Level 2

Semester 4
Module (GIT system, Liver, Nutrition and Metabolism)
Management of Liver Problems II
Tutorial
INSTRUCTOR INFORMATION
• Name: Dr. Eman Zakareya
• Department: Pharmacology
• Official e-mail: ezakareya@yahoo.com
• Mobile or WhatsApp number (optional): 01155918653
• Office hours: Day Saturday
Available time: 1:00-2:00 PM
day: Sunday 1:00-2:00 PM
Office number and place: 315
 Learning Outcomes
By the end of the tutorial, the students will be able to:

1. Discuss causes of liver diseases

2. Describe management of hepatitis A, B and C
3. Describe management of cirrhosis, portal hypertension, ascites,
encephalopathy and varices
Liver Cirrhosis and its
complications
 Introduction
• The liver’s role in detoxification (phase I and phase II metabolism)
takes place within the hepatocytes,
• The nonparenchymal cell population provides physical and
biochemical structure to the liver as well as active transport of
substances into the bile.
• Although the liver has a strong capacity to regenerate, this ability
can be impaired by toxic or viral agents, such as ethanol and
hepatitis viruses.
 Definition of cirrhosis
• It involves replacement of normal hepatic architecture with
fibrous scar tissue. Scarring is accompanied by loss of viable
hepatocytes.

• Cirrhosis is characterized by
1. progressive damage and deterioration of liver function, but
even with extensive scarring some patients remain
asymptomatic.
2. Advanced cirrhosis is irreversible and leads to portal
hypertension, which in turn is responsible for the complications
 PATHOGENESIS OF CIRRHOSIS
1. Viral infections; hepatitis A (HAV), B (HBV), C (HCV), D (HDV) and E (HEV).
2. Alcohol
3. Non-alcohol related fatty liver disease
4. Immune disorders; Autoimmune hepatitis (AIH), Primary biliary cirrhosis (PBC)
5. Vascular abnormalities; The Budd–Chiari syndrome (BCS) is a rare and potentially
fatal condition related to the obstruction of the hepatic venous outflow tract.
6. Metabolic and genetic disorders; Hereditary haemachromatosis (HH) is associated
with increased absorption of dietary iron resulting in deposition within the liver,
heart, pancreas, joints, pituitary gland and other organs. This can lead to cirrhosis
and hepatocellular carcinoma.
7. Drugs; are an important cause of abnormal liver function tests and acute liver injury,
including ALF and chronic liver diseases including steatosis, fibrosis/cirrhosis,
autoimmune and vascular disease.
• Fatty liver or steatosis from ethanol, the first stage of liver
injury, is characterized by lipid deposition in the hepatocytes.

• Steatosis is followed by liver inflammation (steatohepatitis),

hepatocyte death, and collagen deposition leading to
fibrosis.

• The progression of liver disease in patients with HCV is

dependent on both patient and viral factors.
 Signs and symptoms of cirrhosis
• Fibrosis scar tissue nodules modify the basic architecture of the liver, disrupting hepatic blood flow and liver
function.

• Reduced hepatic blood flow significantly alters normal metabolic processes and decreases protein synthesis.

• Hepatic drug metabolism is reduced, which can result in higher systemic drug concentrations and toxicity by
extending half-life of drugs normally eliminated by the liver (especially those with high first-pass
metabolism).

• In cirrhosis, bilirubin (from the enzymatic breakdown of heme) can accumulate, causing jaundice, scleral
icterus (yellowing of the sclera), and tea-colored urine (urinary bilirubin excreted as urobilinogen).
• Changes in steroid hormone production, conversion, and handling are prominent
features of cirrhosis (I.E: decreased libido, gynecomastia, testicular atrophy, and
feminization in men).

• Another effect of changes in sex hormone metabolism is development of palmar

erythema and spider angiomata (nevi) (i.e. the number and size correlate with
disease severity, and their presence relates to risk of variceal hemorrhage).

• Increased intrahepatic resistance to portal blood flow increases pressure on the

entire splanchnic bed; splenomegaly is a common finding in cirrhotic patients.

