DIFFERENCIAL DIAGNOSIS OF LIVER FAILURE AND

JAUNDICE

INITIAL EVALUATION
The initial evaluation includes obtaining a history to identify potential risk factors for liver disease
and performing a physical examination to look for clues to the etiology and for signs of chronic
liver disease. Subsequent testing is determined based on the information gathered from the history
and physical examination as well as the pattern of test abnormalities.
History — A thorough medical history is central to the evaluation of a patient with abnormal liver
tests. The history should determine if the patient has had exposure to any potential hepatotoxins
(including alcohol and medications), is at risk for viral hepatitis, has other disorders that are
associated with liver disease, or has symptoms that may be related to the liver disease or a possible
predisposing condition.
Risk factors for viral hepatitis include potential parenteral exposures (eg, intravenous drug use,
blood transfusion prior to 1992), travel to areas endemic for hepatitis, and exposure to patients with
jaundice. Hepatitis B and C are transmitted parenterally, whereas hepatitis A and E are transmitted
from person to person via a fecal-oral route (often via contaminated food).
Patients should be asked about conditions that are associated with hepatobiliary disease, such as
right-sided heart failure (congestive hepatopathy), diabetes mellitus, skin pigmentation, arthritis,
hypogonadism and dilated cardiomyopathy (hemochromatosis), and obesity (nonalcoholic fatty
liver disease), pregnancy (gallstones), inflammatory bowel disease (primary sclerosing cholangitis,
gallstones), early onset emphysema (alpha-1 antitrypsin deficiency).
Finally, patients should be questioned about occupational or recreational exposure to hepatotoxins
(eg, mushroom picking).
Physical examination — The physical examination may suggest the presence of liver disease and
may point to the underlying cause of the liver disease.
●Temporal and proximal muscle wasting suggest longstanding disease.
●Stigmata of liver disease include spider nevi, palmar erythema, gynecomastia, and caput
medusae.
●Ascites or hepatic encephalopathy may be seen in patients with decompensated cirrhosis.
●Dupuytren's contractures, parotid gland enlargement, and testicular atrophy are commonly
seen in advanced alcoholic cirrhosis and occasionally in other types of cirrhosis.
●An enlarged left supraclavicular node (Virchow's node) or periumbilical nodule (Sister Mary
Joseph's nodule) suggest an abdominal malignancy.
●Increased jugular venous pressure, a sign of right-sided heart failure, suggests hepatic
congestion.
●A right pleural effusion, in the absence of clinically apparent ascites, may be seen in
advanced cirrhosis.
●Neurologic and psychiatric signs and symptoms may be seen in patients with Wilson disease.
●A history of fever, particularly when associated with chills or right upper quadrant pain
and/or a history of prior biliary surgery, is suggestive of acute cholangitis.
●Symptoms such as anorexia, malaise, and myalgias may suggest viral hepatitis.
●Right upper quadrant pain suggests extrahepatic biliary obstruction.

The physical examination may reveal a Courvoisier sign (a palpable gallbladder, caused by
obstruction distal to the takeoff of the cystic duct by malignancy) or signs of chronic liver
failure/portal hypertension such as ascites, splenomegaly, spider angiomata, and gynecomastia.
Certain findings suggest specific diseases, such as hyperpigmentation in hemochromatosis, Kayser-
Fleischer rings in Wilson disease, and xanthomas in primary biliary cholangitis.

The abdominal examination should focus on the size and consistency of the liver, the size of the
spleen and an assessment for. A grossly enlarged, hard, nodular liver or an obvious abdominal mass
suggests malignancy. An enlarged, tender liver could be due to viral or alcoholic hepatitis or, less
often, an acutely congested liver secondary to right-sided heart failure or Budd-Chiari syndrome.
Severe right upper quadrant tenderness with a positive Murphy's sign (respiratory arrest on
inspiration while pressing on the right upper quadrant) suggests cholecystitis or, occasionally,
ascending cholangitis. Ascites in the presence of jaundice suggests either cirrhosis or malignancy
with peritoneal spread.

Laboratory tests — The pattern of liver test abnormalities may suggest that the underlying cause
of the patient's liver disease is primarily the result of hepatocyte injury (elevated aminotransferases)
or cholestasis (elevated alkaline phosphatase). In addition, the magnitude of the liver test
abnormalities and the ratio of the aspartate aminotransferase (AST) to alanine aminotransferase
(ALT) may make certain diagnoses more or less likely. ALT is a more specific marker of hepatic
injury as compared with AST.

