1
Liver and biliary tract diseases
MUDr. Martina Žižlavská
2
1. Introduction
This material covers the diagnosis of the most common liver and biliary tract disease and is an extension
to previous knowledge of the physiology and pathophysiology of the liver and gall bladder. If you are not
familiar with this topic, make sure to study liver structure and function, especially metabolic liver
functions, bilirubin metabolism, the role of liver enzymes, the pathophysiology of liver failure, fibrosis
and cirrhosis, first.
While there are many causes of liver disease (see the Annex at the end of this material), these disorders
generally present clinically in a few distinct patterns. They are classified as hepatocellular, cholestatic
(obstructive), or mixed. A diagnosis usually can be made accurately by careful elicitation of the patient´s
history, physical examination and application of basic laboratory tests. Diagnostic imaging methods
also play a key role and with their improvement, the need for invasive liver biopsy is reduced.
Liver diseases are an important topic to medical doctors of various specializations – if you become a
general practitioner, and choose to work in internal medicine or surgery, you are going to meet patients
with these diseases on a daily routine. This material is an introduction to the clinically most important
topics.
3
2. Diagnosis of liver disease
(a) Laboratory tests
i. Bilirubin
Bilirubin, a breakdown product of heme-containing proteins, is found in blood in two fractions.
Unconjugated bilirubin (indirect fraction) elevation is rarely due to liver disease. It is seen primarily in
hemolytic disorders and many genetic conditions such as Crigler-Najjar and Gilbert´s syndromes.
Isolated unconjugated hyperbilirubinemia should prompt a workup for hemolysis, in the absence of
hemolysis in an otherwise healthy patient it can be attributed to Gilbert´s syndrome.
In contrast, conjugated hyperbilirubinemia (direct fraction) almost always implies liver or biliary tract
disease. The rate-limiting step in bilirubin metabolism is not the conjugation of bilirubin, but rather the
transport of conjugated bilirubin into the bile canaliculi. Thus, the elevation of the conjugated fraction
may be seen in any type of liver disease including fulminant liver failure.
In most liver diseases, both fractions of the bilirubin tend to be elevated. Except in the presence of
purely unconjugated hyperbilirubinemia, fractionation of the bilirubin is rarely helpful in determining the
cause of jaundice. Unconjugated bilirubin always binds to albumin in the serum and is not filtered by the
kidney. Therefore, any bilirubin found in the urine is conjugated bilirubin; the presence of bilirubinuria
implies the presence of liver disease.
ii. Liver function tests
Serum biochemical tests (liver function tests) can be used to detect the presence of liver disease,
distinguish among different types of disorders, evaluate the extent of liver damage and follow the
response to treatment. Keep in mind that they lack sensitivity and specificity – they can be normal in
patients with serious liver disease and abnormal in patients with diseases that do not affect the liver at
all. As always in medicine, you must consider the patient history and presentation when evaluating any
laboratory results.
The aminotransferases (transaminases) are sensitive indicators of hepatocyte injury and help
recognize acute hepatocellular diseases such as hepatitis. They include aspartate aminotransferase
(AST), which is also found in many other tissues (cardiac and skeletal muscle, kidneys, brain and others)
and alanine aminotransferase (ALT), which is found primarily in the liver and therefore is more specific.
The pattern of the aminotransferase elevation can be helpful diagnostically. In most acute
hepatocellular disorders, the ALT is higher than or equal to the AST. Whereas the AST: ALT ratio is
typically <1 in patients with chronic viral hepatitis and nonalcoholic fatty liver disease, and as cirrhosis
develops, this ratio rises to >1. An AST: ALT ratio >2:1 is suggestive, whereas a ratio >3:1 is highly
4
suggestive, of alcoholic liver disease. A low level of ALT in the serum is due to an alcohol-induced
deficiency of pyridoxal phosphate. The aminotransferases are usually not greatly elevated in obstructive
jaundice. One notable exception occurs during the acute phase of biliary obstruction caused by the
passage of a gallstone into the common bile duct. In this setting, the aminotransferases can briefly be
extremely high. However, aminotransferase levels decrease quickly, and the biochemical tests rapidly
evolve into those typical of cholestasis.