• Splenic platelet sequestration secondary to splenomegaly is one of the causes of

thrombocytopenia in cirrhotic patients.
 COMPLICATIONS OF CIRRHOSIS
1. Portal Hypertension
2. Ascites
3. Spontaneous bacterial peritonitis (SBP),
4. Hepatic encephalopathy (HE),
5. Hepatorenal syndrome (HRS), and
6. Variceal bleeding.
 Classification of cirrhosis
• Two main categories;
1. Compensated: cirrhotic patients with a portal pressure less than 10 mm
Hg and an absence of the complications of cirrhosis (e.g., ascites, variceal
hemorrhage, or encephalopathy).

2. Decompensated: patient presenting with complications of cirrhosis.

 Investigations
• Biochemical liver function tests; alkaline phosphatase and γ-glutamyl
transpeptidase, Aspartate transaminase (AST) and alanine transaminase
(ALT), Alkaline phosphatase, Bilirubin, Prothrombin time (PT),
international normalised ratio (INR).
• Laboratory investigation of aetiology; to screen for hepatitis A, B, and
C, Auto-antibodies and immunoglobulins for autoimmune disease and
Serum ferritin.
• Imaging techniques; Ultrasound, Computed tomography (CT) and
magnetic resonance (MR) scans.
• Liver biopsy
The Child-Turcotte-Pugh classification of liver
disease severity
 1. Portal hypertension
• Portal hypertension results from both an increase in
resistance to portal flow and also an increase in portal
venous inflow.
• Normal portal pressure is generally below 6 mm Hg,
and in cirrhotic patients may increase to 7 to 9 mm
Hg.
• Clinically significant portal hypertension develops,
when the portal pressure increases to greater than 10
to 12 mm Hg, the threshold for complications of
portal hypertension, such as esophageal varices and
ascites.
• Portal hypertension can be classified as prehepatic, intrahepatic, or
posthepatic
• Persistent portal hypertension may
(a) change both blood flow as well as the lymphatic circulation and lead to
ascites formation;
(b) increase pressure in the vessels that branch off the portal vein, such as the
coronary veins, leading to the formation of esophageal varices; and
(c) lead to the development of increased abdominal collateral circulation.

• Other complications associated with advanced cirrhosis and portal

hypertension are; Hepatic encephalopathy and hepatorenal syndrome.
 Pathophysiology
• Portal hypertension mediates systemic and splanchnic arterial vasodilation
by increasing production of nitric oxide and other vasodilators in an
attempt to counteract the increased pressure gradient.

• Nitric oxide causes a fall in systemic arterial pressure; this drop in pressure
activates the renin–angiotensin–aldosterone system (RAAS) and
sympathetic nervous system, and increases antidiuretic hormone (ADH,
vasopressin) production.
• These systems are activated in an attempt to maintain arterial blood pressure
and renal blood flow by increasing sodium and water retention.

• The excess sodium and water puts increased pressure on the vascular system.
As a result, the umbilical vein, which is usually eradicated in infancy, may
become patent and cause prominent dilated veins that are visible on the
surface of the abdomen (= Caput medusae).
 2. Ascites
• Ascites, or accumulation of fluid in the peritoneal cavity, is the most
commonly encountered clinical symptom of cirrhosis.
• Indicates a poor prognosis.
• Can be detected during the physical examination when more than 3 L of
fluid has accumulated.
• Ascites can be confirmed with ultrasound.
• In cirrhosis, hepatic venous outflow is restricted, resulting in an increase in
the portal vein back-pressure.
 Pathophysiology
1. Hypoalbuminemia; albumin is responsible for maintaining vascular
oncotic pressure. so, low serum albumin levels, elevated hydrostatic
pressure, and increased capillary permeability allow fluid to leak from
the vascular space into body tissues. (This results in ascites, peripheral
edema, and fluid in the pulmonary system).
2. Obstruction of hepatic sinusoids and hepatic lymph nodes also allows
fluid to seep into the peritoneal cavity, further contributing to ascitic
fluid formation.
3. Increasing sodium and water retention
 3. Hepatic Encephalopathy
• In severe hepatic disease, systemic circulation bypasses the liver; substances that are
normally metabolized by the liver accumulate in the systemic circulation.

