

A is made during acute illness by
demonstrating anti-HAV of the IgM
class.

Patients with serum anti-HAV are

immune to reinfection.
(Harrison et al, 2022)

Hepatitis B
HBV is a DNA virus with a remarkably compact genomic structure; despite its small, circular,
3200-bp size.
Once thought to be unique among viruses, HBV is now recognized as one of a family of animal
viruses, hepadnaviruses (hepatotropic DNA viruses), and is classified as hepadnavirus type
1.

Particulate forms of HBV:

- HBsAg (surface antigen)
- HBcAg (core antigen)
- HBeAg
Replicate in the liver but exist in extrahepatic sites, contain their own endogenous DNA
polymerase, have partially double-strand and partially single-strand genomes.
Are associated with acute and chronic hepatitis and hepatocellular carcinoma.
Chronic hepatitis → Cirrhosis → Hepatocellular carcinoma (HCC)
○ Direct path: DNA integrates into hepatocytes → suppression of p53 → HCC
(Harrison et al, 2022)

Hepatitis B
GEN S:

The S gene codes for the “major”

envelope protein, HBsAg.
GEN P:
The largest gene, P, codes
for DNA polymerase.
GEN C:
The C gene codes for two
nucleocapsid proteins,
HBeAg, a soluble,
secreted protein (initiation
from the pre-C region of
the gene), and HBcAg, the
intracellular core protein
(initiation after pre-C).
GEN X:
The X gene codes for
HBxAg, its clinical
relevance is not known, but
it may contribute to
carcinogenesis by binding
to p53 (cellular tumor
antigen p53).
(Harrison et al, 2022)

Hepatitis B
The first virologic marker detectable
in serum within 1–12 weeks, usually
between 8 and 12 weeks, is HBsAg
Circulating HBsAg precedes elevations
of serum aminotransferase activity and
clinical symptoms by 2–6 weeks and
remains detectable during the entire
icteric or symptomatic phase of acute
hepatitis B and beyond.
HBsAg becomes undetectable 1–2
months after the onset of jaundice and
rarely persists beyond 6 months.
After HBsAg disappears, antibody to
HBsAg (anti-HBs) becomes
detectable in serum and remains
detectable indefinitely thereafter.
HBcAg is intracellular and, when in
the serum, sequestered within an
HBsAg coat, naked core particles do
not circulate in serum, and therefore,
HBcAg is not detectable routinely in
the serum HBeAg - Highly infectious.
HBsAg - Ongoing infection
(Harrison et al, 2022)

Hepatitis B
(Harrison et al, 2022)

Hepatitis D
The delta hepatitis agent, or HDV, the only member of the genus Deltavirus, is a defective RNA virus that
co-infects with and requires the helper function of HBV (or other hepadnaviruses) for its replication
and expression.

Its nucleocapsid expresses HDV antigen (HDAg), which bears no

antigenic homology with any of the HBV antigens, and contains
the virus genome. The HDV core is “encapsidated” by an
outer envelope of HBsAg, indistinguishable from that of HBV

HDAg exists in two forms: a small, 195-amino-acid species,

which plays a role in facilitating HDV RNA replication, and a
large, 214-amino-acid species, which appears to suppress
replication but is required for assembly of the antigen into
virions.

Viral assembly requires farnesylation of the large HDAg for ribonucleoprotein anchoring to HBsAg.

HBV and HDV enter hepatocytes via the sodium taurocholate cotransporting polypeptide receptor.
(Harrison et al, 2022)

Hepatitis D
HDV can either infect a person simultaneously with HBV (co-infection) or superinfect a
person already infected with HBV (superinfection).

Because HDV relies absolutely on HBV, the duration of HDV infection is determined by the
duration of (and cannot outlast) HBV infection.

HDV replication tends to suppress HBV replication; therefore, patients with hepatitis D tend
to have lower levels of HBV replication.

HDV antigen is expressed primarily in hepatocyte nuclei and is occasionally detectable in

serum

During acute HDV infection, anti-HDV of the IgM class predominates, and 30–40 days may
elapse after symptoms appear before anti-HDV can be detected.