The serum elevation of alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase (GGT)
are associated with cholestasis, as their blood levels rise with higher pressure in the biliary ducts.
Isolated GGT elevation is most often associated with increased alcohol intake.
The normal serum alkaline phosphatase consists of many distinct isoenzymes (found in the liver,
bone, placenta, and, less commonly, in the small intestine). Alkaline phosphatase elevations greater
than four times occur primarily in patients with cholestatic liver disorders, infiltrative liver diseases such
as cancer and amyloidosis, and bone conditions characterized by rapid bone turnover. To specify the
source of ALP elevation, ask the laboratory to determine specific isoenzymes.
iii. Indicators of Liver Metabolic Function
Albumin is the most important plasmatic protein and is synthesized exclusively by hepatocytes. It has
a long half-life of 18-20 days; therefore, it is not a good indicator of acute or mild hepatic dysfunction.
Hypoalbuminemia is more common in chronic liver disorders such as cirrhosis and reflects severe liver
damage. In patients with ascites, hypoalbuminemia does not necessarily mean severe liver damage but
is caused by increased volume of albumin distribution. Hypoalbuminemia is not specific to liver disease
only but can be found in protein malnutrition, nephrotic syndrome, chronic infections and others.
The blood clotting factors are, except for factor VIII, all made exclusively in hepatocytes. Their serum
half-lives are much shorter (6h to 5 days) which makes them the single best acute measure of hepatic
synthetic function. They are used in diagnosis and assessing the prognosis of acute liver disease. Most
useful is the serum prothrombin time (routinely evaluated as INR, international normalized ratio),
which is also measured to evaluate warfarin therapy, and therefore is available in every laboratory. It
may be elevated in hepatitis and cirrhosis as well as in disorders that lead to vitamin K deficiency such
as obstructive jaundice or fat malabsorption of any kind. Because of coagulopathy, patients with high
INR with acute liver failure are at a high risk of bleeding, especially if gastroesophageal varices develop.
iv. Other laboratory findings
• Immunoglobulins diffuse polyclonal increases in IgG levels are common in autoimmune
hepatitis; increases >100% should alert the clinician to this possibility. Increases in the IgM
levels are common in primary biliary cirrhosis, whereas increases in the IgA levels occur in
alcoholic liver disease.
5
• Ammonia is produced by intestinal bacteria and the liver plays a role in detoxification by
converting it to urea. It can be used for detecting encephalopathy or for monitoring hepatic
synthetic function, but the correlation between the presence or severity of acute
encephalopathy, hepatic function and elevation of blood ammonia, is very poor. Occasionally it
can be useful for identifying occult liver disease in patients with altered mental status.
• Creatinine is elevated when hepatorenal syndromes develop and may mark a poor prognosis.
• Glycaemia – Acute liver failure can be accompanied by symptomatic hypoglycaemia because
of the sudden cessation of gluconeogenesis. The cirrhotic liver does not respond adequately to
insulin. Thus, glucose cannot enter the cells and stays elevated in the blood (diabetes). Patients
with cirrhosis are not able to mobilize glucose out of the body's reserves, and they can easily
develop hypoglycaemia.
• Ceruloplasmin – Low levels of ceruloplasmin are specific for Wilson´s disease.
• Specific antibodies and others: see examples in the annex
(b) History taking and physical examination
Obtaining a clinical history should focus on the symptoms of liver disease, their characterization,
patterns of onset, their dynamics and potential risk factors for liver disease. Keep in mind that patients
with acute liver failure might not be in a state to give you any information, you might have to ask the
patient's family and friends some very sensitive questions.
Chronic alcohol or drug users are often not compliant enough to tell you the truth, and some of
them can be easily agitated and act aggressively – always think about your and your staff´s safety first.
Also, the patient´s verbal or physical aggressivity should be understood as a symptom, not their personal
characteristic – this view will make it easier for you to stay professional at all times and facilitate very
harsh situations with the patient´s family. Maintaining social connection is an important key to dealing
with any kind of addiction or severe disease and may have a life-or-death meaning for your patient.
(c) Signs and symptoms
• Fatigue is the most common symptom of chronic liver disease, described as lethargy,
weakness, increased need for sleep, and poor energy. Typically, it arises after exercise, in the
afternoon, and is not present after adequate rest – in the morning.