• These byproducts, especially nitrogenous waste, are neurotoxic.

• Ammonia (NH3) is just one of the toxins implicated in HE. It is a metabolic byproduct of
protein catabolism and is also generated by gut bacteria.

• In a normally functioning liver, hepatocytes degrade ammonia to form urea, which is

renally excreted.
• In cirrhosis, conversion to urea is reduced and ammonia accumulates, causing
encephalopathy.

• HE is a clinical diagnosis; decreased cognition, confusion, and changes in behavior

combined with physical signs such as asterixis (characteristic flapping of hands upon
extension of arms with wrist flexion) indicate HE.

• Infections, variceal hemorrhage, renal insufficiency, electrolyte abnormalities, and

increased dietary protein have all been associated with acute HE.
 Goal of therapy of cirrhosis and complications
• Patients with compensated cirrhosis are managed by;
1. Treatment of the underlying cause of the cirrhosis,
2. Prevention (primary prophylaxis), as well as early diagnosis of the
complications of cirrhosis.

• For patients with decompensated cirrhosis, the aim is to;

1. Treat the complications of cirrhosis and
2. Prevent sequela (secondary prevention).
 Nonpharmacologic Therapy
Lifestyle modifications can limit disease complications and slow further liver
damage;
1. Immediate cessation of alcohol use
2. Patients with ascites require dietary sodium restriction (limited to 2 g
sodium chloride per day).
3. Dietary supplements, herbal remedies, and nutraceuticals have not been
well studied in hepatic impairment and cannot be recommended.
4. In patients with variceal bleeding, nasogastric (NG) suction reduces the risk
of aspirating stomach contents; aspiration pneumonia is a major cause of
death in patients with variceal bleeding.
5. Endoscopic band ligation (EBL) involves application of a stricture around the
varix to stop acutely bleeding varices (effective in up to 90% of patients).
6. During episodes of acute HE, temporary protein restriction to decrease
ammonia production can be a useful adjuvant to pharmacologic therapy, but
long-term protein restriction in cirrhotic patients is not recommended.
7. Hepatitis A and B vaccination is recommended in patients with cirrhosis to
prevent additional liver damage from an acute viral infection.
8. Pneumococcal and influenza vaccination may also be appropriate and can
reduce hospitalizations.
9. Shunts are long-term solutions to decrease elevated portal pressure.
 Pharmacologic Therapy
• Drug therapy directed at;
Reducing portal hypertension that can alleviate symptoms and prevent
complications
but cannot reverse cirrhosis.
 Therapy of Portal Hypertension
• Nonselective B–blockers such as propranolol and nadolol are first-line
treatments for portal hypertension.

• They reduce bleeding and decrease mortality in patients with known varices.

• Blockade of B1 receptors reduces cardiac output and splanchnic blood flow,

while B2-adrenergic blockade prevents B2-receptor–mediated splanchnic
vasodilation while allowing unopposed α-adrenergic effects; this enhances
vasoconstriction of the systemic and splanchnic vascular beds.
• Because -blockers decrease blood pressure and heart rate, they should be
started at low doses to increase tolerability.
• Propranolol is hepatically metabolized, so initial drug concentration, half-life,
and pharmacologic effects are all increased in cirrhosis. A reasonable starting
dose of propranolol is 10 to 20 mg once or twice daily.
• Doses should be titrated as tolerated with the goal of decreasing heart rate
by 25%.
• Carvedilol is a unique NSBB that also blocks α1 receptors inducing
intrahepatic vasodilation for a more potent decrease in portal pressure
compared to other NSBB, but it also mediates greater decreases in mean
arterial pressure. Should be avoided in patients with refractory ascites to
avoid additional vasodilation.
 Therapy of Ascites
• The goals are to minimize acute discomfort, reequilibrate ascitic fluid, and
prevent SBP.
• Treatment should modify underlying disease pathology; without directed
therapy, fluid rapidly reaccumulates.
• Acute discomfort may be ameliorated by therapeutic paracentesis. Often
removing just 1 to 2 L of ascitic fluid provides relief from pain and fullness.
• 6 to 8 g of IV albumin should be given per liter of fluid removed.
• Large-volume paracentesis without albumin administration can precipitate
HRS through decreased perfusion.
• Albumin is not beneficial in hemodynamically stable patients if less than 5 L
of fluid is removed.

