LIVER DISEASE

(Hepatic Disease)

Dr. Mahesh N.M.

Professor & Head, Department of Pharmacy Practice
KAHER, KLE College of Pharmacy, Bangalore-560010
 What it is?

• Liver disease (LD):

….it is a damage to the cells of the liver.

• ICD-10-CM Number: K70-77

 Types of LD
Acute LD (ALD) Chronic LD (CLD)

• Liver cells damage is self- • Liver cells damage is present

limited for long period
• Liver cells structure is
• Resolve spontaneously in permanently changed &
most of the cases irreversible
• Liver architecture changes
• Rarely,
• Progress to cirrhosis (5-20Y) →
Liver function deteriorates + Nodules forms
Encephalopathy + • Cirrhosis → Liver failure →
Coagulopathy Portal hypertension → Liver
carcinoma

• Less than 6months • More than 6 months

 Hepatitis?
• Hepatitis:
--- is an inflammation of the liver.

Hepatitis can be acute or chronic LD.

Mainly viruses followed by bacteria, toxic
chemicals (Alcohol, drugs) & autoimmune
diseases cause hepatitis.

Hepatitis leads to Cirrhosis if not treated.

 Epidemiology
• Prevalence population • Statistics of CLD

A. Global • 50 million people

B. India • 10Lac new cases added/Y
C. Men • 33%
D. Women • 30%
E. Age (40-50Y) • More
F. Drinking alcohol • Genetic link (weak)
G. Japanese Americans • 6.9%
H. Latinos • 6.7%
I. White • 4.1%
J. Black • 3.9%
 AETIOLOGY
1. Viral infections • Inflammation of liver
(Hepatitis A, B, C, D & E) (Acute)

2. Chronic alcohol drinking • Inflammation of liver

3. Non-alcoholic fatty liver • Inflammation of liver

(Obesity, Diabetes mellitus)
 AETIOLOGY
4. Autoimmune disorders • Inflammation of liver or bile
duct obstruction
Examples:
A. Autoimmune hepatitis • Inflammation of liver
B. Primary biliary cirrhosis • Destruction of bile ducts
C. Primary sclerosing cholangitis • Biliary stricture & cholestasis

5. Vascular abnormalities
Example: Budd-Chiary syndrome • Obstruction of Hepatic venous
outflow

6. Drugs • Liver cells damage or change

liver cells function
 AETIOLOGY
7. Inherited metabolic disorders
Examples:
A. Haemachromatosis • ↑ dietary iron absorption & deposition in
liver
B. Wilson’s disease • ↑ dietary copper absorption & deposition
in liver
C. α1- Antitrypsin deficiency • ↓ α1- Antitrypsin levels in liver

D. Glycogen storage disease • ↑ Glycogen accumulation in liver

E. Gilbert’s syndrome • ↑ Bilirubin levels in blood

 Pathophysiology
Chemicals
↓
Liver cells damage
↓
Viral infections → Hepatitis
↓ (Long-period)
Liver cells structure change
↓
Hepatic stellate cells ---- → Pericellular fibrosis around liver cells develops
↓
Liver cells starts dying
↓
Micronodular fibrotic bands further develops
↓
Cirrhosis
Pathophysiology Contd…

Cirrhosis
↓
↑ resistance to blood flow from portal system – Portal HTN
↓ Gradually
Liver cells death
↓
↓ Functioning Liver cells
↓
Chronic Liver Failure [Figure 1]
Pathophysiology [Figure 1]
 Clinical Manifestations
Symptoms Characteristic to LD
• Weakness, Fatigue, Malaise
• Jaundice (Striking symptom)
• Bleeding complications • Common in all LD
• Loss of muscle bulk • (ALD/CLD)
• Abdominal discomfort