• Nausea and sometimes vomiting occur with more severe liver disease. It may be provoked by
food odour and eating fatty foods. Poor appetite with weight loss occurs in acute liver disease.
• Right upper quadrant discomfort or pain is most typical of gallbladder disease, liver abscess
and sinusoidal obstruction syndrome, and occasionally can be present in acute hepatitis.
6
Hepatic tenderness is a discomfort or pain when the liver region is touched and is considered
a very reliable physical finding.
• Jaundice, icterus is the hallmark symptom of liver disease and serves also as a marker of
severity. At first, patients report darkening of the urine (not in the case of unconjugated
hyperbilirubinemia), but scleral icterus is detectable later. Jaundice of the skin is not present
with bilirubin levels < 40 μmol/L and the noticeability depends on the lightening of the room
(natural light is the best) and the tone of the patient´s skin. In dark-skinned individuals,
examination of mucous membranes below the tongue can demonstrate jaundice.
• Steatorrhea is a light-coloured stool, caused by the absence of bile acids in the intestine and
accompanies severe cholestasis. It may be accompanied by diarrhoea.
• Hepatomegaly is not a highly reliable sign because of liver size variability and the possibility of
inaccurate physical examination. Marked hepatomegaly is typical of cirrhosis, sinusoidal
obstruction syndrome, alcoholic hepatitis and infiltrative disorders.
• Spider angiomata and palmar erythema occur in both acute and chronic liver disease and
are most prominent in patients with cirrhosis. They can develop in normal individuals during
pregnancy.
• Hepatic encephalopathy can be nonspecific – change in personality and sleep patterns,
irritability. Thereafter, disorientation, confusion, stupor and eventually coma may follow. It
is a major criterion for diagnosis of fulminant hepatitis and indicates a poor prognosis. Asterixis
(flapping tremor) is a specific sign of hepatic encephalopathy and means a tremor of the hand
when the wrist is extended, sometimes said to resemble a bird flapping its wings.
• Excitability and mania may be present in acute liver failure.
• Ascites and/or peripheral oedema are most often signs of advanced liver disease and
hypoalbuminemia. Ascites is best evaluated by detecting shifting dullness by careful percussion,
but always should be confirmed by ultrasound. With ascites, hydrothorax may develop as well.
• Caput medusae are prominent veins over the abdomen.
• Splenomegaly
• Muscle wasting is found in chronic liver disease in general, although severe cachexia is more
typical for metastatic liver disease or hepatocellular carcinoma.
• Bruising is an early sign of coagulopathy.
• Hepatic fetor is a slightly sweet, ammoniacal odour.
• Kayser-Fleischer rings found in Wilson disease are golden brown copper pigment deposits at
the periphery of the cornea.
• Dupuytren contracture and parotid enlargement are signs of chronic alcoholism and
alcoholic liver disease.
7
(d) Risk factors
• Alcohol use
• Medication use
• Personal habits, diet, occupation
• Sexual activity
• Travel
• Exposure to jaundiced or other high-risk persons
• Injection drug use
• Recent surgery or transfusion of blood or blood products
• Family history of liver disease
To indicate abuse or dependence on alcohol, you can use the CAGE questions set, where one
yes means suspicion of an alcohol use problem, and more than one is a strong indication:
• Have you ever felt you ought to cut down on your drinking?
• Have people annoyed you by criticizing your drinking?
• Have you ever felt guilty or bad about your drinking?
• Have you ever had a drink first thing in the morning to steady your nerves or get rid of a
hangover (eye-opener)?
(e) Diagnostic imaging and liver biopsy
Ultrasonography is the first diagnostic test to be used in patients whose liver tests suggest
cholestasis. It will confirm or exclude the presence of a dilated intrahepatic or extrahepatic biliary tree
or identify gallstones and cholecystitis. It shows lesions within the liver and distinguishes between cystic
and solid masses. US transient elastography provides an indirect assessment of fibrosis and cirrhosis
and can eliminate the need for liver biopsy.
CT is also highly sensitive for detecting biliary duct dilation and can be the first-line option for
investigating suspected obstructive jaundice. It is not a method of choice to detect gallstones. CT and
MRI modifications can be used to quantify liver fat. MR elastography is more sensitive than US
elastography.