Abnormal liver biochemical and function tests are frequently detected in asymptomatic patients.
ALT and AST, alkaline phosphatase and bilirubin are biochemical markers of liver injury. Albumin,
bilirubin, and prothrombin time are markers of hepatocellular function.
Elevations of liver enzymes often reflect damage to the liver or biliary obstruction, whereas an
abnormal serum albumin or prothrombin time may be seen in the setting of impaired hepatic
synthetic function.

Liver enzymes — Liver enzymes that are commonly measured in the serum include:
● ALT and AST
●Alkaline phosphatase
●Gamma-glutamyl transpeptidase (GGT)
●Lactate dehydrogenase (LDH).

Function tests — Tests of hepatic synthetic function include:

●Serum albumin
●Prothrombin time/international normalized ratio

Patterns of liver test abnormalities — Liver test abnormalities can often be grouped into one of
several patterns: the abnormalities may be acute, subacute, or chronic based on whether they have
been present for less than six weeks (acute), six weeks to six months (subacute), or more than six
months (chronic). Based on the pattern of elevation, liver test abnormalities may be grouped as
hepatocellular, cholestatic, or isolated hyperbilirubinemia.
●Hepatocellular pattern:
•Disproportionate elevation in the serum aminotransferases compared with the alkaline
phosphatase
•Serum bilirubin may be elevated
•Tests of synthetic function may be abnormal
●Cholestatic pattern:
•Disproportionate elevation in the alkaline phosphatase compared with the serum
aminotransferases
•Serum bilirubin may be elevated
•Tests of synthetic function may be abnormal
 ●Isolated hyperbilirubinemia: As the term implies, patients with isolated hyperbilirubinemia
have an elevated bilirubin level with normal serum aminotransferases and alkaline phosphatase

Abnormal tests of synthetic function may be seen with both hepatocellular injury and cholestasis. A
low albumin suggests a chronic process, such as cirrhosis or cancer, while a normal albumin
suggests a more acute process, such as viral hepatitis or choledocholithiasis. A prolonged
prothrombin time indicates either vitamin K deficiency due to prolonged jaundice and intestinal
malabsorption of vitamin K or significant hepatocellular dysfunction..
AST to ALT ratio — Most causes of hepatocellular injury are associated with a serum AST level
that is lower than the ALT. An AST to ALT ratio of 2:1 or greater is suggestive of alcoholic liver
disease, particularly in the setting of an elevated gamma-glutamyl transpeptidase. However, the
AST to ALT ratio is occasionally elevated in an alcoholic liver disease pattern in patients with
nonalcoholic steatohepatitis, and it is frequently elevated (although not greater than two) in patients
with hepatitis C who have developed cirrhosis. In addition, patients with Wilson disease or cirrhosis
due to viral hepatitis may have an AST that is greater than the ALT, although in patients with
cirrhosis the ratio typically is not greater than two.

JAUNDICE
The normal serum bilirubin concentration is less than 17 micromol/liter. Jaundice is often used
interchangeably with hyperbilirubinemia. However, a careful clinical examination cannot detect
jaundice until the serum bilirubin is greater than 34 micromol/liter, twice the normal upper limit.
Under normal circumstances, bilirubin undergoes conjugation within the liver, making it water-
soluble. It is then excreted via the bile into the GI tract, the majority of which is egested in the
faeces as urobilinogen and stercobilin (the metabolic breakdown product of urobilingoen). Around
10% of urobilinogen is reabsorbed into the bloodstream and excreted through the
kidneys. Jaundice occurs when this pathway is disrupted.

Types of Jaundice
There are three main types of jaundice: pre-hepatic, hepatocellular, and post-hepatic.

Pre-Hepatic
In pre-hepatic jaundice, there is excessive red cell breakdown which overwhelms the liver’s ability
to conjugate bilirubin. This causes an unconjugated hyperbilirubinaemia.Any bilirubin that manages
to become conjugated will be excreted normally, yet it is the unconjugated bilirubin that remains in
the blood stream to cause the jaundice.

Hepatocellular
In hepatocellular (or intrahepatic) jaundice, there is dysfunction of the hepatic cells. The liver loses
the ability to conjugate bilirubin, but in cases where it also may become cirrhotic, it compresses the
intra-hepatic portions of the biliary tree to cause a degree of obstruction. This leads to both
unconjugated and conjugated bilirubin in the blood, termed a ‘mixed picture’.

