Liver disease, types of liver diseases, pathophysiology, stigmata, management, drugs, investigations,criteria for transplant. Pharmacological management, non-pharmacological management, how to diagnose liver disease, ascites management

1. LIVER DISEASES

2. LEARNING OBJECTIVES
Students would improve their knowledge in
Anatomical functions of the Liver
Acute and Chronic Liver disease
Liver Cirrhosis
Alcoholic Liver disease

3. ANATOMICAL FUNCTIONS OF THE LIVER

4. ANATOMICAL FUNCTIONS OF THE LIVER
CONT’D

11. CELLS OF THE LIVER

Cells of the liver include
 hepatocytes,

 hepatic stellate cells - also known as perisinusoidal
lipocytes, or Ito cells - sinusoidal endothelial cells,
 macrophages (Kupffer cells),
 the cells of the biliary tree - cuboidal to columnar
epithelium - and
 connective tissue cells of the capsule and portal tracts.

12.  Inactivation of various substances
 Toxins
 Steroids
 Other hormones
 Synthesis of plasma proteins
 Acute-phase proteins
 Albumin
 Clotting factors
 Steroid-binding and other
 Immunity
 Kupffer cells
hormone-binding proteins

13. 
The glucuronides of the bile pigments, bilirubin and biliverdin,
are responsible for the golden yellow color of bile.

The bile salts are sodium and potassium salts of bile acids,
and all those secreted into the bile are conjugated to glycine or
taurine, a derivative of cysteine.

The bile acids are synthesized from cholesterol.

14. SIGNS AND SYMPTOMS
OF
LIVER
DISEASES

15. Classic Symptoms Of Liver Disease
Nausea and Vomiting
Rt Hypochondrial Pain
Jaundice
Fatigue
Clay coloured stools
Highly coloured urine

16. Weakness
Easy Bruising
Itching
Weight loss
Gynaecomastia
Impotence
Ascites
Muscle Wasting

17. Signs and Symptoms In Head and Neck
• Alopecia
• Jaundice
• Bitot’s spot
• Subconjunctival Hemorrhage
• Anaemia

18. 6. Keyser – Fleischer ring ( Wilsons disease )
7. Parotid Swelling
8. Supraciliary madarosis
9. Spider naevi

19. Signs and Symptoms In Chest
1. Loss of body hair
2. Gynacomastia
3. Spider naevi
4. Scratch Marks

20. Signs and Symptoms In Upper Limb
1. Clubbing
• ia
• Bruising
• Flapping tremor/Asteristix
• Dupuytren’ Contracture
• Palmar Ery hema

21. Signs and Symptoms In Abdomen
1. Scars
2. Abdominal distension
3. Caput medusae
4. Hepatomegaly
5. Splenomegaly
6. Ascites

23. 6. Palpable Gall Bladder
7. Hepatic Bruit
8. Tumor

24. Signs and Symptoms In Lower Limb
1. Pedal Edema
2. Easy bruising
3. Scratch marks

25. Other Features…
Fetor Hepaticus ( sweetish faecal smell of the
breath indicates severe hepatocellular failure.
Paper money skin ( thinning of the skin )
Hepatic encephalopathy (disturbed consciousness, altered sleep
personality changes, intellectual disturbances and asterixis)
Testicular atrophy and loss of libido.
Bounding pulse.

26. Hepatic Facial
Shunken eyes
Hollowed temporal fossa
Pinched up nose with malar symptoms
Parched lips
Muddy complexion of face
Icteric change f conjunctiva
Shallow and dry face

27. Clinical Features of alcoholic liver cirrhosis
Bilateral enlarged Parotids
Duputryren’s contracture
Gynaecomatia
Testicular atro p h y
Muscle wasting and loss of body hair.

28. ACUTE LIVER FAILURE( < 3 MONTHS)
Acute Liver failure is loss of liver function that occurs rapidly in days or weeks
usually in a person who has no pre-existing liver disease.
Acute liver failure (ALF) is a life-threatening multisystem illness resulting
from severe hepatic injury from a variety of potential aetiologies
Despite advances in the understanding of the aetiology and pathogenesis
mortality rates remain high.
In the most severe cases emergency liver transplantation is the only
option

29. Common causes of acute liver failure
•Paracetamol (39%)
•lndeterminant (17%)
•idiosyncratic drug reactions
(13%)
•lschaemic hepatitis (6%)
•Hepatitis B (7%)
•Hepatitis A (4%)
•Autoimmune Hepatitis (4%)
•Wilsons disease (3%)
•Budd-Chiari syndrome (2%)
•HELlP syndrome (1%)
•Acute fatty liver of pregnancy
(1%)
•Metastatic cancer (1%)
•Other (2%)

30. Aetiology of ALF is a primary concern in the management
because it can influence management and help to predict
outcome.
 N-acetylcysteine (NAC) for paracetamol (acetaminophen)
overdose,
 Delivery of the foetus for HELLP or fatty liver of
pregnancy,
 Treatment with lamivudine in Hepatitis B viral infection
AETIOLOGY AND DEFINITION

31. In the developed world paracetamol overdose is the most common
cause of ALF,
However worldwide, viral aetiologies (Hepatitis A, B and E) and
seronegative hepatitis predominate.
.