Co-infection: Patient simultaneously acquires hepatitis B and D → ↑ Risk of liver failure

Super-infection: Patient with chronic hepatitis B acquires hepatitis D → Rapid progression of
cirrhosis
(Harrison et al, 2022)

Hepatitis C
Is a linear, single-strand, positive-sense, 9600-nucleotide RNA virus, the genome of which
is similar in organization to that of flaviviruses and pestiviruses; HCV is the only member
of the genus Hepacivirus in the family Flaviviridae.
Transmitted via blood (Transfusions,IV drug use)
The HCV genome contains a single, large open reading frame (ORF) (gene) that codes
for a virus polyprotein of ~3000 amino acids, which is cleaved after translation to yield
10 viral proteins.
The 5′ end of the genome consists of an untranslated region (containing an internal
ribosomal entry site [IRES]) adjacent to the genes for three structural proteins, the
nucleocapsid core protein, C, and two envelope glycoproteins, E1 and E2.
The 3′ end of the genome also includes an untranslated region and contains the genes
for seven nonstructural (NS) proteins: p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B.
p7 is a membrane ion channel protein necessary for efficient assembly and release of
HCV.
Because HCV does not replicate via a DNA intermediate, it does not integrate into the
host genome.
Majority of cases lead to chronic hepatitis
○ 1⁄5 of chronic hepatitis cases progress to cirrhosis → ↑ Risk for HCC
(Harrison et al, 2022)

Hepatitis C 3′ end
5′ end
p7: a membrane protein adjacent to the structural proteins that
Core: which codes for the nucleocapsid. appears to function as an ion channel.
E1 and E2: which code for envelope NS2: which codes for a cysteine protease
glycoproteins. NS3: which codes for a serine protease and an RNA helicase
NS4 and NS4B: NS5A, a multifunctional membrane-associated
phosphoprotein, an essential component of the viral replication
membranous web
NS5B: which codes for an RNA-dependent RNA polymerase.
(Harrison et al, 2022)

Hepatitis E
HEV is an enterically transmitted virus that causes clinically apparent hepatitis primarily in
India, Asia, Africa, and Central America (in those geographic areas, HEV is the most
common cause of acute hepatitis).

Low mortality (Except in pregnant women)

(Harrison et al, 2022)

Pathogenesis
Under ordinary circumstances, none of the hepatitis viruses is known to be directly cytopathic to
hepatocytes.
Evidence suggests that the clinical manifestations and outcomes after acute liver injury
associated with viral hepatitis are determined by the immunologic responses of the host.
(Harrison et al, 2022)

Pathogenesis: Hepatitis B
For HBV, the existence of inactive hepatitis B carriers with normal liver histology and function suggests that
the virus is not directly cytopathic.
The model that has the most experimental support involves cytolytic T cells sensitized specifically to recognize
host and hepatitis B viral antigens on the liver cell surface. Nucleocapsid proteins (HBcAg and possibly HBeAg),
present on the cell membrane in minute quantities, are the viral target antigens that, with host antigens, invite
cytolytic T cells to destroy HBV-infected hepatocytes. Although a robust cytolytic T-cell response occurs and
eliminates virus-infected liver cells during acute hepatitis B.
“IMMUNOTOLERANT” VERSUS “IMMUNOREACTIVE” CHRONIC HEPATITIS B
An important distinction should be drawn between HBV infection acquired at birth and infection acquired in
adulthood.
Infection in the neonatal period is associated with the acquisition of what appears to be a high level of
immunologic tolerance to HBV and absence of an acute hepatitis illness but the almost invariable
establishment of chronic.
Neonatally acquired HBV infection can culminate decades later in cirrhosis and hepatocellular carcinoma
In contrast, when HBV infection is acquired during adolescence or early adulthood, the host immune response to
HBV-infected hepatocytes tends to be robust, an acute hepatitis-like illness is the rule, and failure to recover is
the exception. Chronicity is uncommon, and the risk of hepatocellular carcinoma is very low.
(Harrison et al, 2022)

