Liver Cirrhosis

成大醫院

吳毅晉
2018.10.1
Anatomy of the liver

Zakim and Boyer's Hepatology, 7th Edition

The portal venous system

Sherlock's Diseases of the Liver and Biliary System, 12th Edition

Classification of portal hypertension

Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, 10th edition

 Causes of liver cirrhosis

Chronic viral hepatitis Cardiac cirrhosis

Hepatitis B Inherited metabolic liver disease
Hepatitis C Wilson’s disease
Alcoholism Hemochromatosis
Nonalcoholic steatohepatitis α1 Antitrypsin deficiency
Autoimmune hepatitis Cystic fibrosis
Biliary cirrhosis Cryptogenic cirrhosis
Primary biliary cholangitis (cirrhosis)
Primary sclerosing cholangitis
Autoimmune cholangiopathy

Harrison's Principles of Internal Medicine, 19th edition

The hepatic lobule

Hepatocytes in zone one are involved in gluconeogenesis, urea

synthesis, and oxidative energy metabolism while those in zone
three carry out the functions of glycolysis and lipogenesis.

Pharmacotherapy: A Pathophysiologic Approach, 10th Edition

Matrix and cellular alterations in hepatic fibrosis

Schiff's diseases of the liver, 12th edition

 Liver Function Tests

• Tests of capacity of liver to transport

organic anions and to metabolize drugs

• Tests to detect injury to hepatocytes

• Tests of the biosynthetic capacity of the

liver
 Conversion of
Heme to Bilirubin

Sources: 1. hemoglobin in senescent

RBC
2. prematurely destroyed
erythroid cells
3. turnover of hemoproteins
in tissues (e.g. cytochrome
P450 in liver)

Sites: reticuloendothelial cells in liver

and spleen
 Handling of Bilirubin
by Hepatocytes

Unconjugated bilirubin

Conjugated bilirubin

G: glucuronic acid
 Cycling of Bilirubin

Urobilin (yellow)

• Clay-colored stool
Stercobilin (brown) • Tea-colored urine

UroB: urobilinogens (colorless )

 Serum Bilirubin
• Direct and indirect bilirubin
- diazo methods
- spectrophotometirc assays
- chromatographic assays
• -bilirubin
- half-life: 12-14 days
(half-life of bilirubin: 4 hours)
Some patients with conjugated hyperbilirubinemia do not have bilirubinuria
during the recovery phase of their disease.
 Hyperbilirubinemia

• Overproduction

• Impaired uptake, conjugation, or excretion

• Regurgitation from damaged hepatocytes

or bile duct.
 Tests to Detect Injury to Hepatocytes
(Serum Enzyme Tests)
• Asparate aminotransferase (AST, GOT)
- liver, cardiac muscle, skeletal muscle,
et al.
- half-life: 18 hours

• Alanine aminotransferase (ALT, GPT)

- liver
- half-life: 48 hours
 AST/ALT Ratio
• Alcoholic liver disease
- ALT < 300 IU and AST/ALT ratio > 2
- pyridoxine deficiency

• Cirrhosis
- AST/ALT ratio > 1
 ALT > 10 x Upper Limit of Normal

• Acute viral hepatitis

• Ischemic hepatitis

• Acute bile duct obstruction caused by

common bile duct stone
 Enzymes for the Detection of
Cholestasis
• Alkaline phosphatase

• -glutamyl transpeptidase (GGT)

• 5’-nucleotidase
 Alkaline Phosphatase
• Regurgitation (bile acids  induce
synthesis and leak)
• Cholestasis, infiltrative liver diseases,
space occupying lesions of the liver, bone
diseases, pregnancy, malignancy (Regan
isoenzyme), et al.

• Half-life: 7 days
• Electrophoresis
 -glutamyl transpeptidase (GGT)

• Diseases of liver, biliary tract, and

pancreas
• Induced by alcohol, barbiturates, and
phenytoin
• Not elevated in bone diseases or
pregnancy
• Half-life: 7 to 10 days
 5’-Nucleotidase

• Not elevated in bone diseases or

pregnancy

• Not necessary elevated in early or modest

liver injury
 Evaluation of
Hyperbilirubinemia

Harrison's Principles of Internal

Medicine, 19th edition, 2015.
 Unconjugated Hyperbilirubinemia
Direct fraction < 15%
Indirect bilirubin > 1.2 mg/dL

• Hemolysis
• Ineffective erythropoiesis
• Drugs
• Inherited condition (Gilbert’s syndrome)
• Neonates
• Hematoma
Patterns of Abnormal Liver Function Test

