CIRRHOSIS

Dr. Aayush Lamichhane

MBBS (KU)
Past Questions:
A. Causes
B. Clinical Features
 Cirrhosis of Liver
🠶 Represents a late stage of progressive hepatic fibrosis.

is a diffuse process characterized by fibrosis and conversion of normal hepatic

🠶 It
architecture to structurally abnormal regenerating nodules of liver cells.
[ micro-nodules< 3mm vs macro-nodules > 3mm]
🠶 lack normal lobular organization surrounded by fibrous tissue.
🠶 This results in a decrease in hepatocellular mass, and thus function, and an alteration of blood flow

🠶 The process involves the whole liver and is essentially irreversible

🠶 histologically an “all or nothing” diagnosis
🠶 Clinically classified by its status as compensated or decompensated
Pathophysiology
 🠶The key pathogenic is activation of hepatic stellate cells which
are known as Ito cells or perisinusoidal cells, are located in the
space of Disse.
🠶 Normally they serve as the main storage site for retinoids
(vitamin A).
🠶In response to injury, they become activated, as a result:
Increased fibrosis by myofibroblasts
1. Increased Connective tissue proliferation due to secreted TGF-β1
2. Decreased Collagen breakdown due to TIMP 1 and 2, naturally
occurring inhibitors of matrix metalloproteinases
3. Increased Secretion of extracellular matrix (collagen types I
and III, sulfated proteoglycans, and glycoproteins)
Etiology
History taking
 History Taking
Drug use [ amoxicillin/clavulanate, amiodarone, methotrexate,
nitrofurantoin, isoniazide, and valproic acid] to name a few
Drug abuse
Alcohol abuse
Sexual activity
Metabolic status [ BMI , HTN , diabetes …]
Recent travel
Remote blood transfusion
Extra-hepatic autoimmune diseases
Family history of liver disease mainly
Malignancy history
Clinicalmanifestation
symptoms and physical findings

Highly variable:
Maybe completely asymptomatic and are incidentally
diagnosed at ultrasound or at surgery.

Non-specific symptoms:
Anorexia
Weight loss,
Weakness, fatigue
Muscle cramps
Nausea, vomiting
Upper abdominal discomfort
 Symptoms of Hepatic
Jaundice
insufficiency
Ascites: increasing abdominal girth
Hepatic Encephalopathy: sleep disturbances, flapping tremors, confusion
Lower extremity edema
Pruritis
Portal Hypertension and its squeals (splenomegaly, development of Porto-
systemic collateral vessels, Variceal bleeding)
Vareceal bleeding: Melena, hematemesis, hematochezia
Hemorrhagic tendencies: d/ t decreased production of coagulation factors by
the liver and thrombocytopenia resulting from hypersplenism, I.e. Bruises,
purpura, epistaxis
Large right pleural effusion: SOB
Endocrine disorder: Loss of libido, loss of pubic/axillary hair, irregular
menses, amenorrhea, atrophy of breast, testicular atrophy, impotence,
gynecomastia
 Signs:
Icterus
Spider naevi
=> Sites: territories drained by Superior Venacava, I.e. head/neck, upper limbs,
front/back of upper chest) (Reason: arteriolar changes d/t hyperestrogenism). (With
the release of Central compression, the arteriole fills from centers and spread out
peripherally)

Palmar erythema (Liver Palm)