Pathogenesis: Hepatitis C
Cell-mediated immune responses and elaboration by T cells of antiviral cytokines contribute to the
multicellular innate and adaptive immune responses involved in the containment of infection and pathogenesis of
liver injury associated with hepatitis C.
The pathogenesis of HCV-associated liver injury of virus-activated CD4+ helper T cells that stimulate, via the
cytokines they elaborate, HCV-specific CD8+ cytotoxic T cells.
These responses appear to be more robust, in those who recover from HCV infection than in those who have chronic
infection.
(Harrison et al, 2022)

Epidemiology
Hepatitis A: ∼ 2,000 cases per year (50% acquired during travels abroad).
• Hepatitis A virus is the second most common cause of acute hepatitis in the US (However, is the
most common cause of acute hepatitis worldwide, accounting for ∼ 25% of all cases).
• Hepatitis A is very common in tropical and subtropical regions.
Hepatitis B:
During 2020, 369 cases of Hepatitis B were registered in Mexico, with a national incidence rate of 0.28
cases per 100,000 inhabitants.
Following the introduction of the hepatitis B vaccine in 1991, rates of acute hepatitis B in the US have
declined by approx. 82%.
The Western Pacific is the most affected region worldwide (6.2% of its population).
Hepatitis C: up to 2% of the US population has chronic HCV infection.
- 1 cases per 100,000 population, > 40,000 new infections per year in the US.
Hepatitis D: 5% of all patients with chronic HBV infection carry HDV.
Hepatitis E: Uncommon in the US.
An important cause of endemic viral hepatitis in developing countries and equatorial regions (e.g., India,
western and northern Africa, Middle East, Mexico)
Epidemiology
Symptoms
● Incubation phase:
○ Not symptoms in this phase.
● Prodromal (pre-interic) phase:
○ Not specific symptoms
■ Anorexia
■ Malaise
■ Nausea
■ Vomiting
■ Fever
■ Right upper quadrant abdominal pain
■ Urticaria (HBV)
■ Artralgia (HBV)
Symptoms
● Icteric phase:
○ Dark yellow urine: Bilirubin isn’t eliminated in stools, just in urine

○ Jaundice: Build up of bilirubin in tissue and blood

○ Gray colored stools: Bilirubin isn’t eliminated in stools, just in urine

○ Mild splenomegaly

(Amboss)
Symptoms
● Recovery phase:
○ Jaundice progressively disappear.
○ 2 - 4 weeks
 Diagnostic viral hepatitis (hepatic function)

● Albumine (bajo)
● Total plasma proteins (bajo)
● ALP (fosfatasa alcalina), ALT (alanina transaminasa) AST (aspartato aminotransferasa) y
GGT (gamma-glutamil transferasa) (alto)
● Bilirubin (pigmento producida por descomposición eritrocitos)
● Lactato-deshidrogenasa (LDH)
● Prothrombin time (TP) (vía extrínseca I, II, V, VII, X)
Diagnostic hepatitis viral (serologic)
Diagnostic hepatitis viral (serologic) (B)
Diagnostic hepatitis viral (serologic)
Diagnostic hepatitis viral (serologic)
Diagnostic hepatitis viral (serologic)
Treatment viral hepatitis
Viral type Treatment

Type A Just support therapy and rest (acute) (alone)

Type B Just support therapy and rest (acute) (alone) → interferon if complicated → entecavir (Baraclude), el
tenofovir (Viread), la lamivudina (Epivir), el adefovir (Hepsera) o la telbivudina

Type C interferon + ribavirin

- Glecaprevir + pibrenstavir
- Sofosbuvir + velpastavir
- Ledipasvir + sofosbuvir

Type D Just support therapy and rest (acute) (alone) → ribavirin and interferon or PEG-IFN-a

Type E Just support therapy and rest (alone) + ribavirin

Viral hepatitis immunization
Drug induced liver injury
Definition: Damage to the liver caused by medications such as antibiotics, anticonvulsants,
OTCs , and herbal or dietary supplements.