Post-Hepatic
Post-hepatic jaundice refers to obstruction of biliary drainage. The bilirubin that is not excreted will
have been conjugated by the liver, hence the result is a conjugated hyperbilirubinaemia. Types of
jaundice are presented in the table 1.
 PRE-HEPATIC HEPATIC POST-HEPATIC
(Hemolytic) (Hepatocellular) (Obstructive)
Serum Unconjugated bilirubin ↑↑↑ Conjugated bilirubin ↑↑ Conjugated bilirubin ↑↑↑
bilirubin Unconjugated bilirubin ↑ Unconjugated bilirubin ↑
Urine colour Normal/Dark Norma/Dark Dark
Stool colour Dark Normal/Pale Subacholic/Acholic
(Subacholic) (Pale or white)
Table 1. Types of jaundice

DISORDERS ASSOCIATED WITH UNCONJUGATED HYPERBILIRUBINEMIA

Three basic pathophysiologic mechanisms, overproduction of bilirubin, reduced bilirubin uptake,
and impaired bilirubin conjugation, are mainly responsible for unconjugated hyperbilirubinemia.
Overproduction of bilirubin — Bilirubin overproduction may result from excessive breakdown of
heme derived from hemoglobin. Extravascular or intravascular hemolysis, extravasation of blood in
tissues, or dyserythropoiesis are causes of enhanced heme catabolism.
Impaired hepatic bilirubin uptake — Impaired delivery of bilirubin to the liver and disorders of
internalization of bilirubin by the hepatocyte result in reduced hepatic bilirubin uptake. Congestive
heart failure or portosystemic shunts (spontaneously occurring collaterals in cirrhosis or surgical
shunts) reduce hepatic blood flow and the delivery of bilirubin to hepatocytes, resulting in
predominantly unconjugated hyperbilirubinemia.
Other causes of abnormal bilirubin uptake include administration of several drugs (eg, rifamycin
antibiotics, probenecid).
Impaired bilirubin conjugation — Reduced bilirubin conjugation as a result of a decreased or
absent UDP-glucuronosyltransferase activity is found both in several acquired conditions and
inherited diseases, such as Crigler-Najjar syndrome, type I and II and Gilbert syndrome. UGT
activity toward bilirubin is modulated by various hormones. Hyperthyroidism and ethinyl estradiol,
but not other oral contraceptives, inhibit bilirubin glucuronidation. Reduced bilirubin
glucuronidation by liver tissue has been reported in chronic persistent hepatitis, advanced cirrhosis,
and Wilson's disease.