Fetor hepaticus
Hyperpigmentation
Clubbing, Cyanosis
Terry nails
Dupuytren’s contracture
Terry Spider
nail naevi
Labs and tests
A liver biopsy is "gold standard" for diagnosing, but the procedure is invasive and will not detect
every case. Assess the severity and type of liver disease.
A) Liver Function Test:
Bilirubin (both conjugated and unconjugated bilirubin are raised.)
Serum Proteins
*Albumin: decreased d/t reduced synthesis
*Globulin: increased d/t stimulation of Reticuloendothelial system
Serum amino transferase (AST, ALT) : only raised 2-3 times
AST:ALT >2 in Alcoholic Cirrhosis
AST:ALT <2 in viral hepatitis
Alkaline phosphatase (ALP): slightly raised.
Prothrombin Time (PT): Prolonged d/t reduced synthesis of clotting
factors.
B) Hematological tests
Complete blood count (CBC) [anemia, thrombocytopenia, leukopenia]
Serological markers for hepatitis B and hepatitis C
Serum electrolytes
* Hyponatremia : indicates severe Liver Disease
* Hypokalemia, Hypomagnesaemia, Hypophophatemia
Blood ammonia
- Raised d/t: *decreased clearance by liver; as well as *Porto-systemic shunting
C) Others:
Antinuclear antibodies (ANA), Anti-smooth-muscle antibody (ASMA)
 Autoimmune chronic hepatitis.
Antimitochondrial antibody test (AMA)  Primary biliary cirrhosis.
Ferritin, Iron, Transferrin saturation: Hemochromatosis
Serum ceruloplasmin , 24-hour urinary copper excretionWilson's disease.
Alpha1-antitrypsin level  Alpha1-antitrypsin deficiency
Alpha-fetoprotein (AFP)  to screen HCC
D) Imaging
1. Ultrasound
Liver size and shape
Fatty changes, fibrosis : produces Diffuse increased echogenicity
Nodularities of liver surface
Arterial vascular architectural distortion
Spleen size : Increased in Portal Hypertension
Ascites
2. ERCP (Endoscopic retrograde cholangiopancreatography)
 Primary sclerosing cholangitis (PSC)
3. Endoscopy Esophageal varices due to portal HTN
4. CT scan/MRI:
Hepatocellular carcinoma
Complications:
Modified Child’s Pugh Classification of Prognosis
or
Child-Turcotte-Pugh score
 Portal hypertension
🠶 defined as the elevation of
the hepatic venous pressure
gradient (HVPG) to >5 mmHg
🠶 Cirrhosis is the most common
cause of portal hypertension in
the United States, and clinically
significant portal hypertension is
HVPG>10-12mmHG
🠶 present in >60% of patients
with cirrhosis
🠶 Signs of a hyper dynamic circulatory state include the following:
🠶 Bounding pulses
🠶 Warm, well-perfused extremities
🠶 Arterial hypotension
🠶 Flow murmur over the pericardium
🠶 Signs of Porto systemic collateral formation include the following:
🠶 Anterior abdominal wall dilated veins: May indicate umbilical epigastric vein shunts
🠶 Caput medusa (par umbilical collateral veins)
🠶 Rectal hemorrhoids , Ascites , Par umbilical hernia
Hematemesis or melena: May indicate gastro esophageal variceal bleeding or bleeding from portal
gastropathy

Mental status changes: May indicate the presence of portosystemic encephalopathy

Increasing abdominal girth: May indicate ascites formation
Hematochezia: May indicate bleeding from portal colonopathy
Diagnosis
 HVPG is gradient between the WHVP and the FHVP, estimate of the pressure gradient between the
portal vein and the inferior vena cava.
An HVPG exceeds 12 mmHg variceal hemorrhaging may occur
WHVP reflecting not the actual hepatic portal vein pressure but the hepatic sinusoidal pressure. It is
determined by wedging a catheter in a hepatic vein, to occlude it
treatment
🠶 Management of active variceal bleeding
resuscitation, blood transfusion if needed .
1. Hemoglobin values should be maintained at about 7-8 g/dL
2. Non selective beta blocker e.g. [Propranolol ]
3. (somatostatin, octreotide or terlipressin), endoscopic banding ligation, balloon tamponade
4. 🠶 The most effective
🠶 is the combination of a vasoconstrictor with endoscopic ,continued for 2 to 5 days
🠶 Prophylaxis of variceal bleeding
Pharmacological if no contraindications (non-specific ß-blockers like Propranolol and isosorbide mononitrate
®monocord )
5. Propranolol Deralin ® is initiated at a dose of 20 mg orally twice a day, whereas
6. Nadolol Corgard® is initiated at a dose of 20 mg orally every day.
7. The dose should be titrated to produce a resting heart rate of about 50 to 55 beats per minute
8. endoscopic (banding ligation) – more than one session is needed
9. both treatments have similar results.
 ligation is a local therapy that has no effect on portal pressure and that can lead to hemorrhage from
ligation-induced ulcers
First line is β-blockers if not contraindicated
Second line is ligation
If no varices, β-blockers don’t prevent the development of varices and associated with more
side effects.
Endoscopy should be repeated
1. every 2 to 3 years in patients with no varices,

