1.

Do liver function tests abnormalities reflect liver pathology on all occasions?

Liver function tests are among the most frequently requested panels of clinical biochemistry tests. The term "liver function tests" (LFT) usually refers to a profile of biochemical parameters which include: total bilirubin, alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT), alanine transaminase (ALT), aspartate transaminase (AST), total protein and albumin. These parameters are customarily included into the collective term, LFT, because they are useful for the diagnosis of hepatobiliary pathology when considered collectively. Certain patterns of abnormalities are suggestive of particular hepatobiliary problem. However, the key to appropriate interpretation of the LFTs lies in the understanding that when considered individually, none of the members of the LFT panel is specific for liver pathology. For example, serum GGT could be elevated in the absence of liver pathology and be a consequence of liver enzyme induction by alcohol or anticonvulsants. Similarly, raised serum AST could be a result of acute myocardial infarction.

What is the cause for the elevated serum ALP concentration?

What tests could be requested to confirm one's suspicion?

Rectal examination revealed a nodular prostate and x-ray revealed multiple osteosclerotic lesions suggestive of bony metastases. Prostate specific antigen (PSA) was markedly elevated. The patient was diagnosed to have prostate carcinoma.

There are several isoenzymes of ALP. They are present in liver, bone, intestine and placenta. Liver or bone pathologies are the most common causes of elevated serum ALP. ALP in the liver and GGT are found on the membranes of the bile canaliculi and ducts. Therefore, if a raised ALP is of liver origin, it indicates cholestasis and is usually associated with an elevated serum GGT. This patient had an isolated elevation in serum ALP in conjunction with the suggestive symptoms and signs of prostate carcinoma. Thus, the raised serum ALP is mostly a consequence of bony metastasis. If there is any doubt, ALP isoenzyme testing could be performed to distinguish between bone and liver origin of an elevated serum ALP.

What is the most likely diagnosis?

Plasma total bilirubin consists of conjugated and unconjugated forms. Unconjugated bilirubin is a metabolic by-product of haem metabolism. Thus, haemolytic disorders are associated with unconjugated hyperbilirubinaemia. Unconjugated bilirubin is normally conjugated by the liver to facilitate biliary excretion of bilirubin. Therefore, most liver pathologies are associated with conjugated hyperbilirubinaemia, except when there are enzymatic deficiencies in the bilirubin conjugation pathway. The illustrated case is one such condition, Gilbert's disease.

Gilbert's disease is a common benign condition which is more commonly seen in males and affects 1-5% of the population. Bilirubin levels typically are <50mmol/L and fluctuate with mild illness, infections and periods of starvation, leading to mild jaundice occasionally. Bilirubinuria (urine darkening on standing) is typically lacking, as bilirubinuria is a sign of conjugated hyperbilirubinaemia. When a haemolytic condition is excluded or unlikely, mild fluctuating unconjugated hyperbilirubinaemia is often due to Gilbert's disease.

2.

How do liver function tests reflect liver pathologies?

When considered collectively, certain patterns of the liver function tests reflect particular types of liver pathology. Such patterns can be broadly categorised as: (i) Hepatocellular pattern; (ii) Cholestatic pattern; and (iii) Mixed pattern of hepatocellular damage and cholestasis.

A hepatocellular pattern is associated with a predominant increase in serum ALT / AST but normal or only mildly elevated ALP / GGT. This is because both ALT and AST are intracellular enzymes in hepatocytes. Therefore, significant damage to hepatocytes results in the release of ALT and AST into the circulation. Causes of hepatocellular damage include: viral hepatitis, drugs (e.g. paracetamol), circulatory shock and liver congestion from cardiac failure.

A cholestatic pattern is associated with a predominant increase in serum ALP / GGT and conjugated bilirubin (partial biliary tree obstruction is an exception, see Case 5), with normal or only mild increase in ALT / AST. Both ALP and GGT are present on the membranes of bile canaliculi. Therefore, bile flow obstruction would result in induced production of GGT and increased release of ALP into the circulation. Causes of cholestasis / biliary obstruction include: gall stones, cholangitis, cholangiocarcinoma, carcinoma of the head of pancreas, liver metastasis, primary biliary cirrhosis, liver cirrhosis and drugs e.g. flucloxacillin, augmentin.