Amboss, 2023; Feldman et al., 2021

Drug induced liver injury
Direct hepatotoxicity DILI
● Direct liver damage caused by hepatotoxic drugs or effects of the immune system
○ Predictable (24 to 48 hours)
○ Have a high incidence
Systemic poisons /
○ Generally have a well-understood mechanism (Dose dependent)
toxic metabolites
● Morphologic abnormalities (Reasonably characteristic and reproducible)

Acetaminophen Carbon tetrachloride & trichloroethylene Amboss, 2023; Feldman et al., 2021
Drug induced liver injury
Idiosyncratic DILI
● Secondary liver damage caused by an abnormal immune reaction to the drug
○ Unpredictable (Between 5 to 90 days following administration)
○ Given at a high dose (>100 mg)
○ Infrequent (1 in 1,000 to 1 to 100,000)
● Mild transient, nonprogressive serum aminotransferase elevations that resolve with continued
drug use
○ Such “adaptation,” the mechanism of which is unknown
● Differences in host susceptibility may result from:
○ Varying kinetics of toxic metabolite generation
○ Genetic polymorphisms in downstream drug-metabolizing pathways
○ Cytokine activation

Amboss, 2023; Feldman et al., 2021

Fontana et al., 2023
Drug induced liver injury
Clinical features Treatment
• Nausea
• Fatigue • Discontinue the offending agent(s)
• Abdominal pain • Consider pharmacological treatment
• Features associated with cholestasis (Jaundice or Pruritus)
• Signs of acute liver failure (Ascites or Encephalopathy) (N-acetylcysteine or glucocorticoids)
• Immunoallergic symptoms (Fever, rash, arthralgia, leukocytosis) • Provide symptomatic management as
needed
Diagnosis
• Careful history-taking
• Liver chemistry findings are abnormal, history of exposure to trigger
drugs or other diagnoses have been discarded.

Liver chemistry Results Other studies Results

ALT and/or AST Normal / ↑ Coagulation panel Normal / ↑ INR

ALP Normal / ↑ Abdominal ultrasound ● Cirrhosis

● Biliary obstruction
Bilirubin Normal / ↑ ● Other parenchymal focal lesions

Albumin Normal / ↓
Amboss, 2023; Feldman et al., 2021
CIRRHOSIS
 CIRRHOSIS
Cirrhosis: diffuse process characterized by fibrosis and conversion of normal
structure into an abnormal nodular arrangement
final stage of various liver diseases of different origin

Fibrosis Bile duct proliferates

 Regenerative nodule

- loss of normal hepatic structure

- necrosis
- formation of regeneration nodules
- cytokines
- proteases
- pro-oxidants
- lipocytes are stimulated to have a
metaplasia → myofibroblast-like cells
- secrete collagen type 1
- contractile ability → redistribute blood
flow Fibrosis
Epidemiology

Alcoholism and viral hepatitis C are the leading causes of end-stage liver disease and
transplantation in Western countries.

4 million people infected with hepatitis C virus in the United States - 20/30% will develop cirrhosis in
the next 30 years. Prevalence of 360 per 100,000 in the United States. It causes 30,000 deaths
annually.

In Mexico, cirrhosis ranked fourth among the top ten causes of death in 2000, and in the 35-55 age
group it was the second. It is estimated that 1.2 million people are infected with hepatitis C virus.

Translated with DeepL.com (free version)

 PATHOPHYSIOLOGY
- End stage liver disease → How fibrotic tissue is formed?
- This process is mediated by stellate cells. In normal tissue:
- Dormant cells and store vitamin A

- When hepatocytes are injured → They secrete

paracrine factors that “activate” and changes
stellate cells.