ERCP and MRCP are a choice for visualization of the biliary tree. ERCP (endoscopic retrograde
cholangiopancreatography) is an invasive method which also permits biopsy and provides several
therapeutic options, such as sphincterotomy, stone extraction, placement of biliary catheters and stents.
MRCP (magnetic resonance cholangiopancreatography) is a superior diagnostic method with
several advantages – no need for contrast media and ionizing radiation, and no risk of pancreatitis. It is
8
useful in the diagnosis of bile duct obstruction and congenital biliary abnormalities. As it is a non-invasive
method, it also does not offer any therapeutic options.
Liver biopsy is a gold standard, particularly in evaluating chronic liver disease. In selected instances,
it is necessary for diagnosis, and in other cases is used for assessment of the severity and stage of liver
damage, prognosis and monitoring response to treatment.
(f) Diagnostic algorithms
Differential diagnosis of liver diseases can get complicated, especially if you consider a large
number of possible diseases. It is important to proceed thoughtfully, considering the severity of problems
when making diagnostic and therapeutic plans. It might be useful to follow algorithms such as the two
shown below, to make sure you are proceeding in the best possible way.
Do not worry – you do not have to remember these algorithms by heart, you can easily find them in the
time of need. Try going through all the pathways and try to understand their logic. Imagine making a
plan for a patient with abnormal liver tests.
How long do you think it would take to confirm obstruction of the bile duct? Or autoimmune
hepatitis? Can you imagine a situation when these algorithms are of no use?
9
Figure 1 Algorithm for evaluation of abnormal liver tests (Source: Harrisons´s principles of
Internal medicine, 20th Edition); α1 AT, α1 antitrypsin; AMA; antimitochondrial antibody; ANA,
antinuclear antibody; anti-HBc, antibody to hepatitis B core (antigen); ERCP, endoscopic retrograde
cholangiopancreatography; HAV, hepatitis A virus; HBsAg, hepatitis B surface antigen; HCV, hepatitis
C virus; MRCP, magnetic resonance cholangiopancreatography; P-ANCA, peripheral antineutrophil
cytoplasmic antibody; SMA, smooth-muscle antibody.
10
Figure 2 Algorithm for the evaluation of chronically abnormal liver tests. (Source: Harrisons´s
principles of Internal medicine, 20th Edition); AMA, antimitochondrial antibody; ANA, antinuclear
antibody; Bx, biopsy; CT, computed tomography; ERCP, endoscopic retrograde
cholangiopancreatography; GGT, gama-glutamyl transpeptidase; MRCP, magnetic resonance
cholangiopancreatography; R/O, rule out; SPEP, serum protein electrophoresis; TIBC, total iron-binding
capacity; W/U, workup.
11
2. Acute liver failure
Acute liver failure is a syndrome that occurs in hepatocyte destruction from various causes. It is defined
by coagulopathy and any degree of encephalopathy in patients without cirrhosis.
Depending on the disease progression it can be classified as:
a) fulminant – onset within 7 days, with often brain oedema
b) acute – 28 days,
c) subacute – 24 weeks, often accompanied by ascites and portal hypertension.
Acute liver failure can be caused by any hepatocyte-damaging processes. The most common etiology
is paracetamol intoxication either in suicidal attempts (doses over 10 grams) or by unintentional
paracetamol overdose, which occurs more often in chronic alcohol abusers (doses from 4 grams and
more).
Can you name any other drugs that induce liver damage?
Clinical presentation of acute liver failure is a variation of manifesting coagulopathy, icterus,
hypoglycaemia and encephalopathy. The presentation is often accompanied by metabolic acidosis,
hypotension and gastrointestinal bleeding.
Subacute liver failure has less specific symptoms – subicterus, fatigue, nausea and hepatic tenderness.
A crucial sign to confirm liver failure is encephalopathy.
Liver failure is often complicated by multiorgan failure, infections sepsis or acid-base disbalance.
