Liver Function Tests II

Dr Donovan McGrowder
Department of Pathology
University of the West Indies
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Disorders of the
Liver

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 Disorders of the liver -
Overview
 Classification:
 Hepatitis – Acute and chronic,
 Cirrhosis,
 Hepatocellular carcinoma; invasion and infiltrations of the liver,
 Metabolic liver diseases,
 Inborn errors of bilirubin metabolism.

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Hepatocellular
Diseases

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 Acute Hepatitis
 Hepatitis is defined by the inflammation of the liver and characterized by the presence of
inflammatory cells.

 Hepatitis is acute when it last for less than six months.

 Acute hepatitis is usually caused by viral infection (particularly viruses A, B, C, D) or toxins

(alcohol, paracetamol and various fungal toxins).

 There is cell membrane damage (cell necrosis & cell swelling) with an increase in plasma
ALT activity which is greater than that of AST.

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 Acute Hepatitis

 In acute hepatitis the areas of abnormal tissue predominantly

contain diffuse sinusoidal and portal mononuclear infiltrates (
lymphocytes, plasma cells) and swollen hepatocytes.

 Necrosis and inflammation of the biliary tree occurs.

 There is no evidence of fibrosis or cirrhosis (fibrosis plus regenerative

nodules) and normal architecture is preserved but there may be
some lobular disarray.

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 Acute Hepatitis

 Cell necrosis causes the release of intracellular enzymes

(ALT & AST), which are then absorbed by the blood
vessels, leading to increased plasma enzyme activity.

 The plasma level of ALT rises early in the disease, prior to

the onset of jaundice and reaches a peak [10 – 100 times
upper limit of normal (ULN)] when jaundice appears.

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 Acute Hepatitis

 The swollen hepatocytes distort the small intrahepatic

bile passages and produce cholestasis, resulting in
retention of bile pigments and increased plasma ALP
levels (enzyme induction).

 The elevated serum bilirubin is mainly conjugated

because of the obstruction and the liver being unable to
excrete all the pigments.

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 Acute Hepatitis

 Unless cholestasis is severe the serum bilirubin

concentrations rarely exceed 350 µmol/L.

 Depending on the severity of the cholestasis

the plasma ALP rarely rises beyond three times
the ULN.

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 Acute Hepatitis

 AST/ALT ratio < 1.0 (albeit the high activities of

ALT and AST).

 Most cases of viral hepatitis resolve completely,

and the chemical indices of abnormality revert to
normal within a few weeks.

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 Acute Alcoholic Hepatitis
 Ethanol is a significant cause of the hepatitis (inflammation of the liver).

 It is caused by excessive intake of alcohol, and occurs in heavy drinkers, often

after a period of increased alcohol intake.

 While distinct from cirrhosis, it is regarded as the earliest stage of

alcoholic liver disease.

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 Acute Alcoholic Hepatitis
 Alcohol seems to injure the liver by blocking the normal metabolism of protein,
fats, and carbohydrates.

 Patients may also have concurrent alcoholic hepatitis with fever, hepatomegaly,
jaundice, and anorexia.

 AST/ALT ratio > 2.0, a value rarely seen in other liver diseases.

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 Acute Alcoholic Hepatitis
 Alcoholic hepatitis can vary from mild with only liver test elevation to severe
liver inflammation with development of jaundice, prolonged prothrombin time,
and liver failure.

 The plasma aminotransferase activities are not usually as markedly elevated as

acute viral hepatitis (moderate elevation of enzymes – in most cases the liver
enzymes such AST nor ALT do not exceed 500 U/L).

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Catabolism of hormones Glucose homeostasis;
and other serum proteins glycogenolysis & gluconeogenesis

Chronic Liver
Disease
Synthesis:
- Albumin
- Coagulation factors
Storage:
Bile excretion - Glycogen
- Iron
- Cu, Iron, vitamins

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 Chronic Hepatitis
 Hepatic inflammation persisting for more than six months.
 Long lasting inflammation of the liver due to viruses or
other causes.
 Two types:

(i) Chronic active hepatitis (CAH)

(ii) Chronic persistent hepatitis (CPH).

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 Causes of chronic
hepatitis
 Viral hepatitis: Hepatitis B with or without hepatitis D,
hepatitis C (neither hepatitis A nor hepatitis E causes
chronic hepatitis)

 Autoimmune: Autoimmune hepatitis

 Drugs: methyldopa, nitrofurantoin, isoniazid, ketoconazole.

 Heredity: Wilson's disease, alpha 1-antitrypsin deficiency .

 Others: Inflammatory bowel disease, ulcerative colitis

and alcohol.