• Diuretics are usually required in addition to sodium restriction.

1. Spironolactone (an aldosterone antagonist) with or without furosemide
forms the basis of pharmacologic therapy for ascites.
• Spironolactine counteracts the effects of RAAS activation.
2. A loop diuretic is typically added to spironolactone for more potent diuresis.
• Doses should be titrated upward every 3 to 5 days.

• Diuretic therapy is typically lifelong.

FIGURE. Approach to the patient with ascites and spontaneous bacterial peritonitis (SBP). A) If PMN is greater than 250/L but
culture is negative, begin empiric antibiotics and retap after 48 hours. If culture is positive but PMN less than 250/L, treat as if
PMN greater than 250/L (presumed SBP). If polymicrobial infection exists, exclude SBP. (BUN, blood urea nitrogen; Na, sodium;
PMN, polymorphonuclear leukocyte; TIPS, transjugular intrahepatic portosystemic shunt.)
 Long-term SBP prophylaxis
• decreases mortality and is recommended in a select group of
patients—those with a history of SBP,

• Oral options are one trimethoprim–sulfamethoxazole daily or

ciprofloxacin 500 mg daily
 Therapy of Varices
• Variceal bleeding is common in cirrhotic patients.
• During acute variceal hemorrhage, it is crucial to control bleeding, prevent rebleeding,
and avoid complications such as SBP.
1. Octreotide (a synthetic somatostatin analog) causes selective
vasoconstriction of the splanchnic bed, decreasing portal venous pressure
with few serious side effects.
• Therapy should continue for at least 24 to 72 hours after bleeding has
stopped.

2. Octreotide combined with endoscopic therapy results in decreased

rebleeding rates and transfusion needs.

3. These patients are at high risk of developing SBP, and prophylactic

antibiotics provide both a morbidity and mortality benefit (ceftriaxone (1 g
IV every 24 hours) for 5 to 7 days has been proven effective).
 Therapy of Encephalopathy
1. Lactulose
• Is the foundation of pharmacologic therapy to prevent and treat HE.
• It is a nondigestible synthetic disaccharide laxative;
• It is hydrolyzed in the gut to an osmotically active compound that draws water into the
colon and stimulates defecation.
• Lactulose lowers colonic pH, which favors the conversion of ammonia (NH3) to
ammonium (NH4 +(which cannot cross back from the gut into the systemic circulation
because it is ionic.
2. Antibiotic Therapy Rifaximin is a nonabsorbable antibiotic that decreases urease-
producing gut bacteria, decreasing ammonia production. It is reserved for use as add-on
therapy after lactulose failure.
Case 1
Scenario 1
A 53-year-old woman was admitted to your unit overnight from the emergency department. She
seems somewhat confused. Chief Complaint: Abdominal pain and fullness; patient states, “I feel
like I’m going to explode.” there was Abdominal pain with nausea and early satiety.