(a) Treatment
Treatment of acute liver failure requires placement in the intensive care unit and cooperation with
hepatologists and other specialists. Severe state leads to metabolic disruption and multiorgan failure
and the treatment is symptomatic. The state requires careful monitoring and adjustments of vital
functions, acid-base balance, electrolytes and glycaemia. For severe coagulopathy it might be
necessary to transfuse plasma and coagulation factors, vitamin K, to avoid bleeding complications and
DIC (disseminated intravascular coagulation).
Renal failure is a frequent complication, leading to hemodialysis. To prevent further damage, avoid
nephrotoxic drugs. To cure sepsis, cephalosporins of the 3rd generation in combination with vancomycin
are recommended. Fungal infections are also frequent.
There is only one causal treatment of liver failure: liver transplantation. Find more information about it
here: https://transplantsurgery.ucsf.edu/conditions--procedures/liver-transplant.aspx
12
(b) Paracetamol intoxication
A lethal dose of paracetamol is 13-25 grams, and acute liver failure may individually develop even in
lower doses. In alcohol abusers or people with present liver disease, even a dose of 4 grams or more
may cause liver failure.
Paracetamol is the most common cause of drug-induced liver failure.
Can you name any other hepatotoxic drugs and chemicals?
https://www.wikiskripta.eu/index.php?title=Toxick%C3%A9_po%C5%A1kozen%C3%AD_jater&oldid=
396545
13
3. Cirrhosis
Cirrhosis is a condition defined by histopathology and has a variety of clinical manifestations and
complications, some of which can be life-threatening.
Cirrhosis may be caused by:
• Alcoholism
• Chronic viral hepatitis B or C
• Autoimmune hepatitis
• Nonalcoholic steatohepatitis
• Biliary cirrhosis (PBC, PSC)
• Cardiac cirrhosis
• Metabolic liver disease (hemochromatosis, Wilson´s disease…)
Major complications of cirrhosis are:
• Portal hypertension
• Hepatorenal syndrome type 1 and type 2
• Hepatic encephalopathy
• Ascites
• Hepatopulmonary syndrome
• Portopulmonary hypertension
• Malnutrition
• Coagulopathy
• Hematologic abnormalities - anaemia, hemolysis, thrombocytopenia, neutropenia
• Bone disease – osteopenia, osteoporosis, osteomalacia
Portal hypertension may lead to gastroesophageal varices, gastropathy, splenomegaly, ascites or
spontaneous bacterial peritonitis. The majority of patients with cirrhosis develop varices in their lifetimes,
and are at a high risk of bleeding, especially if coagulopathy, thrombocytopenia or tension ascites is
present. It is common to screen cirrhotics with endoscopy, perform varices ligation if needed and treat
portal hypertension with non-selective beta-blockers (karvedilol) and diuretics (furosemide,
spironolactone). TIPS is also a possibility: a transjugular intrahepatic portosystemic shunt is a tract
created within the liver using X-ray guidance to connect the higher-pressure portal vein and the lowerpressure
hepatic vein, which relieves portal hypertension.
Hepatorenal syndrome (HRS) is a functional renal failure without renal pathology. It occurs in 10% of
patients with advanced cirrhosis or acute liver failure. It is caused by poorly understood renal
vasoconstriction. Type 1 HRS is characterized by a progressive loss of renal function and a significant
14
reduction in creatinine clearance within 1-2 weeks of presentation. It is associated with a very poor
prognosis. Type 2 HRS is fairly stable and associated with a better outcome than type 1 HRS, although
both types have a poor prognosis unless a transplant can be achieved in a short time.
Prognosis
A current standard method for determining prognosis is MELD (Model for End-stage Liver Disease)
The MELD Score predicts three-month survival in patients (age 12+) with liver cirrhosis. Scores range
from 6 to 40, with higher scores correlating with increased severity of liver dysfunction and higher threemonth
mortality. It is preferable to use the calculator to calculate the MELD. Try it out here and see what
facts and values it evaluates: https://www.mdcalc.com/meld-score-model-end-stage-liver-disease-12-
older.
There is an older model called the Child-Pugh score. Some physicians still use it, but MELD has a
better prognostic value.
15
4. References
1. Jameson, J. L., Kasper, D. L., Fauci, A. S., Hauser, S. L., Longo, D. L., Loscalzo, J., &amp;
Harrison, T. R. (2018). Harrison's principles of internal medicine, 20e. New York: McGraw-Hill
Education.