2. every 1 to 2 years in patients with small varices,

3. and sooner in patients with decompensated disease so that effective therapy can be
instituted before the varices grow in size and bleed.
recommended antibiotic
4. oral norfloxacin ® apirol at a dose of 400 mg twice daily for 5 to 7 days,

5. intravenous ceftriaxone at a dose of 1 g/day for 5 to 7 days is preferable in patients with

advanced liver disease or in those already on norfloxacin

Surgery has no role in primary prophylaxis.
Its role in acute variceal bleeding is exceedingly
limited, because therapy with endoscopic treatment
controls bleeding in 90% of patients

failure is defined as:

a single episode of clinically significant rebreeding
(transfusion requirement of 2 U of blood or more within
24 h]
a systolic blood pressure < 100 mm Hg
a postural change of >20 mm Hg, and/or a pulse
rate greater than 100 bpm)
Hepatic encephalopathy

1.Pathophysiology
2.Secondary complications
3.clinical manifestations
4.Symptoms
5.Labs and diagnosis
6.treatment
 Pathogenesis
The portal system metabolize 80-90% nitrogen-containing compounds through the
urea cycle and/or excreted immediately
The most important is ammonia (NH3).
It crosses the blood–brain barrier
is absorbed and metabolized by the astrocytes, [30% of the cerebral cortex]
Astrocytes use ammonia when synthesizing glutamine from glutamate.
Increases glutamine lead to an increase in osmotic pressure in the astrocytes, which become
swollen
Ammonia are elevated but aren’t correlated with the severity of liver disease
 Definition :
an alteration in mental status and cognitive function occurring in the presence of liver failure
Causes :
In a small proportion of cases, the encephalopathy is caused directly by liver failure;
more likely in acute liver failure.
More commonly, especially in chronic liver disease,
hepatic encephalopathy is caused or aggravated by an additional cause
accumulation in the bloodstream of toxic substances that are normally removed by the liver.
changes in
Ammonia mental
levels arestatus can elevated
typically occur within
in weeks to months.
Brain edema
patients mainly
with hepatic the cerebral cortex
encephalopathy, but thecan be seen in
correlation these patients, with severe encephalopathy
between
Cerebral
severity herniation
of liver diseaseisand
a feared
height complication of brain
of ammonia levels edemapoor
is often in acute liver failure
Diagnosis
 Classification and grading

West Haven Criteria

based on
1. the level of impairment of autonomy
2. changes in consciousness
3. intellectual function, behavior,
4. the dependence on therapy
Grade 1 - lack of awareness; euphoria or anxiety; shortened attention span; impaired
Impaired fine motor skills , fine tremor
Grade 2 - Lethargy or apathy; minimal disorientation for time or place; subtle personality change; inappropriate
behavior
asterexsis, ataxia , slurred speech, Flapping tremor
Grade 3 - Somnolence to semi stupor, but responsive to verbal stimuli; confusion; gross disorientation
Clonus , rigor , asterexsis
Grade 4 - Coma (unresponsive to verbal or noxious stimuli)
Sing of increased intra cranial pressure .
A classification of hepatic encephalopathy was introduced at the World
Congress of Gastroenterology 1998 in Vienna.