32. There are multiple classifications of ALF.
The most widely used classifies ALF by the speed of onset of
encephalopathy when the patient becomes symptomatic.
These definitions have prognostic implications and can provide
clues regarding potential aetiology
c

33. Hyperacute: Fulminant (hyperacute) hepatic failure (FHF) is a
syndrome of abrupt onset (fulminant explosive), characterized
by progressively severe encephalopathy occurring within 7–14
days of the onset of jaundice. FHF is the result of massive
hepatocellular necrosis, i.e. death of the liver parenchyma, or
other severe functional impairment. : In the UK hyper-acute presentations
are almost exclusively related to paracetamol toxicity, contributing stimuli such
as ischaemic insults, viral pathogens and toxins have been
identified.

34. Acute: In acute hepatic failure encephalopathy occurs within
14–28 days of the onset of jaundice
This type of presentation is commonly seen with viral aetiologies (e.g.
Hepatitis B).
It is associated with a moderate spontaneous survival rate but a
slightly higher rate of transplantation when compared to
hyperacute presentations.

35. Subacute: Subacute hepatic failure is defined as acute failure occurring in
patients without preexisting liver disease, in whom the signs of encephalopathy
develop more than 8 weeks after the onset of illness. These patients are
generally older than those with FHF and tend not to have viral hepatitis.
Survivors may have autoimmune hepatitis.A protracted course of acute liver
failure is associated with a significantly higher mortality and the aetiology is
often more frequently non-paracetamol drug-related.This type of presentation
is difficult to distinguish from acute on chronic liver failure so a careful

36. Diagnosis
 The diagnosis of ALF is made with reference to the specific criteria
listed below.
However, the clinical picture is dominated by coagulopathy and
encephalopathy.
1. Absence of chronic liver disease
2. Acute hepatitis (elevation in AST/ALT) accompanied by
elevation in INR >1.5
3. Any degree of mental alteration (encephalopathy)
4. Illness less than 26 weeks duration

37. Investigations
Serum biochemistry
(AST) and (ALT) will be acutely elevated reflecting hepatocellular damage.
Serum bilirubin will also be elevated with levels exceeding
300 µmol/l indicating severe disease.
Serum albumin a poor marker of acute hepatic failure.
Renal failure often accompanies ALF and the patient’s initial
presentation
be that of an acute kidney injury (AKI).
hypoglycaemia,
hyponatraemia
metabolic acidosis.

38.  A deranged prothrombin time is used in the
diagnosis of ALF
 It is also used as a prognostic indicator for the
consideration of liver transplantation
Coagulation

39.  hepatic Doppler ultrasound to exclude chronic
liver disease in the form of
varices or a nodular liver.
 This technique can also assess for intra-
abdominal malignancy, which is a
contraindication to liver transplantation.
 Hepatic vein patency is also assessed
to exclude Budd-Chiari syndrome.
Radiology

40. Histological data is unlikely to change the therapy
being provided
it may provide information about specific viral
aetiologies or information
that would preclude a liver transplant e.g. metastatic
malignancy or
lymphoma.
Has to be balanced against the risk of performing
such a procedure in
these coagulopathic patients
Liver Biopsy

41. Management
FHF due to paracetamol (acetaminophen) overdose,
gastric aspiration and absorption with activated charcoal is
carried out if ingestion occurred within 2 h of hospital
admission.
1. IV infusion of N-acetylcysteine (NAC) in 5% glucose
2. Oral methionine is also used if appropriate facilities for
infusion are not available.
3. Methionine must be used with care in patients with
known hepatic impairment, because it may precipitate
coma

