Because cholestasis characterises a different pathophysiology and consequently completely different approach to management, its syndromic manifestations, though overlapping with the hepatitides (transaminitis), remain important from which to differentiate it.
Clinical History
- drugs, both oral and parenteral
- pain and radiation
- ascending cholangitis
- pruritus
- weight loss
Physical Examination
- hepatosplenomegaly
- large gallbladder
- signs of chronic liver disease
- supraclavicular lymph node?
Specific Investigations
- USS
- CT / MRI
- ERCP
- MRCP
- HAV, HBV, & HCV serology
- Tissue antibodies
- ± direct / indirect bilirubin
- Liver Biopsy
Pathophysiological classification is traditionally divided along biliary lines:
Extrahepatic: larger duct obstruction of bile flow distal to bile canaliculi
- stones (recall Charcot’s Triad) ⇒ USS
- malignancy – head/uncinate pancreas or bile duct ⇒ CT / MRI
- pancreatitis ⇒ ERCP (or PTC)
Note: Ideally, extrahepatic disease should be excluded first so that subsequent investigation (ultimately, liver biopsy) of presumed intrahepatic disease does not inadvertently cause a biliary peritonitis.
Intrahepatic: parenchymal liver damage (swelling of hepatocytes and oedema) or excretory dysfunction of bile canaliculi at cellular (microscopic) level
- fatty liver (NASH) ⇒ USS
- alcohol and other drugs ⇔ History ⇒ liver biopsy
- phenothiazines
- erythromycin
- testosterones
- viral hepatitis (HBV, HAV etc.) ⇒ serology (IgM)
- chronic active hepatitis ⇒ autoantibodies ⇒ liver biopsy
- PBC ⇒ AMA ⇒ liver biopsy
- haemochromatosis ⇒ ferritin, Fe, TIBC ⇒ liver biopsy
- idiopathic cirrhosis ⇒ liver biopsy
- Gilbert’s syndrome ⇒ unconjugated bilirubin
- hepatoma ⇒ alpha-fetoprotein (AFP) ⇒ liver biopsy
- metastases ⇒ USS ⇒ CT/MRI ⇒ ? liver biopsy
Cholestatic enzymes
Alkaline phosphatase (ALP) is a zinc-requiring family of isoenzymes found in liver, bone, intestine, placenta, kidney, and leukocytes, that catalyse the hydrolysis of phosphate esters. the bone isoenzyme is heat labile (think: bone “burns”). ALP is elevated in states of cholestasis (usually 4-6 x normal) and also with hepatic carcinoma (> 1,000). An isolated elevation of ALP is sometimes seen in elderly and should prompt the clinician to the likelihood of Paget’s Disease of the bone.
An increase in gamma-glutamyl transpeptidase (GGT) helps to confirm that any raised ALP is probably of hepatic origin. GGT transfers gamma-glutamyl groups from peptides to amino acids, such as glutathione. It is produced in luminal epithelial cells lining the fine biliary ductules of the hepatobiliary tree. There are two isoenzymes and they are sensitive indicators of biliary disease. Consequently, levels are elevated in:
- cholestasis
- pancreatic disease
- hepatocellular cancer
- COAD
- diabetes
- alcoholism
- drugs (induced by phenytoin, for instance)
- chronic renal failure
- myocardial infarction
An isolated elevation of GGT should suggests a drug (classically, phenytoin) or alcohol as implicated. Indeed, GGT may be seen as a good guide to alcohol intake and can be useful as a screening test for this.
Alternatively, you might like to think of aetiology more in terms of frequency of diagnosis, in which case they are, top to bottom from most frequent to least frequent:
- stones
- malignancy
- drugs
- infective / viral
- chemical / toxins
- steatosis
- others
- pregnancy
- pancreatitis
- cirrhosis
- PBC
- sclerosing cholangitis
- storage diseases