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 Chronic Active Hepatitis
 It is caused by active hepatocellular destruction with
episodes of relapses and remissions.

 It may follow acute hepatitis, or it may develop insidiously.

 There is an active, continuing inflammation of the liver

associated with liver necrosis and fibrosis.

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 Chronic Active Hepatitis
 A potentially fatal form of hepatitis complicated by portal
inflammation and extending into the parenchyma.

 There may be progressive destruction of the liver lobule with

necrosis and fibrosis leading to scarring, cirrhosis and liver
decompensation.

 The possible causes include viral infections, drugs, and

autoimmune reactions.

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 Chronic Active Hepatitis -
Biochemistry
(i) As the disease progresses more cells are destroyed and the
plasma AST activity may rise to or exceed that of ALT.

(ii) Elevated ALP – cholestasis due to fibrosis.

(iii) Elevated Bilirubin (mild to moderate in 70%) – cholestasis.
(iv) Elevated plasma globulins – chronic inflammatory response.
(v) Decreased albumin – severe liver dysfunction.

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 Chronic Alcoholic
Hepatitis
 The finding of a raised plasma gamma-glutamyl transferase activity,
associated with hyperuricaemia and hypertriglyceridaemia is
suggestive of chronic alcohol ingestion.

 Serum bilirubin increased in 60 – 90% of patients.

 Serum albumin may be decreased.
 Gamma globulins elevated in 50 – 75% of individuals even in the
absence of cirrhosis.

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 Chronic Persistent
Hepatitis
 Chronic persistent hepatitis describes longstanding, but mild,
inflammation of the liver that does not result in liver failure.

 Causes include hepatitis B (HBV), hepatitis C (HCV), hepatitis D

(HDV), autoimmune diseases such as lupus, alcohol, and drugs.

 The condition may be asymptomatic and recognized only because of

a previous episode of acute hepatitis or because of biochemical tests
undertaken for other reasons.

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 Chronic Persistent
Hepatitis
 Examination is usually normal but may show slight hepatomegaly. There are no features of
chronic liver disease.

 Biochemical tests:

(i) The plasma total bilirubin may be normal or slightly raised.

(ii) Plasma aminotransferase (AST and ALT) may be variably elevated, and the alkaline
phosphatase is normal.

(iii) Plasma albumin and globulin concentrations are normal.

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Cirrhosis

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 Cirrhosis

 Cirrhosis is a consequence of chronic liver disease

characterized by replacement of liver tissue by fibrosis, scar
tissue and regenerative nodules (lumps that occur as a
result of a process in which damaged tissue is
regenerated), leading to loss of liver function.

 From a clinical and biochemical aspect, three stages are

identified.

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 Cirrhosis
(i) Quiescent (compensated) phase:
The disease is temporarily halted and associated with minimal disturbances in
LFTs.

(ii) Active phase:

There is progressive liver cell necrosis ( elevated ALT & AST ) and fibrosis which
often results in cholestasis (↑ ALP, ↑Bilirubin).

(iii) Decompensation phase:

Severe liver dysfunction with gross hypoalbuminaemia and hyperbilirubinaemia
(liver failure).

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 Causes of Cirrhosis
 Globally, 57% of cirrhosis is attributable to either hepatitis B (30%) or Hepatitis C (27%); alcohol
accounts for about 20% of the cases.

 Alcoholic liver disease (ALD). Alcoholic cirrhosis develops for 10–20 % of individuals who drink heavily for
a decade or more.

 Non-alcoholic steatohepatitis: Fat builds up in the liver and eventually causes scar tissue.

 Chronic hepatitis C. Infection with the hepatitis C virus causes inflammation of the liver and a variable
grade of damage to the organ that over several decades can lead to cirrhosis.

 Chronic hepatitis B. The hepatitis B virus causes liver inflammation and injury that over several decades
can lead to cirrhosis.

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 Causes of Cirrhosis
 Primary biliary cirrhosis, primary sclerosing cholangitis.

 Autoimmune hepatitis. This disease is caused by the immunologic damage to the liver causing inflammation
and eventually scarring and cirrhosis.

 Hereditary hemochromatosis.

 Wilson's disease. Autosomal recessive disorder characterized by low serum ceruloplasmin and increased hepatic
copper content on liver biopsy.

 Alpha 1-antitrypsin deficiency (A1AD). Autosomal recessive disorder. Patients may also have COPD, especially if
they have a history of tobacco smoking.

 Galactosemia, glycogen storage disease type IV, cystic fibrosis and hepatotoxic drugs or toxins.

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 Cirrhosis
Biochemical Tests:

(i) (a) The activities of transaminases (AST and ALT) reflects

the extent and severity of the damage.