• Acute viral hepatitis

• Acute cholangitis caused by common bile duct

stone

• Obstructive jaundice caused by peri-ampullary

tumor

• Decompensated cirrhosis
Interpretation of liver function tests

Pharmacotherapy: A Pathophysiologic Approach, 10th Edition

 Tests of the Biosynthetic Capacity of
the Liver
• Albumin
- half-life: 20 days
- sensitivity and specificity

• Prothrombin time
- factor VII: half-life: 4-6 hours
- prognosis
- INR
 Child-Pugh Classification of Cirrhosis
Factor 1 2 3

Serum bilirubin (mg/dL) <2.0 2.0–3.0 >3.0

Serum albumin (g/dL) >3.5 3.0–3.5 <3.0

Prothrombin time (second) <4 4–6 >6

(INR) <1.7 1.7–2.3 >2.3

Easily Poorly
Ascites None
controlled controlled

Hepatic encephalopathy None Minimal Advanced

A: 5 to 6, B: 7 to 9, C: 10 or above
Model for End-Stage Liver Disease (MELD) Score

• MELD score = 0.957 x Loge(creatinine in mg/dL) + 0.378

x Loge(bilirubin in mg/dL) + 1.120 x Loge(INR) + 0.643

• http://www.mayoclinic.org/meld/
• Mortality risk in patients with end-stage liver
disease
• Post-operative mortality risk in patients with
cirrhosis
• A disease severity index to determine organ
allocation priorities
 Diagnosis of liver cirrhosis

• Abdominal sonography, CT, or MRI.

• Liver biopsy

• Ultrasound elastography (Fibroscan)

• Endoscopic findings

• Thrombocytopenia
 Esophageal and Gastric Varices –
Control of Acute Bleeding
• Endoscopic variceal ligation (EVL) and histoacryl
injection therapy
- Prophylactic antibiotics

• Vasoconstricting agents: somatostatin, octreotide,

terlipressin, and vasopressin + nitroglycerin.

• Ballon tamponade (Sengstaken-Blakemore tube)

• Transjugular intrahepatic portosystemic shunt (TIPS)

 Esophageal and Gastric Varices –
Prevention of Recurrent Bleeding
• EVL
• Propranolol, nadolol, or carvedilol
- Nonselective beta blockers
- Target heart rate: 25% below baseline or 55 to 60
beat/min with systolic blood pressure > 90 mmHg
- Contraindications: asthma, COPD, high degree AV block,
refractory ascites.

• TIPS

• Portosystemic shunt surgery

Prevention of initial bleeding

Band ligation for control of esophageal variceal bleeding

Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, 10th edition

Sengstaken – Blakemore tube

Sherlock's Diseases of the Liver and Biliary System, 12th Edition

Transjugular intrahepatic portosystemic shunt (TIPS)

Pharmacotherapy: A Pathophysiologic Approach, 10th Edition

Management of acute variceal hemorrhage

Pharmacotherapy: A Pathophysiologic Approach, 10th Edition

 The differential effect of beta-blockers in cirrhosis

Gastroenterology 2014 146, 1680-1690.e1DOI: (10.1053/j.gastro.2014.03.005)

J Hepatol 2014;60:643-53
When Should the -Blocker Window in Cirrhosis Close?

Gastroenterology 2014;146:1597-1599
Pathogenesis of ascites

Pharmacotherapy: A Pathophysiologic Approach, 10th Edition

 Algorithm for the diagnosis of ascites

SAAG : serum-ascites albumin gradient

Harrison's Principles of Internal Medicine, 19th edition

Differential diagnosis of ascites

UpToDate, http://www.uptodate.com/
 Ascites
• Salt restriction: Na < 2g/day (88 mmol/day)

• Diuretics
- Spironolactone (100mg/day) and furosemide (40 mg/day) initially
- The doses can be increased simultaneously every 3 to 5 days if
necessary (maintaining the ratio)
- Maximum weight loss < 0.5 kg/day

• Monitor weight, serum electrolytes, serum creatinine, random urine

Na/K, 24-hour urine Na (random urine Na/K > 1 means 24-hour
urine Na > 78 mmol/day).

• Refractory ascites
- Paracentasis
- Albumin infusion (6-8 g/L ascites removed) for
large-volume paracentesis ( 5 L)
- Midodrine 7.5 mg three times daily
- TIPS and liver transplantation
 Spontaneous bacterial peritonitis
• Initial presentation: fever, altered mental status, abdominal
pain or discomfort.

• Ascites fluid PMN > 250/mm3

• Ascites culture (E.coli and other gut bacteria)

• Exclude secondary bacterial peritonitis: multiple organisms

(frequently including fungi and enterococcus), and at least two
of the following criteria: total protein > 1 g/dL, LDH > ULN for
serum, and glucose < 50 mg/dL  Abdominal CT

• Intravenous antibiotic to which the organism is highly

susceptible (e.g., cefotaxime)

• Intravenous albumin may improve survival

• Prophylaxis
Grading system for hepatic encephalopathy

Pharmacotherapy: A Pathophysiologic Approach, 10th Edition

 Hepatic encephalopathy

• Correct the precipitation causes

- GI bleeding, sepsis, constipation, high protein meal,
dehydration, electrolytes imbalance, sedatives.