• Abdominal pain (Right quadrant) • Hepatobiliary LD

• Tenderness over liver position • Acute hepatitis/Cancer
• Pruritus (Worst at night) • Cholestatic LD
• Weight loss & Anorexia • CLD
 Clinical Manifestations
Signs Characteristic to LD
• Hyperpigmentation • Primary Biliary Cirrhosis,
Haemachromatosis
• Hepatomegaly • ALD
• Palmer erythema • ALD, CLD
• Abdominal distention • ALD, CLD
• Jaundice (Sclerae) • ALD, CLD
• Splenomegaly • CLD with Portal HTN
• Dilated abdominal • CLD with Portal HTN
wall veins
• Finger clubbing • Hepato-pulmonary syndrome
 Clinical Manifestations
Signs Characteristic to LD
• Leukonychia • CLD
• Portal HTN • CLD
• Ascites • CLD
• Menstrual irregularities • CLD
• Hypogonadism • CLD (Alcohol Induced)
(Male & Females)
• Gynaecomastia • CLD (Alcohol Induced)
 Clinical Investigations
Tests Diagnosis
• ↑ Aspartate transaminase • ALD, CLD
• ↑ Alanine transaminase • ALD, CLD
• ↑ Bilirubin • ALD, CLD
• ↓ Albumin • CLD
• ↑ Prothrombin time • CLD
• ↑ International Normalized • CLD
Ratio (INR)
• Hepatitis virus test • ALD
• Auto-antibodies & • Auto-immune LD
Immunoglobulins

• ↑ Alkaline phosphatase • Cholestasis

 Clinical Investigations
Tests Diagnosis
• Ultrasound scanning
• Computed Tomography (CT) • ALD, CLD, Liver cancer &
• Magnetic resonance (MR) Hepatobiliary malignancies
• (CT & MR measure accurately)

• Liver biopsy (Gold Standard) • CLD

• Fibroscanning • Hepatitis C Virus-LD

 Treatment of LD
1. Patient Specific Therapy 2. Disease Specific Therapy
 Patient Specific Therapy
(Based on clinically significant symptoms)

1. Pruritus: Classification of drugs:

(Itching mainly due A. Anion exchange resins
to cholestasis LD) Ex: Colestyramine, Colestipol

B. Antihistaminics
Ex: Cetirizine, Loratidine
Chlorpheniramine, Hydroxyzine

C. Opioid antagonists
Ex: Naloxone, Naltrexone, Nalmefene

D. Ursodeoxycholic acid (UDCA), Rifampicin

E. Calamine lotion, Menthol (2%) aqueous cream
F. Plasmapheresis, Liver transplantation
Pruritus Contd…

Choice of Drugs:
Colestyramine > antihistaminics > UDCA > Rifampicin > Others

Therapeutic M/A:
Colestyramine + Bile Salts → C-BS complex → Inhibit bile salts reabsorption →
Antipruritic effect

Efficacy and Safety:

 Very effective among others
 Onset of action is within a week
 Side effects are tolerable [Constipation/ diarrhoea, abdominal discomfort, fat &
vitamin mal-absorption]
 Posses interaction potential with drugs by PO. Hence such drugs (Ex: Digoxin,
Thyroxine) are admd. either 1hr before or 4hrs after Colestipol administration.
 Palatability varies. But, patient education improves medication adherence.

Dose/RoA/DOA/Preparation:
4-16g (Tablet/Granules) in 2-3 divided doses by PO
2. Clotting abnormalities

[Clotting factors synthesis is decreased in LD. Hemostatic abnormality develops in

75% patients with CLD and 100% in ALF patients]

Choice of Drugs:
Vitamin K (Phytomenadione)

Therapeutic M/A:
Vitamin K is a co-factor for the synthesis of majority of clotting factors in liver .

Caution:
NSAIDS & anticoagulants should be avoided in LD due to risk of bleeding.