(b) Normal levels may be found in the compensated

phase, and just prior to terminal liver failure (few
remaining undamaged hepatocytes).

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 Cirrhosis
(ii) (a) The plasma level of ALP is usually increased,
especially in the active and late phases, indicating
cholestasis due to progressive fibrosis.

(iii) In the majority of cases the plasma albumin levels is

decreased, indicating impaired protein synthesis (liver cell
dysfunction & and reduced functioning cell mass).

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 Cirrhosis

(iv) Most cases show an increase in gamma-globulin fraction. This

may be due to reticuloendothelial hyperplasia, or to an autoimmune
process.

(v) Early in the disease the plasma bilirubin levels were variable, but
are often increased. In the active phase and during hepatic
decompensation very high levels of bilirubin (total and direct) may
be reached.

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Hepatic Invasion or
Infiltration

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 Hepatic Invasion or
Infiltration of Liver
 Liver is a common site for tumour metastasis- infiltration by lymphoma,
cancer of the colon or breast etc.
 Invasion of the liver by secondary carcinoma – raised AST (ALT raised to a
lesser extent), ALP and GGT.
 49-year-old with history of breast cancer. Investigation revealed that the
patient had anemia (Hct, 23%) and abnormal liver function test results
[total bilirubin, 890 μmol/L (N, < 18); direct bilirubin, 599 μmol/L (N, <
6); AST, 1152 U/L (N, 7 – 32 U/L); ALT, 114 U/L (N, 0 – 55 U/L); ALP, 845
U/L (N, 15 – 105); GGT 727 U/L (N, 10 – 70 U/L)].

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 Hepatocellular Carcinoma
 Hepatocellular carcinoma is the most common type of liver cancer.

 Hepatocellular carcinoma most commonly appears in a patient with

chronic viral hepatitis (hepatitis B or hepatitis C, 20%) or/and with
cirrhosis (about 80%; alcoholism being the most common cause of hepatic
cirrhosis).

 Most cases of hepatocellular carcinoma are secondary to either a viral

hepatitis infection (hepatitis B or C) or cirrhosis (alcoholism being the most
common cause of hepatic cirrhosis).

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 Hepatocellular Carcinoma
 Hepatocellular carcinoma may present with jaundice, bloating from ascites,
easy bruising from blood clotting abnormalities or as loss of appetite.

 The main risk factors for hepatocellular carcinoma are: alcoholism, hepatitis B,
hepatitis C (25% of causes globally), cirrhosis of the liver, haemochromatosis,
Wilson's disease and type 2 diabetes (probably aided by obesity).

 Primary hepatocellular carcinoma develops: increased AST and ALT, high

plasma [alpha-fetoprotein].

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Metabolic Liver
Disease

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 Metabolic Liver Diseases

 Alpha-1-antitrypsin deficiency

 Wilson’s disease

 Haemochromatosis.

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 Alpha-1-Antitrypsin
Deficiency
 Alpha 1-antitrypsin (A1AT) is produced in the liver, and one of its
functions is to protect the lungs from the neutrophil elastase
enzyme, which can disrupt connective tissue.

 Alpha 1-antitrypsin deficiency is an autosomal recessive

genetic disorder caused by defective production of alpha 1-antitrypsin
(A1AT), leading to decreased A1AT activity in the blood and lungs,
and deposition of excessive abnormal A1AT protein in liver cells.

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 Alpha-1-Antitrypsin
Deficiency
 A1AD also causes impaired liver function in some patients and
may lead to cirrhosis and liver failure (15%).

 It is usually associated with neonatal hepatitis.

 A1AT deficiency causes emphysema or chronic obstructive

pulmonary disease (COPD) in adult life in many people with the
condition.

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 Wilson‘s Disease
 Wilson's disease is an autosomal recessive genetic disorder
in which copper accumulates in tissues; this manifests
as neurological or psychiatric symptoms and liver disease.

 This is a rare recessively inherited disorder caused by

reduced biliary excretion of copper and impaired
hepatic incorporation of copper into caeruloplasmin .

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 Wilson‘s Disease
 The symptoms are due to excessive accumulation of copper
in the liver, brain and kidneys and present with evidence of
acute liver failure, chronic hepatitis or cirrhosis in children or
in young adults.

 It is treated with medication that reduces copper absorption

or removes the excess copper from the body, but
occasionally a liver transplant is required.

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 Haemochromatosis
 An autosomal recessive disease characterized by excessive
iron uptake from the gut and iron deposition in the tissues
which can affect many organs including the liver .

 It presents, usually in middle age, and the most common

presentation is hepatic cirrhosis in combination with
hypopituitarism, cardiomyopathy, diabetes mellitus, arthritis, or
hyperpigmentation.