42. NAC protects the liver against the depletion of glutathione by the reactive
metabolite N-acetylbenzoquinoneimine (NBQ).
If NAC is not used, hepatic glutathione is exhausted and the NBQ then reacts with
hepatic intracellular protein sulphydryl groups, causing hepatocellular necrosis.
NAC also acts as a cardiac inotrope, increasing peripheral blood flow and oxygen
extraction, and may potentiate vasodilatation due to endothelium-derived
relaxing factor (EDRF, nitric oxide), thus increasing hepatic and cerebral blood
flow.
Prophylactic parenteral H2-RAs reduce the incidence of gastro-oesophageal
bleeding, but regrettably have little influence on mortality

43. Over-dosage with the popular combination analgesic co-
proxamol (paracetamol + dextropropoxyphene) poses a greater
risk than does plain paracetamol, because dextropropoxyphene
causes CNS depression and inhibition of liver enzymes.
Dextropropoxyphene is a mild opioid, so naloxone is required
as an opioid antidote in addition to NAC, and ventilatory
support may be needed.

44. Management
Neurological-ALF and cerebral oedema
Metabolising ammonia, a by-product of normal protein metabolism to
a less toxic compound urea would be prevented.
Glutamine synthase
urea ====-glutamine
accumulation of glutamine within cerebral astrocytes.
The astrocytes subsequently swell secondary to this cerebral
osmotic disturbance leading to cerebral oedema and intracranial
hypertension.

45. Inflammatory mediators
Disrupted cerebral auto-regulation, resulting in
increased cerebral blood flow, are contributing
factors
Ammonia levels - prognostic marker in ALF

46. Simple neuro-protective measures
should be implemented
Elevate head to 30 degrees to improve cerebral
perfusion pressure (CPP)
The patient should be appropriately sedated to
prevent stimuli from rising intracranial pressure.
Avoid hypotension. This may require use of
vasoactive drugs
Prevent hypoxaemia
Tight glycaemic control with blood glucose target
between 4 and 10 mmol/L

47.  Mannitol
hypertonic saline-- 1-2ml/kg of 5% Saline may be given, ideally via a
central line, targeting a serum sodium concentration of
between 145-155 mmol/l


48. Hepatic encephalopathy
 As the clinical course of ALF progresses, hepatic
feature.
encephalopathy becomes the predominant
, hepatic encephalopathy is a clinical diagnosis and is graded
Grades of Encephalopathy
Altered mood, impaired concentration
Grade
Grade
Grade
Grade
1
2
3
4
and psychomotor function, rousable
Drowsy, inappropriate behaviour, able to talk
Very drowsy, disorientated, agitated, aggressive
Coma, may respond to painful stimuli

50.  grade 3 encephalopathy or above will require sedation and mechanical
ventilation for airway protection..

51.  . Mechanical ventilation
 Facilitates the use of sedation and analgesia
Reduce cerebral metabolic demand and cerebral blood flow
Minimising intracranial pressure rises associated with agitation and painful stimuli.



52. Respiratory
 Grade 3 or 4 encephalopathy
order to protect the airway
- Indication for intubation and ventilation in
 Complications of liver disease,
 Intra-abdominal hypertension (IAH) secondary to bowel oedema or ascites,
pleural effusions,
acute lung injury and acute respiratory distress syndrome
compromise a patient’s respiratory function and



may lead to the requirement for ventilatory support

53.  Mechanical ventilation are at risk of ventilator acquired pneumonia.
immune compromise associated with ALF. Due to the inability to mobilise
cellular components of the immune system and a diminished acute phase and
complement response.
High levels of (PEEP) should be avoided if possible because they may
increase hepatic venous pressure and ICP.

54. Cardiovascular
 The majority are intravascularly
insensible losses,
vomiting and
reduced oral intake.
depleted secondary to a combination of



 Reduced systemic vascular resistance is characteristic in ALF. This may result
hepatic hypoperfusion despite a sometimes elevated cardiac output.
profound hyperlactataemia
in


55.  Fluid resuscitation is an important early management step.
No definitive guidance exists for the type of fluid to be utilised,.
Avoid Hartmann’s or lactated Ringer’s.
5% Dextrose solutions lack suitable volume expanding properties and result in
hyponatraemia that can worsen cerebral oedema.
Hypotension that persists despite fluid resuscitation require inotropic support.
For reduced systemic vascular resistance vasopressors such as norepinephrine, dopamine
or vasopressin can be used.