Dose/RoA/DOA/Preparation:
10mg/day injected iv for 3 days. Repeated when required.
3. Ascites

(Abnormal collection of Classification of drugs/methods:

third space fluid in the A. Low salt diet
abdominal cavity [Intra-
abdominal fluid])
B. Diuretics
Ex: Spironolactone, Furosemide, Amiloride
Treatment goal: To reduce
volume of ascites fluid C. Paracentesis

D. Trans-jugular Intrahepatic Porto-systemic

Shunting [TIPS]
Ascites Contd…

Choice of drugs/methods:
1 Line: (a) Low salt diet (Low volume ascites)
(b) Diuretics (Moderate-Large volume ascites)
(c) Paracentesis (Moderate-Large volume ascites)
2 Line: TIPS

(a) Low Salt Diet with Fluid Restriction:

Therapeutic M/A: ↓ Fluid formation + Body weight + Oedema

Efficacy and Safety:

 Simple and effective approach
 Excessive body reduction can ↓ intravascular fluid & renal failure. Hence,
caution needed while reducing body weight.
Dose/RoA/DOA/Preparation:
Salt: 1.5-2mg/day + Fluid: 1-1.5L/day , administered PO.
Ascites Contd…

(b) Diuretics (Moderate-large volume of non-refractory ascites)

Choice of drugs/methods:
Spironolactone > Amiloride (Alone or with Furosemide, loop diuretic)

Therapeutic M/A:
Spironolactone → ↓ Na+ reabsorption → Diuresis (↑ Na+ Excretion)
@ distal renal tubule
Efficacy and Safety:
 Produce slow diuresis
 Tolerable side effects (Hyperkalemia, Gynaecomastia)
 Administered with furosemide if diuresis by Spironolactone is unacceptable
 Caution is required as excessive diuresis can produce renal failure. Monitoring
of urea, Na+ & K+ is required during the diuretic therapy.

Dose/RoA/DOA/Preparation:
Spiron: 50-400mg/day by PO (Tab). With Furosemide: 40-160mg/day by PO (Tab)
Ascites Contd…

(c) Paracentesis (Moderate-large volume of refractory ascites)

Therapeutic M/A:
Ascite is perforated with hollow needle to remove the fluid in large amount.

Efficacy and Safety:

 Performed in out-patient setting once in 2-4 weeks
 Non-invasive. Lost fluid can be replaced with plasma expander (Ex: Albumin)
 It does not prevent fluid accumulation/formation. Ascites recur later.
 If repeated frequently, it produces renal failure & systemic circulatory collapse.

Dose/RoA/DOA/Preparation:
Paracentesis is done once in 2-4 weeks. Additionally, 6-8g albumin is administered
iv/1L of ascite fluid removed
OR
100ml of human albumin solution (20%) administered iv/2.5L Ascite fluid removed
4. Spontaneous Bacterial Peritonitis (SBP)

(Peritoneal cavity is infected by Classification of drugs:

enteric & dermal bacteria in the
ratio 3:1) A. Cephalosporins
Ex: Cefotaxime

B. Penicillins
Ex: Amoxycillin + Clavulanic acid

C. Quinolones
Ex: Norfloxacin
Spontaneous Bacterial Peritonitis (SBP) Contd…

Choice of drugs:
Cefotaxime > Penicillins & Quinolones

Therapeutic M/A:
Cefotaxime → Inhibit bacterial cell wall synthesis → Antibacterial effect

Efficacy and Safety:

 Effective in 85% patients
 Tolerability profile is better
 Used also against other associated soft-tissue infections

Dose/RoA/DOA/Preparation:
2gms injected tid by iv route.
5. Hepatic encephalopathy

(Neuropsychiatry complication Classification of drugs:

due to entry of ammonia &
other substances such as free A. Laxatives
fatty acids, ɣ-GABA & glutamate Ex: Lactulose
into the brain)
B. Antibaterial drugs
Treatment goal: ↓ ammonia Ex: Metronidazole, Rifaximin
and other nitrogenous products
level in the circulating system in C. Others
cirrhosis patients) Ex: L-Ornithine-L-Aspartate, L-dopa,
Sodium benzoate, flumazenil
Bromocriptine
Hepatic encephalopathy Contd…

Choice of drugs:
Lactulose > Antibacterial drugs > Other drugs

Therapeutic M/A:
Gut Flora

Lactulose -------→ Lactic acid + Acetic acid + Formic acid --→ Acidity colonic content
↓
↓ Absorption of nitrogenous products ←----- Ionization of nitrogenous products
(@GIT)

Efficacy and Safety:

 Non-absorbable disaccharide
 Tolerability profile is better

Dose/RoA/DOA/Preparation:
30-40ml/day titrated PO till 2-3 bowel motions/day is maintained
6. Oesophageal varices

(Blood vessels are dilated in Classification of drugs/methods:

oesophageal area. At least one A. Endoscopic banding
bleeding episode occurs in 30% B. Sclerotherapy
cases especially in patients suffering C. TIPS
from cirrhosis with portal D. Surgical decompressive shunts
hypertension) E. Fluid treatment
Ex: Packed red cells
Treatment goal: ↓bleeding episodes F. Ballon Tamponade
G. Tissue adhesives & Glue injection
H. Cyanoacrylate
I. Drugs
Ex: Terlipressin, Vasopressin,
Octreotide, Somatostatin,
Propranolol
Oesophageal varices Contd…

Choice of drugs:
Terlipressin > Somatostatin, Octreotide
Propranolol is used prevent re-bleeding as 1 Line treatment

Therapeutic M/A:

Terlipressin produces vasoconstriction. Portal venous pressure decreases.

Efficacy and Safety:

 Highly effective in controlling bleeding
 More favorable side effects
 ↓ Mortality
 Terlipressin can be administered for 2-5 days by infusion

Dose/RoA/DOA/Preparation:
1-2mgs administered as iv bolus 4-6 times/day for 48hrs.
Oesophageal varices Contd…

Invasive, non-invasive and drugs are used to treat oesophageal varices as alone
or combined therapy in step wise manner. Meaning of some non-drug techniques
is mentioned below [Figure 2]:

Endoscopic Banding: Rubber bands are placed around varices in oesophagus

through flexible endoscope, which is used to visualize blood vessels.

Sclerotherapy: Salt solution is injected directly into varicose vein. Solution irritates
lining of blood vessels & causes it to collapse & stick together & blood to clot.

TIPS: Shunt is created between intrahepatic vein and inferior venacava.

Surgical decompression shunt: Shunt is placed between hepatic vein and inferior
venacava. It can decompress portal vein system side to side to create a channel.

Ballon Tamponade: Ballons are inserted in oesophagus, stomach or uterus and

inflated to alleviate or prevent refractory bleeding.
Oesophageal Varices Haemorrhage Management [Figure 2] Contd…
7. Acute Liver Failure (ALF)

(Rapid deterioration in liver function Classification of drugs/methods:

with encephalopathy, coagulopathy,
cerebral oedema & renal A. Therapy is directed to support
impairment–Multi-systems disorder) CVS, CNS, Renal system and
haemostatic system.

B. Broad spectrum antibiotics and

anti-fungal drugs are used as
standard practice to treat
infections in ALF patients.
8. Liver Transplantation

(Replacement of part or complete Classification of drugs:

non-functioning liver with normally A. Calcineurin inhibitors
functioning liver) Ex: Ciclosporin, Tacrolimus

This procedure is used in patients with B. Corticosteroids (First 3 months)

ALF, CLD, inherited metabolic disorder
and primary liver cancer. C. Long-term drugs
Ex: Azathioprene, Sirolimus,
Grafted organs are rejected after one Mycophenolate, Everolimus
year period if graft function is not
managed properly especially the renal Choice of drugs:
function and cardiovascular fuctions. Ciclosporin + Corticosteroid >
Other drugs
 Disease Specific Therapy
(Based on cause of the disease)

1. Hepatitis B: Classification of drugs (NICE guidelines)

(Primary goal in the
management of chronic HBV A. Oral antivirals
infection is to prevent EX: Tenofovir, Entecavir, Lamivudine,
cirrhosis, hepatic failure & Telbivudine, Adefovir
Hepatocellular carcinoma)
B. Interferons
Treatment goal is continuous Ex: Pegylated Interferon alpha-2a
viral suppression. Virus can
not be eradicated completely.
HBV is present in extra hepatic
reservoir and integrated in
human genome.
Hepatitis B Contd…
Choice of Drugs:
Tenofovir=Entecavir > Tebivudine > Adefovir, Lamivudine,