• Lactulose or lactitol (2 to 3 soft stools per day)

• Metronidazole (ototoxicity and peripheral neuropathy),

neomycin (renal insufficiency), or rifaximin

• Liver transplantation
 Hepatorenal syndrome (HRS)

• Functional renal failure without renal pathology

• Type 1 HRS: severe and rapidly progressive renal failure

within 2 weeks
Type 2 HRS: a more indolent course with a better outcome

• Liver transplantation

• Terlipressin, octreotide, -adrenergic agonists (midodrine

and norepinephrine), and intravenous albumin.
(UpToDate, http://www.uptodate.com/)
 Case 3 (liver cirrhosis with massive ascites)
• A 53-year-old man
2018/3/12 - 2018/7/6
• Diagnosis:
1. Liver cirrhosis, Child-Pugh class C, with massive
ascites
2. Spontaneous bacterial peritonitis
3. Esophageal varices bleeding post endoscopic
variceal ligation
4. Chronic hepatitis C, genotype 2
5. Suspected liver abscess, complicated cyst, or
hematoma ---> suspected hepatocellular
carcinoma (infiltrative type)
 Questions
• Problem Identification
1.a. Create a list of the patient’s drug therapy problems.
1.b. What information (signs, symptoms, lab values) indicates the presence of ascites in this
patient?
1.c. What information (signs, symptoms, lab values) indicates the presence or absence of
spontaneous bacterial peritonitis in this patient?
1.d. What classification system is used to evaluate the prognosis of chronic liver disease?
Use this system to calculate the score and grade for this patient.
• Desired Outcome
2. What are the goals of pharmacotherapy for managing ascites and related complications of
cirrhosis?
• Therapeutic Alternatives
3.a. What nonpharmacologic therapies might be considered for this patient?
3.b. What pharmacologic therapies should be considered for this patient?
 Questions
• Optimal Plan
4.a. Outline a suitable pharmaceutical care plan for the acute management of this patient.
Include drug, dosage form, dose, dosing schedule, and duration of therapy.
4.b. Outline a suitable pharmacologic care plan for the chronic management of this patient.
Include drug, dosage form, dose, dosing schedule, and duration of therapy.
4.c. If the initial therapy fails or is intolerable for the patient, what pharmacologic alternatives
should be considered?
• Outcome Evaluation
5. How should the recommended therapy be monitored for efficacy and adverse effects?
• Patient Education
6. On discharge from the hospital, what information should be provided to the patient to
enhance compliance, ensure successful treatment, and minimize or prevent adverse effects?
 Case 4 (liver cirrhosis with esophageal varices)
• A56-year-old man
2018/9/22 - 2018/9/28
• Diagnosis:
1. Esophageal varices bleeding
2. Hepatic encephalopathy
3. Liver cirrhosis, Child-Pugh class C, with ascites
4. Chronic hepatitis B, HBeAg (-)
5. Hepatocellular carcinoma post right lobectomy
(2013/10) with tumor recurrence (S4), post
radiation therapy (2017/7 - 2017/8) with multiple
tumor recurrence
 Questions
• Problem Identification
1.a. Create a list of the patient’s drug therapy problems.
1.b. What information supports the diagnosis of bleeding esophageal varices, and what indicates
the relative severity of disease?
1.c. What information indicates the presence or severity of hepatic encephalopathy in this patient?
1.d. What precipitating factors in this patient could potentially cause an episode of hepatic
encephalopathy?
1.e. What additional information is needed to satisfactorily assess the hepatic encephalopathy of
this patient?
• Desired Outcome
2. What are the goals and general principles for the management of esophageal varices and
hepatic encephalopathy?
• Therapeutic Alternatives
3.a. What nondrug interventions are important before initiating pharmacotherapeutic agents for
the treatment of esophageal varices and hepatic encephalopathy?
3.b. What pharmacotherapeutic alternatives are available for the treatment of esophageal varices
and hepatic encephalopathy?
 Questions
• Optimal Plan
4. Outline a pharmacotherapeutic plan for this patient’s drug therapy problems. Include the drugs,
dosage forms, doses, schedules, and duration of treatment for each problem.
• Outcome Evaluation
5. What clinical and laboratory parameters should be followed to evaluate the therapeutic
efficacy and to minimize the risk of adverse effects?
• Patient Education
6. What medication-related information should be provided to the patient about her therapy on
discharge?