- Stellate cells are activated → lose vitamin A and

start secreting TGF-B1 → causes them to
produce collagen type 1 → main ingredient in the
extracellular tissue → fibrosis → scar tissue
 Pathophysiology

→ As the fibrotic tissue builds up, it starts compressing the central vein
and sinusoids → Complications arise

• ↑ Pressure. Intrasinusoidal or portal hypertension

Fluid get pushed into the tissues and across tissue into large open
spaces like the peritoneal cavity.
• Fluids move to peritoneal cavity → Ascites
Leads to congestive splenomegaly and hypersplenism
• All the fluid cant go to the liver, so back up to the spleen

• Also there are portosystemic shunts. Because of the high pressure.

• Hepatorenal failures may arise.
Pathophysiology

● ↓ Liver function
○ ↓ Detoxification → hepatic encephalopathy → Asterixis
■ Ammonia

○ Estrogens are not breaked down → ↑ estrogens

■ Gynecomastia
■ Spider angiomata
■ Palmar erythema

○ ↓ Albumin production
○ ↓ Clotting factor production
 CHRONIC DAMAGE TO THE LIVER

cytokines
Inflammatory Regenerative
Underlying Cause proteases
Response Nodules prooxidants

Synthesis and
FIBROSIS deposit collagen Activate Lipocytes
type I

Hepatocellular mass
& Altered blood flow
Function
 NATURAL HISTORY

fatigue, weight loss, abdominal

distention and spider angiomata
Compensated cirrhosis Decompensated cirrhosis

asymptomatic progressive phase

development of complications secondary
to:
- portal hypertension
- liver dysfunction

- ascites
- portal hemorrhagic hypertension
- Encephalopathy
- Jaundice
clinical course of liver cirrhosis

Ascites

varicose veins
 CLINICAL FEATURES
DERMAL

● Caput medusae
○ periumbilical dilation of
subcutaneous veins
● pruritus
● palmar/plantar erythema
Jaundice Telangiectasia Caput medusae ○ ↑ estrogen → ↑ vasodilation
● dry, atrophic skin
● nail clubbing
○ especially with hypoxemia
● petechiae & purpura
○ ↓ coagulation factors

nail clubbing
 CLINICAL FEATURES
Ascites
ABDOMINAL

● Nausea
● Vomit
● Hepatomegaly → In advanced stages of
cirrhosis, the destruction of hepatocytes
causes the liver to contract and reduce its
size.
● Splenomegaly → Portal hypertension
causes splenic congestion
● Ascites → Portal hypertension causes Splenomegaly
 CLINICAL FEATURES
HORMONAL OTHERS

● Hyperestrogenism → due to changes in ● fetor hepaticus

hepatic metabolism of sex hormones ● peripheral edema
○ imbalance in estrogen-androgen ration ● asterixis
○ ↑ systemic estrogen levels
- men: gynecomastia, hypogonadism & Asterixis

↓body hair
- women: can cause amenorrhea
 DIAGNOSTICS
ROUTINE LAB STUDIES

● LIVER CHEMISTRY ● CBC

○ ↑ ALT & AST ○ Anemia

○ ALT>AST: most liver diseases ○ Thrombocytopenia ← because of ↓

○ AST>ALT: alcoholic liver disease production of thrombopoietin

○ ↑ bilirubin ○ Leukopenia

● COAGULATION STUDIES ● CMP

○ ↑ Prothrombin time → because of ↓ ○ ↓ alumin

production of coagulation factors ○ ↓ total protein

○ hyponatremia
 IMAGING
Abdominal
ultrasound CT abdomen

heterogeneous blunt margin

parenchyma

atrophy & nodules

nodular changes

best initial test when ultrasound is not possible

 BIOPSY
Gold standard

● when there is uncertainty

● grading and staging according to inflammation
and fibrosis
● can evaluate focal lesions
 STAGING
CHILD-PUGH SCORE

● Class A: 5-6 points

○ (100% survival 1 year)
● Class B: 7-9 points
○ (80% survival 1 year)
● Class C: 10-15 points
○ (45% survival 1 year)
Complications of cirrhosis
 Portal Hypertension
Definition Elevation of the hepatic venous pressure gradient (HVPG) to 5 >mmHg