According to this classification, hepatic encephalopathy is

subdivided in type A, B and C depending on the underlying cause.
Type A (=acute) describes hepatic encephalopathy associated
with acute liver failure, typically associated with cerebral
oedema
Type B (=bypass) is caused by portal-systemic shunting
without associated intrinsic liver disease
Type C (=cirrhosis) occurs in patients with cirrhosis - this type is
subdivided in episodic, persistent and minimal encephalopathy
(MHE) is defined as encephalopathy that does not lead to clinically overt cognitive dysfunction, but can be
demonstrated with neuropsychological studies
treatment
 Define the grade of the encephalopathy [1-4]
Glasgow coma scale
Consider nasogastric tube
Keep the patient at 30 degrees to maintain perfusion
Intubation required if :
1. Glasgow coma scale < 8
2. Grade 3 /4 encephalopathy

Ammonia level targeted therapy :

1. Try to avoid sedative agents and BZD if necessary use propofol.
2. decreasing ammonia production in the gut are lactulose [ less efficient ]
3. no absorbable antibiotics such as neomycin , metronidazole , rifaximin
4. LOLA as combination therapy - preparation of L-ornithine and L-aspartate used
to increase the generation of urea through the urea cycle

Edema targeted therapy :

First monitor the ICP , range 50-60 mmHg
Measure INR before , apply coagulation factors if needed
1. Hyperventilation  reduced ICP
2. Hypothermia  reduced ICP
3. Osmotherapy if renal function preserved : mannitol , 30% saline [Keep Na+
140-155]
4. Corticosteroids e.g. dexamethasone
Ascites
 The most common cause of ascites is cirrhosis, which accounts for 80% of cases
another 15% of cases:
1. Peritoneal malignancy (e.g., peritoneal metastases from GI tumors or ovarian cancer)
2. heart failure (Chapter 58)s
3. peritoneal tuberculosis (Chapter 332)
4. The initial, most cost-effective, and least invasive method to confirm the presence of
ascites is abdominal ultrasonography.

Diagnostic paracentesis
Initial tests that should be performed on the ascitic
●Appearance assessment (eg, clear, bloody, cloudy, milky)
●Serum-to-ascites albumin gradient determination (SAAG)
●Cell count and differential
●Total protein concentration
Additional tests that may be performed
●Culture with bedside inoculation of aerobic and anaerobic blood
culture bottles (infection, bowel perforation)
●Glucose concentration (malignancy, infection, bowel perforation)
●LDH concentration (malignancy, infection, bowel perforation)
●Gram stain (suspected bowel perforation)
●Amylase concentration (pancreatic ascites or bowel perforation)
●Tuberculosis smear, culture, and adenosine deaminase activity
(tuberculous peritonitis)
●Cytology and possibly antigen level (malignancy)
●Triglyceride concentration (chylous ascites)
●Bilirubin concentration (bowel or biliary perforation)
●Serum pro-brain natriuretic peptide (heart failure)
 The goal is weight loss Spironolactone100
1 kg in the first week mg/day adjusted
2 kg/week subsequently. every 3 to 4 days
Na < 2 to a maximal
g/day. effective dose of
400 mg/day.
Reduce the dose or switch protocol if :
weight loss is greater than 0.5 kg/day in patients
without peripheral edema
Inadequate response
more than 1 kg/day in patients with peripheral
or hyperkalemia
edema.
Furosemide, at an
escalated dose from
Refractory ascites 10 to 20% 40 to 160 mg/day

Side effects
1) electrolyte abnormalities large-volume paracentesis + albumin of 6 to 8
2) renal dysfunction, g IV per liter of ascites removed,
3) Encephalopathy
Particularly when more than 5 L is removed at once
4) painful gynecomastia