History of increasing abdominal girth over the past 2 weeks; abdominal pain and intense tightness
started yesterday afternoon
PMH: DVT “long time ago,” and “bleeding ulcer” 2 years ago
she uses alcohol on a “recreational” basis only. Cannot quantify intake.
Meds (Outpatient): OTC NSAIDs (ibuprofen, naproxen), antacids occasionally
PE: BP 84/58 mm Hg, P 110 beats/min, T 38.7°C, RR 20 breaths/min, oxygen saturation 99% (0.99)
on room air, BMI 19.3 kg/m2
General: Somnolent, ill-looking woman who appears older than stated age
(+) scleral icterus, jaundiced skin
CV: Tachycardic,
Abd: Distended tense abdomen that is tender to palpation, hypoactive bowel sounds,
hepatosplenomegaly, large ascites
2+ pitting edema
 Questions
Q1: What signs and symptoms does she have that are consistent with cirrhosis?
Q2: Based on the current information, what is the most likely cause of her abdominal
pain?
Q3: What are the risk factors of cirrhosis?
Q4: What test(s), should be done to further investigate the source of abdominal pain?
Q5: What is the treatment of her abdominal pain?
 Answer of Q1
• anorexia, fatigue, weakness,
• disturbances in sleep patterns.
• (+) scleral icterus,
• jaundiced skin
• Tachycardia,
• Distended tense abdomen that is tender to palpation, hypoactive bowel sounds,
hepatosplenomegaly,
• large ascites (feelings of abdominal fullnessand pain, nausea, shortness of breath, and early satiety)
• 2+ pitting edema

• Neurologic changes from HE(Somnolent, ill-looking woman, confused ) Back

 Answer of Q2
• Patient has SBP that present with fever, painful tympanic abdomen, and changes in mental status.

Back
 Answer of Q3
1. Viral infections; hepatitis A (HAV), B (HBV), C (HCV), D (HDV) and E (HEV).
2. Alcohol
3. Non-alcohol related fatty liver disease
4. Immune disorders; Autoimmune hepatitis (AIH), Primary biliary cirrhosis (PBC)
5. Vascular abnormalities; The Budd–Chiari syndrome (BCS) is a rare and potentially fatal condition
related to the obstruction of the hepatic venous outflow tract.
6. Metabolic and genetic disorders; Hereditary haemachromatosis (HH) is associated with increased
absorption of dietary iron resulting in deposition within the liver, heart, pancreas, joints, pituitary
gland and other organs. This can lead to cirrhosis and hepatocellular carcinoma.
7. Drugs; are an important cause of abnormal liver function tests and acute liver injury, including ALF and
chronic liver diseases including steatosis, fibrosis/cirrhosis, autoimmune and vascular disease.
Back
Answer of Q4 & 5
Case 2
Scenario 2
An ultrasound-guided paracentesis was performed, and 7 L of fluid was removed. The analysis
reveals clear yellowish fluid, total protein 8 g/L, PMNs 255 cells/mm3 (255 × 106/L), Gram stain
was negative, sample sent for culture.

Q1: Should the patient receive fluids (crystalloid or colloid) after the paracentesis?
Q2: If so, what specific therapy would you initiate and why?
Q3: What is the mechanism of action of drugs used to treat ascites listed in Q2?
Q4: What are potential sources of her confusion?
Q5:How should her confusion be treated?
Answer 1
No

Back
Answer 2
• Antibiotics for treating SBP as listed before.

• 6 to 8 g of IV albumin should be given per liter of fluid removed.

• Large-volume paracentesis without albumin administration can precipitate HRS through
decreased perfusion.

• Spironolactone (an aldosterone antagonist) with or without furosemide forms the basis of
pharmacologic therapy for ascites.

Back
Answer 3
1. Albumin is responsible for maintaining vascular oncotic pressure. so, low serum albumin levels,
elevated hydrostatic pressure, and increased capillary permeability allow fluid to leak from the
vascular space into body tissues. (This results in ascites, peripheral edema, and fluid in the
pulmonary system)

2. Spironolactone (an aldosterone antagonist) that counteracts the effects of RAAS activation.

3. loop diuretic as frusemide increase the excretion of Na+ and water by the kidneys by inhibiting
their reabsorption from the proximal and distal tubules, as well as the loop of Henle by
inhibiting Na-K-2Cl cotransport.

Back
Answer 4
• The patient has Hepatic encephalopathy.
• In severe hepatic disease, systemic circulation bypasses the liver; Ammonia that are normally
metabolized by the liver accumulate in the systemic circulation.

• It is a metabolic byproduct of protein catabolism and is also generated by gut bacteria.

• In cirrhosis, conversion to urea is reduced and ammonia accumulates, causing encephalopathy.
• These byproducts, especially nitrogenous waste, are neurotoxic.