56. Renal
 Acute kidney injury (AKI) is common
with paracetamol toxicity.
AKI can be secondary to
Direct nephrotoxic effects of drugs
Raised intraabdominal pressure,
Hepatorenal syndrome
in the setting of ALF, especially if associated




 Acute tubular necrosis (ATN) due to profound hypovolaemia and hypotension

57.  Renal replacement therapy (RRT) should be provided early
To prevent worsening acidosis and fluid overload.

 Continuous veno-venous haemodialysis (CVVHD) is preferred over
Haemodialysis due to the associated haemodynamic instability

58. Hepato-renal syndrome
 The progressive rise in cardiac output and reduction in SVR results in
reduced total vascular resistance and, ultimately, a decline in renal
perfusion.
The end result is reduced glomerular filtration rate (GFR) and sodium
excretion.
The pathological basis associated with the accumulation of vasoactive
substances such as endotoxin, which are usually cleared in the liver.
Hepato-renal syndrome is a condition that is often irreversible and may
rapidly fatal.


 be

59. Nutrition
 ALF is a catabolic
feasibly possible.
state and nutritional support should be instigated as soon as
 Enteral and parenteral routes are both accepted methods of delivery.
Protein intake should not be restricted
Dietary laxatives (e.g. lactulose) should be administered to speed the evacuation
nitrogenous waste.
Due to the loss of hepatic glycogen stores with diminished gluconeogenesis and
hyperinsulinaemia, hypoglycaemia often complicates ALF.
Infusion of 10% Dextrose solutions may be required,
Target blood glucose above 3.5mmol/l is

 of




60. Infection
 Prone to Gram negative and Gram positive bacteria and fungi infections.
 Patients being considered for liver transplantation may benefit from
prophylactic antibiotics because sepsis can prevent the proposed procedure.

61. Coagulation
 The liver synthesises all the coagulation factors apart from factor VIII.
 Deficient protein C and anti thrombin III and coexistent sepsis causes severe
coagulopathy.
The routine use of fresh frozen plasma (FFP) to correct coagulopathies should be
discouraged.
FFP will mask the trends in the prothrombin time that can be used as a prognostic
marker.
Thrombocytopenia should also not be routinely corrected.




62. N-acetylcysteine
 N-acetylcysteine (NAC) is a proven effective therapy for paracetamol
hepatotoxicity and should be administered as soon as possible following
the overdose as guided by treatment nomograms.
NAC should be administered in all cases of ALF, especially where the
underlying aetiology is unclear.
However, survival benefits have only been shown in paracetamol related
hepatotoxicity.



63. Liver Transplantation
 The only effective therapy for ALF patients
spontaneously.
who fail to recover
 the Kings College Hospital Criteria is probably the most widely
the most diagnostic accuracy.
Contraindications to liver transplantation include
used with

 irreversible brain damage,
Accelerating inotrope requirements,
Uncontrolled sepsis and severe respiratory failure.



64. Table 4: Kings College Hospital criteria for liver transplantation in acute liver failure
Paracetamol (acetaminophen) overdose
• pH <7.3 (irrespective ofencephalopathy)
Or all of the following:
•
•
•
Grade Ill-IV encephalopathy
Creatinine >300umol/litre
Prothrombin time>100 seconds (INR >6.5)
Non-paracetamol aetiology
• Prothrombin time >100 seconds
Or any 3 of the following:
•
•
•
•
•
Age <10 years or >40 years
Prothrombin time >SO seconds
Bilirubin >300umol/litre
Time from jaundice to encephalopathy >2 days
Non-A, non-B hepatitis, halothane or drug-induced acute liver failure

65. Chronic liver disease
Multiple causes,
common manifestation

66. A consequence of CLD
Characterized by replacement of
tissue by fibrosis & regenerative
nodules
Leads to irreversible loss of liver
function & its complications
Micronodular- alcohol or

liver



Macronodular- chronic viral hepatitis
Cirrhosis

67. CLINICAL PRESENTATION
Cirrhotic patients may present in a variety of ways, from asymptomatic patients with abnormal
laboratory tests noted on routine blood tests to acute life-threatening hemorrhage in an
emergency room.

69. Muscle wasting
Scratch marks
Pallor, jaundice
Parotid enlargement
Xanthelasma
Clubbing
Palmar erythema
Dupuytren’s contracture
Spider nevi/angiomata
Petechiae, purpura
Decreased body hair
Gynecomastia
Testicular atrophy
Caput medusae
Edema, ascites
Splenomegaly
Asterixis
Fetor hepaticus
 
 
 
 
 
 
 
 
 
Stigmata of CLD

70. Liver biopsy- gold standard, but not
necessary
Deranged LFT-
± elevated SGPT, alkaline phosphatase, GGT
Increased bilirubin
Low albumin, increased globulins
Increased PT/INR
Thrombocytopenia
Low sodium
Ultrasound- shrunken liver, ± portal
EGD/UGIE- varices
always








HT/HCC


Investigation

71. Based on Child-Turcotte-Pugh scoring
system

Includes- each given
Ascitis
Encephalopathy
Bilirubin
Albumon
PT/INR
score of 1-3