Therapeutic M/A:
Tenofovir --------- → Competes with natural nucleotide ----- → HBV polymerase
(Nucleotide analogue) & binds to active site of HBV polymerase (Inhibited)

Efficacy and Safety:

 Potent antivirals
 Viral resistance against first line drugs is less to no
 Side effects are tolerable

Dose/RoA/DOA/Preparation of Tenovir:
8mg/kg by PO (Tablet/Powder). Maximum dose: 300mg/day.
2. Hepatitis C

(Primary goal is same as HBV) Classification of drugs (NICE):

A. Interferons
Treatment goal is sustained Ex: Pegylated interferon, Ribavirin
virologic response (SVR).
Absence of viremia 6 months B. Protease inhibitors
after discontinuation of Ex: Telaprevir, Boceprevir
antiviral therapy.
Hepatitis C Contd…
Choice of Drugs:
Pegylated interferon + Ribavirin > Tebivudine > Adefovir, Lamivudine,

Therapeutic M/A:
Peg Interferon inhibits replication of HCV & stimulates apoptosis in the infected cells.
+
Ribavirin is converted to Ribavirin triphosphate. R. triphosphate binds to nucleotide
binding site at RNA polymerase by competing with correct nucleotide. RNA synthesis
in inhibited.

Efficacy and Safety:

 SVR varies from 55-85%
 Poor tolerance to side effects [Influenza-like, GIT, Haematological, thyroid &
psychiatric complaints]
 Monitoring side effects and viral load is needed during the therapy

Dose/RoA/DOA/Preparation:
Peg. Interferon: 180micrograms/week for 6-12months by transfusion
Ribavirin: 400-800mg/day for 6-12months by transfusion
3. Autoimmune hepatitis

(Primary goal is same as HBV) Classification of drugs (NICE guidelines):

A. Corticosteroids
Treatment goal is to inhibit Ex: Prednisone, Prednisolone, Budesonide
excessive immune response
against liver cells. B. Immunosuppressants
Ex: Azathioprene, Tacrolimus,
Mycophenolate
Autoimmune hepatitis Contd…
Choice of Drugs:
Prednisone + Azathioprene > Similar combinations with other drugs

Therapeutic M/A:
Inhibits antigen-antibody induced consequences in the liver.

Efficacy and Safety:

 Better efficacy and safety profile was found for combination
 Blood cells count is to be monitored regularly
 Bone mass is to monitored

Dose/RoA/DOA/Preparation:
Prednisone: 40-60mg/d PO for 6 weeks. Later, dose is to be reduced to 7.5mg/day
up to 3 months + Azathioprene: 1-1.5mg/kg/day
4. Primary Biliary Cirrhosis (PBC) & 5. Primary Sclerosing Cholangitis (PSC)

Choice of Drugs:
Ursodeoxycholic acid (UDCA)

Therapeutic M/A:
Protects against cytotoxic effects of hydroxy bile acids.

Efficacy and Safety:

 Widely used
 But, it does not prevent ongoing bile duct injury
 Liver transplantation is option at the end stage of the disease

Dose/RoA/DOA/Preparation :
PBC: 10 mg/kg/day in two divided doses. PSC: 15mg/kg/day.
6. Wilson’s disease
Choice of Drugs:
Penicillamine > Trientine >> ZInc

Therapeutic M/A:
Prevents copper accumulation & promotes its excretion in urine by forming chelate
complex.

Efficacy and Safety:

 Widely used
 Neurological symptoms worsens initially due to deposition of mobilized copper in
basal ganglia. Such symptoms disappear over a period of several weeks.
 Side effects are renal dysfunction, haematological abnormalities and lupus
erythmatosis. Blood cells and electrolytes monitoring is required regularly.
 Pyridoxine is co-administered to prevent neurological symptoms and antipyrdoxine
effect of penicillamine

Dose/RoA/DOA/Preparation :
1.5-2gms/day by PO in divided doses with Pyridoxine, 25mg/day
References

A. Kennady P, O’Grady JG. In: Roger Walker, Cate Whittelesea, editors. Clinical
Pharmacy and Therapeutics. 5th ed. London, Elsevier Publishing; 2012.

B. Research articles