• In a normally functioning liver, hepatocytes degrade ammonia to form urea, which is renally
excreted.
Back
Answer 5
1. Lactulose
• It is a nondigestible synthetic disaccharide laxative;
• Lactulose lowers colonic pH, which favors the conversion of ammonia (NH3) to ammonium
(NH4 +(which cannot cross back from the gut into the systemic circulation because it is ionic.

2. Antibiotic Therapy Rifaximin is a nonabsorbable antibiotic that decreases urease-producing gut

bacteria, decreasing ammonia production. It is reserved for use as add-on therapy after lactulose
failure.
Case 3
Scenario 3
The next day, the patient’s mental status has improved, she is less somnolent, and she states that
her pain is much better, but feels like she has more fluid in her belly than immediately after the
paracentesis.
On physical examination, her abdomen is less tense than on admission, and she has decreased
tenderness to palpation.

Q1: What pharmacologic and nonpharmacologic treatments are appropriate to reduce

reaccumulation of ascitic fluid?
Answer
• Acute discomfort may be ameliorated by therapeutic paracentesis. Often removing just 1 to 2 L of
ascitic fluid provides relief from pain and fullness.
• 6 to 8 g of IV albumin should be given per liter of fluid removed.
• Large-volume paracentesis without albumin administration can precipitate HRS through
decreased perfusion.
• Diuretics are usually required in addition to sodium restriction.
1. Spironolactone (an aldosterone antagonist) with or without furosemide forms the basis of
pharmacologic therapy for ascites.
• Spironolactine counteracts the effects of RAAS activation.
2. A loop diuretic is typically added to spironolactone for more potent diuresis.
• Diuretic therapy is typically lifelong.
Case 4
 Case scenario 4
C.R., a 48-year-old man, presents to the ED with jaundice, complaints of
incapacitating fatigue, and vague intermittent abdominal pain for the past
month. C.R. was diagnosed with HBV infection 12 years ago. His social history
includes IV drug abuse and alcohol abuse. Several weeks ago, C.R. noted
darkening of his urine and yellowing of his eyes. Additionally, C.R. has a history
of severe depression, managed with escitalopram.
Physical examination reveals a thin man in no apparent distress. He is afebrile,
and his blood pressure, heart rate, and respiratory rate are within normal
limits. Moderate scleral icterus is noted. The abdomen is soft and not
distended. The liver is enlarged, nontender, and smooth. Investigations
showed decompensated liver.
Q1. What are the goals of therapy for chronic hepatitis secondary to HBV?

To achieve sustained suppression of HBV replication and remission of liver

disease.

Ultimately, achieving these goals should lead to resolving ongoing

hepatocellular damage and reducing the development of cirrhosis and HCC.
Q2. What are the reasons for avoiding PegIFN-α therapy in C.R.?

 Adverse effects associated with PegIFN therapy can be categorized as early

side effects that rarely limit the use of PegIFN, and late side effects that may
necessitate dose reduction or discontinuation of therapy altogether.
The early side effects appear hours after administration as influenza-like
syndrome with fever, chills, anorexia, nausea, myalgias, fatigue, and headache.
They tend to resolve after repeated exposure to the drug over time.
Administration ofPegIFN at bedtime may decrease the severity of early onset
of the side effects.
Acetaminophen can be used to treat early side effects of PegIFN therapy.
The late-onset side effects usually are observed after 2 to 4 weeks of therapy
and are more serious, include worsening of the flu-like syndrome, alopecia,
bone marrow suppression, bacterial infections, thyroid dysfunction (both
hypothyroidism and hyperthyroidism), and psychiatric disturbances (emotional
lability, irritability, depression, anxiety, delirium, and suicidal ideation).

C.R.’s history of severe depression should be considered a relative

contraindication to treating him with PegIFN. Furthermore, the use of PegIFN in
patients with decompensated liver disease may lead to FHF. Therefore, this
agent, although approved for HBV, is not optimal for him.
Discussion & Feedback

Ask questions
 References & recommended readings

• Pharmacology (Lippincott Illustrated Reviews Series)