A mixed pattern is usually associated with raised ALT, AST, ALP, GGT and bilirubin. Such a pattern is often evident when the liver insult is prolonged. For example, prolonged biliary obstruction may lead to significant liver cell destruction (due to back pressure), and vice versa (acute hepatitis may give rise to severe cholestasis due to hepatic congestion).

Case 3
A 45 year-old woman had returned from a 2-week holiday in India and developed fever, rigors and sweats. The next day she developed nausea, anorexia, and right upper quadrant pain.

What is the most likely pathology?

What further test(s) could one request to determine the underlying cause?

Initially, the serum biochemical results revealed a marked elevation in ALT, gradual increase in serum bilirubin, with milder elevations in GGT and ALP. Therefore, this is suggestive of a hepatocellular condition with an acute time course, compatible with acute hepatitis. Viral serology was requested and hepatitis A IgM was positive and thus, the diagnosis was Hepatitis A. It can be noted that in the later stage of the disease, the liver function profile evolves into a mixed pattern. This is due to the development of a cholestatic component consequent to hepatic congestion and the progressive clearance of ALT.

Case 4
A 48 year-old woman with a past history of several episodes of recurrent right upper quadrant pain.

What pathology does the biochemical profile suggest?

What investigation could be requested to determine the underlying cause?

The predominant elevations in ALP and conjugated bilirubin are compatible with biliary tree obstruction (cholestasis). Ultrasound of the hepatobiliary system indeed revealed the presence of several gall stones in the gall bladder.

Case 5
57 year-old woman had LFTs done during a follow-up visit 3 months after resection of a rectal carcinoma.

What is the likely tissue source of the elevated serum ALP and why?

What is the most likely diagnosis?

Why is the bilirubin not elevated?

The elevated serum ALP is most likely to be derived from the liver as GGT is also elevated. Biliary tree obstruction leads to elevation of both ALP and GGT. The most likely diagnosis is liver metastases from the rectal carcinoma. Metastatic foci usually cause partial biliary tree obstruction. Drainage of bilirubin by the non-affected parts of the liver is adequate to maintain a normal serum total bilirubin concentration.

3.

What other information can be gained from the liver function tests?

Albumin is synthesised by the liver. Therefore, hypoalbuminaemia in association with liver

pathology is a marker reflective of the chronic nature of the illness. Besides the LFT panel of tests, there are other tests which are useful in the assessment of hepatic function.

Case 6
The following results are obtained from a 55 year-old man known to be a chronic hepatitis B carrier. On examination, spider naevi, petechiae, palmar erythema were found peripherally. The liver was nodular and palpable.

Is the biochemical profile typical for chronic liver disease?

What test would be useful for assessing the severity of the chronic liver disease?

If the patient presents with acute confusion and hepatic flap, what test would be requested?

As chronic liver disease develops insidiously with adequate opportunity for compensatory mechanisms to adapt, the biochemical profile is often normal except when in advanced stage, particularly when cirrhotic nodules obstruct biliary drainage. Hypoalbuminaemia is usually associated with chronic liver disease due both to reduced hepatic albumin synthesis and haemodilution consequent to generalised oedema. Prolongation of prothrombin time is often considered a marker reflective of the severity of the chronic liver disease as the clotting factors II, VII, IX and X are produced by the liver via a Vitamin K dependent pathway. However, Vitamin K deficiency due to fat malabsorption, for example due to biliary obstruction, could also result in prolongation of the prothrombin time. Plasma ammonia is measured in the assessment of hepatic encephalopathy as ammonia is normally detoxified by the liver and excreted as urea. The accumulation of ammonia in a patient with liver disease is a sign of hepatic failure.