Caused by two hemodynamic processes

1. Increased intrahepatic resistance to the passage of blood flow through the liver due to cirrhosis and regenerative nodules
2. Increased splanchnic blood flow secondary to vasodilation within the splanchnic vascular bed

Etiology
Causes of portal hypertension are described based on the anatomical location of the lesion and subcategorized

Prehepatic
Affecting the portal venous system before it enters the liver
● Portal vein thrombosis
● Splenic vein thrombosis

Intrahepatic
Accounts for 95% of cases of portal hypertension and are represented by the major forms of cirrhosis
Presinusoidal: congenital hepatic fibrosis and schistosomiasis
Sinusoidal: cirrhosis (most common cause of portal hypertension in the US)
Postsinusoidal: veno-occlusive disease

Post-hepatic
Those affecting the hepatic veins and venous drainage to the heart
● Budd-Chiari syndrome (hepatic vein obstruction that leads to hepatomegaly, ascites, and abdominal
discomfort)
● Veno-occlusive disease
● Chronic right-sided cardiac congestion
Portal Hypertension
Clinical features
Cirrhosis
● Jaundice
● Scleral icterus
● Spider angioma
Complications (increased blood flow)
● Varices
● Hematemesis/melena to to esophageal/gastric varices
● Caput medusa (A pathognomonic sign of portal hypertension characterized by the presence of engorged, tortuous
paraumbilical veins)
● Hypersplenism
● Abdominal distention due to ascites

Diagnosis
● CBM: thrombocytopenia (most common finding in portal hypertension)
● Imaging: transient elastography (recommended noninvasive test for diagnostic confirmation in patients with suspected portal
hypertension)
○ Liver stiffness >25 kPa
● Hepatic Venous pressure gradient (HVPG) measurement
○ >5 mm Hg: mild portal hypertension
○ ≥ 10 mm Hg: clinically significant portal hypertension
○ > 12 mm Hg: associated with complications
 NASH
Ascites is the accumulation of liquid in the peritoneal cavity.
Ascites fluid analytics
 Complications: Ascites
Ascites is the accumulation of liquid in the peritoneal cavity.
Ascites fluid analytics
Complications: Ascites
Hepatocellular carcinoma
Clinical Features

● Early satiety
● Weight gain
● Dyspnea
● Abdominal pain
● Flank dullness
● Shifting dullness: change of
resonance from dull to tympanic
resonance when a patient
changes from supine to lateral
decubitus.
● Fluid wave test
Complications: Hepatic Encephalopathy

Alterations in mental status and cognitive function

• Liver is not able to remove toxins → absorbed in intestine → increases
toxins concentrations → systemic circulation
• Blood-brain barrier increases permeability
• Ammonia levels elevated !!!

Incidence in Mexico on cirrhotic patients: 18.6%

Complications: Hepatic Encephalopathy

Clinical Features:
❏ Violent
❏ Sleepy
❏ Asterixis
❏ Inability to write
REFERENCES
AMBOSS GmbH. Drug-induced liver injury.https://next.amboss.com/us/article/HF0Kj3#L6879acad86df459379e38a432ad7a247.
Accessed February 21st, 2024.

Fontana, R. J., Liou, I., Reuben, A., Suzuki, A., Fiel, M. I., Lee, W., & Navarro, V. (2023). AASLD practice guidance on drug, herbal,
and dietary supplement-induced liver injury. Hepatology (Baltimore, Md.), 77(3), 1036–1065. https://doi.org/10.1002/hep.32689

Feldman, M., Friedman, L. S., & Brandt, L. J. (Eds.). (2021). Sleisenger Y Fordtran. Enfermedades Digestivas Y Hepaticas:
Fisiopatologia, Diagnostico Y Tratamiento (11a ed.). Elsevier.

Loscalzo J, & Fauci A, & Kasper D, & Hauser S, & Longo D, & Jameson J(Eds.), [publicationyear2] Harrison. Principios de
Medicina Interna, 21e. McGraw-Hill Education.
https://accessmedicina.mhmedical.com/content.aspx?bookid=3118&sectionid=267804475