(with spironolactone).
 Spontaneous Bacterial Peritonitis

Definition :
infection of ascitic fluid occurs in the absence of perforation of a hollow viscus or an intra-
abdominal inflammatory
Causes :
a) abscess, acute pancreatitis, or cholecystitis. Bacterial translocation,

the main mechanism : migration of bacteria from the intestinal lumen to

mesenteric. b)Mainly gram-negative bacteria
Impaired local and systemic
b) Transient bacteremia due to :

1. Shunting of the blood away from kupffer cells collaterals

2. bacterial overgrowth attributed to a decrease in small bowel motility and intestinal transit

time.
Infections, particularly from
 Hepato-renal syndrome
Definition :
1. a form of functional renal failure without renal pathology
2. Reduced renal perfusion ,associated with reduced GFR and sodium excretion
3. HRS is often seen in patients with refractory ascites
Epidemiology: occurs in about 10% of patients with advanced cirrhosis or acute liver
failure
causes :
1. Splanchinc vasodialation , reduced systemic SVR  hypoperfusion
2. Local increase in the femoral and renal vascular resistance RAAS and
sympathomimetic agents
Type 1 hepatorenal syndrome –more serious type; a progressive impairment
1. 2 X serum creatinine = 50%reduction in creatinine clearance

2. a level greater than 2.5 mg/dL

3. during a period of less than two weeks.

4. Oliguria may occure

Type 2 hepatorenal syndrome – is less severe; fairly stable . The major

clinical feature is ascites that is resistant to diuretics.

Terlipressin in combination with albumin

initial treatment with norepinephrine in combination with
albumin.
Norepinephrine IV as until mean arterial pressure raise by 10
mmgH
albumin is given for at least two days as an intravenous bolus
Midodrine along with octreotide in combination with albumin
The best therapy for HRS is liver transplantation;
 Cardiopulmonary Complications

cirrhotic cardiomyopathy
1. The hyper dynamic  high-output heart failure with decreased peripheral

utilization of oxygen
2. Cirrhosis  increased cholesterol decreased cardiomyocytes membrane fluidity

1. Decreased fluidity causes :

Reduced amount of receptors and channel [ K , beta adrenergic , Ca+2 ]
Impaired signaling
Reduced response
Wong F. Cirrhotic cardiomyopathy. Hepatology International 2009;3(1):294-304.
 Hepato-pulmonary
The hallmark is pulmonary bed vasodilation  arterial
hypoxemia
More than one RBC at the time  reduced oxygenation
which causes the equivalent of a right-to-left shunt.

Porto pulmonary hypertension

vasoconstrictive substances that may be produced in the splanchnic circulation and

bypass metabolism by the liver;
the initial result is reversible pulmonary hypertension.
However, irreversible pulmonary hypertension can occur due to :
1. endothelial proliferation
2. Vasoconstriction
3. in situ thrombosis thrombosis
4. obliteration of vessels
 Coagulopathy
Coagulopathy is almost universal in patients with cirrhosis.
decreased synthesis of clotting factors
impaired clearance of anticoagulants.
thrombocytopenia from hypersplenism due to portal hypertension.
Decreased hepatic mass  reduced synthesis
Vitamin K requires biliary excretion for its absorption;
HypoCoagulable state :
Vitamin K–dependent clotting factors are Factors 1972 ☺
HyperCoagulable state :
( protein C, protein S, anti-thrombin)
Treatment:
IM or IV vitamin K can quickly correct this abnormality.
Platelet function is often abnormal in patients with chronic liver disease, in
addition to decreases in platelet levels due to hypersplenism
Fresh frozen plasma
Cryocepitate
 Hematologic abnormalities
Numerous hematologic manifestations of cirrhosis are
present
including anemia from a variety of causes :
1. Hypersplenism

2. Hemolysis e.g. [ HBC , cryo]

3. iron deficiency

4. Bleeding due to portal HTN

5. B12 /folate deficiency from malnutrition.

6. neutropenia may be seen as a result of hypersplenism

Definitive treatment Vs best treatment
transplantation Vs prevention