2. Češka, R., Štulc, T., Tesař, V., &amp; Lukáš, M. (2015). Interna. V Praze: Stanislav Juhaňák -
Triton.
3. Longmore, J. M., Wilkinson, I. B., Baldwin, A., &amp; Wallin, E. (2014). Oxford handbook of
clinical medicine. Oxford: Oxford Univ. Press.
4. Sabatine, M. S. (2020). Pocket medicine: The Massachusetts General Hospital handbook of
internal medicine. Philadelphia: Wolters Kluwer.
16
5. Annex
(a) Overview of liver diseases
Disease Main diagnostic tests or findings
Inherited hyperbilirubinemia
Gilbert syndrome mild unconjugated hyperbilirubinemia
Crigler-Najjar syndrome, types I and II unconjugated hyperbilirubinemia
Dubin-Johnson syndrome conjugated hyperbilirubinemia
Rotor syndrome conjugated hyperbilirubinemia
Viral hepatitis
Hepatitis A Anti-HAV IgM
Hepatitis B - acute HBsAg and anti-HBc IgM
Hepatitis B - chronic HBsAg and HBeAg and/or HBV DNA
Hepatitis C Anti-HCV and HCV RNA
Hepatitis D HBsAg and anti-HDV
Hepatitis E Anti-HEV IgM and HEV RNA
Others (Epstein-Barr virus [mononucleosis]
herpesvirus, cytomegalovirus, adenovirus)
Cryptogenic hepatitis
Immune and autoimmune liver diseases
Primary biliary cholangitis
Mitochondrial antibody, elevated IgM levels, and
compatible histology
Autoimmune hepatitis
ANA or SMA, elevated IgG levels, and
compatible histology
Sclerosing cholangitis P-ANCA, cholangiography
Graft-versus-host disease
Allograft rejection
Genetic liver diseases
α1 antitrypsin deficiency
Reduced α1 antitrypsin levels, phenotype PiZZ
or PiSZ
Hemochromatosis
Elevated iron saturation and serum ferritin;
genetic testing for HFE gene mutations
Wilson disease
Decreased serum ceruloplasmin and increased
urinary copper; increased hepatic copper level
Benign recurrent intrahepatic cholestasis history of pruritus attacks
Progressive familial intrahepatic
cholestasis, types I–III
Others (galactosemia, tyrosinemia, cystic
fibrosis, Niemann-Pick-disease, Gaucher’s
disease)
Alcoholic liver disease
History of excessive alcohol intake and
compatible histology
Acute fatty liver
Acute alcoholic hepatitis
Laënnec cirrhosis
Nonalcoholic fatty liver
Ultrasound or CT evidence of fatty liver and/or
compatible histology
Steatosis
Steatohepatitis
Acute fatty liver of pregnancy
Liver involvement in systemic diseases
17
Sarcoidosis
Amyloidosis
Glycogen storage diseases
Celiac disease
Tuberculosis
Mycobacterium avium-intracellulare
infection
Cholestatic syndromes hyperbilirubinaemia, elevated liver tests
Benign postoperative cholestasis
Jaundice of sepsis
Total parenteral-nutrition-induced–induced
jaundice
Cholestasis of pregnancy
Cholangitis and cholecystitis
Extrahepatic biliary obstruction (stone,
stricture, cancer)
Biliary atresia
Caroli disease
Cryptosporidiosis
Drug-induced liver disease History of drug ingestion
Hepatocellular patterns (isoniazid,
acetaminophen) very high aminotransferases
Cholestatic patterns (methyltestosterone) high ALP, GMT
Mixed patterns (sulfonamides, phenytoin)
Micro- and macrovesicular steatosis
(methotrexate, fialuridine)
Vascular injury
Sinusoidal obstruction syndrome
Budd-Chiari syndrome
Ischemic hepatitis
Passive congestion
Portal vein thrombosis
Nodular regenerative hyperplasia
Mass lesions
Hepatocellular carcinoma
Elevated α-fetoprotein level (to >500 ng/mL);
ultrasound or CT image of mass
Cholangiocarcinoma
Adenoma
Focal nodular hyperplasia
Metastatic tumours
Abscess
Cysts
Hemangioma