Class-
A- 5-6
B- 7-9
C- 10-15
total score




Staging of CLD

75. Management
To retard progression & reduce
complications
Abstinence from alcohol
Vaccination- Hep A & B
Treat underlying cause

76. Ascites
Spontaneous bacterial peritonitis-
Variceal bleed
Hepatic encephalopathy
Hepatorenal syndrome
Hepatocellular carcinoma- HCC
SBP





Complications

77. Diagnostic paracentesis- SAAG >1.1
Cause- Portal
HPT
Hypoalbuminemia
Raised renin-angiotensin-aldosterone levels
causing Na retention by kidneys





Ascitis

78. Ascites, from the Greek askos, meaning water bag or wineskin, is the
pathologic accumulation of lymph fluid within the peritoneal cavity.

79. Salt ± fluid restriction
Diuretics- Spironolactone ± Furosemide
Large volume paracentesis-
With massive or refractory ascitis
>5 lit. fluid removed in one go
Albumin- ~8 gm/lit. fluid removed
Avoid hepatorenal syndrome
TIPS- transjugular intrahepatic portosystemic
For refractory ascitis or refractory variceal bleed
Preferred for short duration, pending liver transplant
Increases risk of hepatic encephalopathy,
shunt occlusion/infection







shunt




Ascitis- treatment

81. s/s-
Abdominal pain, fever,
ascitis & encephalopathy
Dx- paracentesis
PMN >250/microlitre
Ascitic fluid culture- bedside,
Gram –ve bacteria
Rx- Cefotaxime/Ciprofloxacin


worsened


commonly


Prophylaxis- Ciprofloxacin/Co-trimoxazole
Prognosis- 30% mortality during hospital stay
& 70% within 1 year


SBP

82. Varices- dilated submucosal veins,
esophagus or stomach
Cause- portal HT
in


Causes ~80% of UGI bleed
Risk factors for bleed-
Size of varices
Severity of liver disease
Continued alcohol intake
in CLD





UGIE- wale markings, hematocystic/red spots on
Dx- EGD/UGIE
varix


Variceal bleed

84. Acute-
Resuscitation
FFP, platelets,
Prevent rebleed-
Band ligation- over repeated
sessions
Non-selective β- blockers-
Propanolol/Nadolol
TIPS- for recurrent bleed or
bleed from gastric varices
Surgery- portosystemic
shunts
Liver transplantation
 
 
vit. K


Terlipressin/octreotide
Lactulose
UGIE
Banding/sclerotherapy






Balloon
TIPS
Surgery
tamponade




Management

86. Confusiondrowsinessstuporcoma

Ammonia is an identified/measurable
Precipitants-
GI bleed
Constipation
Alkalosis, hypokalemia
Sedatives
Paracentesishypovolemia
Infection
TIPS
Dx- clinical- s/s of CLD
toxin










with asterixis & altered sensorium
Hepatic encephalopathy

87. Correct underlying precipitating factor
Avoid sedatives
Restrict dietary protein intake
Lactulose- 2-3 loose stools a day
Oral antibiotic- Metronidazole,
Rifaximin, Neomycin





Management

88. Occurs in patients with advanced CLD &
ascitis
Marked by renal impairment in the absence
any renal parenchymal disease or shock
Oliguria, hyponatremia & low urinary Na
accompany raised creatinine
Albumin infusion, with vasoconstrictors
(norepinephrine, terlipressin/ornipressin,
octreotide) may help
Liver transplantation is Rx of choice

of




Hepatorenal syndrome

89. Associated with cirrhosis in ~80%
Suspect if- worsening of CLD, enlarged
hemorrhagic ascitis, weight loss
Dx-
CT/MRI with contrast- vascular SOL in cirrhotic liver
Raised AFP- α-fetoprotein
Liver biopsy
Rx-
Early-resection

liver,







Advanced- liver transplantation or local palliative treatment
Screening- US & AFP every 6 months


Hepatocellular carcinoma

90. Liver transplantation
Option in ESLD
Donor, cost, technical expertise
 (GVHD),
recurrence

91. There are no laboratory or radiographic tests of hepatic function despite the commonly
ordered liver function tests. These commonly measured markers are substances produced
by the liver and released into the bloodstream during hepatocellular injury, and are more
correctly termed liver dysfunction tests.
True liver function tests that assess the ability of the liver to eliminate substances that
undergo hepatic metabolism, such as the 14C-aminopyrine breath test, are limited by
complexity and availability.
LIVER FUNCTION TESTS