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 Haemochromatosis
 The diagnosis is made by measuring plasma iron concentration
and total binding capacity (TIBC), as an indicator of transferrin
concentration, with almost total saturation.

 Serum ferritin is elevated, but can be elevated in a range of

other medical conditions unrelated to iron levels including
infection, inflammation, fever, liver disease, renal disease, and
cancer.

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Inborn errors of
Bilirubin
metabolism
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 Inbornn Errors of
Metabolism
 Conditions in which jaundice is caused by inherited abnormality of bilirubin
metabolism (congenital non-haemolytic hyperbilirubinaemia).
 Unconjugated hyperbilirubinaemia:

Gilbert’s syndrome

Crigler-Najjar syndrome
 Conjugated hyperbilirubinaemia:

Dubin-Johnson syndrome

Rotor’s syndrome

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 Gilbert‘s Syndrome

 Gilbert's syndrome is the most common hereditary cause of increased b

ilirubin.

 A major characteristic is jaundice, caused by elevated levels of

unconjugated bilirubin in the bloodstream.

 Gilbert‘s syndrome is characterized by a 70%-80% reduction, rather

than more severe loss of activity of UDP-glucuronosyltransferase.

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 Gilbert‘s Syndrome
 Persons with Gilbert’s syndrome predominantly have elevated unconjugated
bilirubin, while conjugated bilirubin is usually within the normal range
and is less than 20% of the total.

 Levels of total bilirubin in Gilbert’s syndrome patients are reported to be

from 20 μmol/L to 90 μmol/L.

 Gilbert’s
syndrome is associated with normal values for the other LFTs, normal hepatic histol
ogy, and no overt haemolysis
.

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 Gilbert‘s Syndrome
 A 24-year old man presented with intermittent mild jaundice. There was no
conjugated bilirubin in his urine. Laboratory test results are as follows:
Serum
Total Bili 42 μmol (< 18)
Direct Bili 10 μmol (< 6)
Alb 46 g/L (38 – 52)
ALT 30 U/L (< 35)
ALP 75 U/L (30 – 120)
Further test revealed decreased activity of
uridinediphosphate (UDP)- glucuronosyltransferase.

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 Crigler-Naijjar Syndrome

 The disorder results in an inherited form of non-hemolytic

jaundice, which results in high levels of unconjugated
bilirubin and often leads to brain damage in infants.

 There is defective uridyl diphosphate (UDP)-glucoronosyl

transferase but of greater severity than in Gilbert’s
syndrome.

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 Crigler-Naijjar Syndrome

 There are two types of the disorder:

(i) Type I – absolute deficiency of the enzyme which results in

kernicterus and death soon after birth.

(ii) Type II – partial deficiency of the enzyme which is not fatal

but results in life-long unconjugated hyperbilirubinaemia.

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 Crigler-Naijjar Syndrome

 Intense jaundice appears in the first days of life and persists

thereafter.

 Type 1 is characterised by a serum total bilirubin usually above

345 µmol/L. Intense jaundice appears in the first days of life and
persist thereafter.

 In Type II the serum total bilirubin levels are generally below

345 µmol/L and some cases are only detected later in life.

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 Crigler-Naijjar Syndrome

 Because of lower serum bilirubin (compared with

Gilbert’s syndrome, kernicterus is rare in type II.

 Other routine liver function tests are normal; normal

hepatic histology.

 There is no evidence for hemolysis.

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 Dubin-Johnson Syndrome

 This is an autosomal recessive disorder due to defective

excretion of conjugated bilirubin, but not of bile acids,
and is characterized by slightly raised plasma
conjugated bilirubin levels that tend to fluctuate.

 There may be hepatomegaly and the liver is dark brown

in appearance.

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Dubin-Johnson Syndrome

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 Dubin-Johnson Syndrome

 Most patients are asymptomatic with serum total bilirubin

levels ranging from 30 – 90 µmol/L and bilirubinuria.

 It is usually asymptomatic but may be diagnosed in early

infancy based on laboratory tests.

 Plasma ALP activity is normal and there is no elevation of

ALT or AST.

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 Rotor Syndrome

 Rotor syndrome, also called Rotor type

hyperbilirubinemia, is a rare, relatively benign
autosomal recessive bilirubin disorder of unknown
origin.

 It is a distinct disorder, yet similar to Dubin-Johnson

syndrome - both diseases cause an increase in
conjugated bilirubin.

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Rotor Syndrome

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 Rotor Syndrome

 Rotor syndrome has many things in common with

Dubin-Johnson syndrome, an exception being that
the liver cells are not pigmented (normal histology
and appearance).

 The main symptom is a non-itching jaundice.

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Thank you

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