DISORDERS ASSOCIATED WITH CONJUGATED HYPERBILIRUBINEMIA

Avariety of acquired disorders with conjugated hyperbilirubinemia can be categorized according to
their histopathology and pathophysiology: biliary obstruction (extrahepatic cholestasis), intrahepatic
cholestasis, and hepatocellular injury.
Biliary obstruction — In biliary obstruction, both conjugated and unconjugated bilirubin
accumulate in serum. The serum concentrations of conjugated bilirubin and alkaline phosphatase
can be used as markers for hepatobiliary obstruction. The diagnosis can usually be established with
the help of noninvasive and invasive imaging techniques.
Differential diagnosis of conjugated hyperbilirubinemia due to biliary obstruction is age dependent.
In adults, it includes cholelithiasis, intrinsic and extrinsic tumors, primary sclerosing cholangitis
(PSC), parasitic infections, lymphoma, acute and chronic pancreatitis, and strictures after invasive
procedures.
Intrahepatic causes — A number of intrahepatic disorders can lead to jaundice and an elevated
serum alkaline phosphatase (in relation to serum aminotransferases). This presentation mimics that
of biliary obstruction but the bile ducts are patent.
Viral hepatitis — Viral hepatitis can present as a predominantly cholestatic syndrome with marked
pruritus. Unless the patient has risk factors for viral hepatitis, it is difficult to distinguish this
clinically from other causes of cholestasis.
Alcoholic hepatitis — Cholestasis with fever and leukocytosis is often the distinctive sign of
alcoholic hepatitis. The diagnosis should be strongly considered in the jaundiced patient with
ethanol dependency, especially if the ratio of serum AST to ALT exceeds 2.0.
Nonalcoholic steatohepatitis — Nonalcoholic steatohepatitis has features similar to alcoholic
hepatitis both in terms of histology and signs of cholestasis. A variety of conditions such as diabetes
mellitus, morbid obesity can cause this disorder.
Primary biliary cholangitis — Primary biliary cholangitis typically presents with a cholestatic
picture, though evidence of hepatocellular injury also exists.
Sepsis and low perfusion states — Bacterial sepsis is very often accompanied by cholestasis.
Multiple factors including hypotension, drugs, and bacterial endotoxins are responsible for the
jaundice in these patients.
Liver infiltration — Infiltrative processes of the liver (eg, amyloidosis, lymphoma, sarcoidosis,
tuberculosis) can precipitate intrahepatic cholestasis.
Inherited diseases — Elevated levels of conjugated bilirubin may occur in inherited diseases such
as Dubin-Johnson syndrome, Rotor syndrome.
Total parenteral nutrition — Steatosis, lipidosis, and cholestasis are frequently encountered in
patients receiving total parenteral nutrition (TPN). This complication usually requires at least two to
three weeks of therapy for the development of cholestasis. The underlying illness, preexisting liver
disease, hepatotoxic drugs, and the TPN itself all may contribute to the cholestasis.
Postoperative patient — Jaundice occurs regularly in postoperative patients and is usually
multifactorial in origin. Serum unconjugated bilirubin levels may increase because of blood
transfusions, hematoma resorption, and hemolysis after heart surgery. Other contributing factors
include sepsis, TPN, the administration of hepatotoxic drugs during surgery, postoperative hypoxia,
hypotension, or a newly acquired viral hepatitis.
End-stage liver disease — The hallmarks of end-stage liver disease and cirrhosis, regardless of its
etiology, include jaundice with an elevation of both conjugated and unconjugated bilirubin as well
as portal hypertension and decreased hepatic synthetic function. Most common causes of liver
failure and jaundice are presented in the table 2.

Unconjugated hyperbilirubinemia Conjugated hyperbilirubinemia

Increased bilirubin production Dubin-Johnson syndrome
Extravascular hemolysis Rotor syndrome
Extravasation of blood into tissues Extrahepatic cholestasis (biliary obstruction)
Intravascular hemolysis Choledocholithiasis
Intrinsic and extrinsic tumors (eg,
Impaired hepatic bilirubin uptake
cholangiocarcinoma, pancreatic cancer)
Heart failure Primary sclerosing cholangitis
Portosystemic shunts Acute and chronic pancreatitis
Some patients with Gilbert syndrome Strictures after invasive procedures
Certain parasitic infections (eg, Ascaris
Certain drugs – Rifampin, probenecid
lumbricoides, liver flukes)
Impaired bilirubin conjugation Intrahepatic cholestasis
Crigler-Najjar syndrome types I and II Viral hepatitis
Gilbert syndrome Alcohol-associated hepatitis
Neonates Non-alcohol-associated steatohepatitis
Hyperthyroidism Chronic hepatitis
Liver diseases – Chronic hepatitis, advanced Primary biliary cholangitis
cirrhosis
Drugs and toxins
Sepsis and hypoperfusion states
Infiltrative diseases (eg, amyloidosis,
lymphoma, sarcoidosis, tuberculosis)
Total parenteral nutrition
Postoperative cholestasis
Following organ transplantation
Pregnancy
End-stage liver disease
Table 2. Causes of liver failure and jaundice

VIRAL HEPATITIS
Several viruses have been associated with acute liver failure, including hepatitis A, B, C, D, and E.
In addition, acute liver failure can be seen with herpes simplex virus, varicella zoster virus, Epstein-
Barr virus, adenovirus, and cytomegalovirus.

ALCOHOL-ASSOCIATED LIVER DISEASE

Alcohol-associated liver disease (ALD) includes several liver disorders, including alcoholic
hepatitis, alcohol-associated steatosis, alcohol-associated steatohepatitis, and alcohol-associated
cirrhosis.
Signs and symptoms — Patients with alcohol-associated fatty liver are typically asymptomatic.
Patients who have developed cirrhosis may report jaundice, weakness, peripheral edema, abdominal
distension, or symptoms of gastrointestinal bleeding, such as hematemesis or melena. Patients with
hepatic encephalopathy may note disturbances in their sleep pattern and confusion.
Physical examination findings — Physical examination findings in patients with ALD range from
a normal physical examination to evidence of cirrhosis with hepatic decompensation. Patients with
steatosis may have a normal examination or hepatomegaly. Patients who have developed cirrhosis
may have stigmata of chronic liver disease (eg, spider angiomata, palmar erythema, gynecomastia).
With hepatic decompensation, patients may develop ascites, peripheral edema, or hepatic
encephalopathy.Patients with ALD often have coexisting dysfunction in other organs and may have
signs of cardiomyopathy, neuropathies, pancreatic dysfunction, and skeletal muscle wasting.
Laboratory tests — There are several characteristic laboratory abnormalities in patients with ALD,
but none are diagnostic, classic finding are:

 Serum AST>ALT (ratio usually >2.0)

 Elevated serum GGT
 High MCV
Radiographic imaging — Transabdominal ultrasound, abdominal computed tomography, and
abdominal magnetic resonance imaging may show signs of hepatic steatosis or cirrhosis in patients
with ALD.
Diagnosis – Alkohol-associated liver disease may be suspected in a patient with a compatible
history who has elevated serum aminotransferases, a suggestion of fatty liver on imaging tests, or is
found to have steatosis on liver biopsy. Liver tests are generally normal or modestly elevated, and
jaundice is unusual.
Clinical and laboratory features are often adequate for establishing the diagnosis of ALD in a
patient with a history of excessive alcohol use, provided the patient does not have risk factors for
other causes of liver disease and testing for other common causes of liver disease is negative. A
liver biopsy may be required if the diagnosis remains uncertain following a noninvasive evaluation.
In addition, it can establish the severity of liver disease.

Treatment - Goals for patients with ALD include:

 Establishing and maintaining abstinence from alcohol
 Stabilizing liver function
 For patients with cirrhosis, screening for complications (eg, varices)
The cornerstone of managing ALD is abstinence from alcohol because abstinence has been
associated with improvement in hepatic steatosis, hepatic fibrosis, and survival.

CIRRHOSIS (ANY ETHIOLOGY)

Cirrhosis represents a late stage of progressive hepatic fibrosis characterized by distortion of the
hepatic architecture and the formation of regenerative nodules.
Clinical manifestation - The clinical manifestations of cirrhosis may include nonspecific
symptoms (eg, anorexia, weight loss, weakness, fatigue) or signs and symptoms of hepatic
decompensation (jaundice, pruritus, signs of upper gastrointestinal bleeding, abdominal distension
from ascites, confusion due to hepatic encephalopathy). Physical examination findings may include
jaundice, spider angiomata, gynecomastia, ascites, splenomegaly, palmar erythema, digital
clubbing, and asterixis. Laboratory abnormalities may include elevated serum bilirubin, abnormal
aminotransferases, elevated alkaline phosphatase/gamma-glutamyl transpeptidase, a prolonged
prothrombin time/elevated international normalized ratio (INR), hyponatremia, hypoalbuminemia,
and thrombocytopenia.
Symptoms - Patients with compensated cirrhosis may be asymptomatic or they may report
nonspecific symptoms, such as anorexia, weight loss, weakness, and fatigue. Patients with
decompensated cirrhosis may present with jaundice, pruritus, signs of upper gastrointestinal
bleeding (hematemesis, melena), abdominal distension from ascites, or confusion due to hepatic
encephalopathy. Men with cirrhosis may develop hypogonadism. It is manifested by impotence,
infertility, loss of sexual drive, and testicular atrophy. It is a feature seen predominantly in patients
with alcoholic cirrhosis and hemochromatosis. Head and neck findings in patients with cirrhosis
may include parotid gland enlargement and fetor hepaticus. Parotid gland enlargement is typically
seen in patients with alcoholic liver disease and is probably due to alcohol, not cirrhosis per se.
Gynecomastia is seen in up to two-thirds of patients with cirrhosis. Findings on abdominal
examination include hepatomegaly, splenomegaly, ascites, caput medusae. Findings on examination
of the extremities of a patient with cirrhosis may include palmar erythema, nail changes, clubbing,
Dupuytren's contracture
Laboratory findings — laboratory abnormalities may be the first indication that a patient has
cirrhosis. Common abnormalities include elevated serum bilirubin, abnormal aminotransferases,
elevated alkaline phosphatase/gamma-glutamyl transpeptidase, a prolonged prothrombin
time/elevated international normalized ratio (INR), hyponatremia, and thrombocytopenia
Radiologic findings — Radiologic studies such as abdominal ultrasound, computed tomography
scan, and magnetic resonance imaging may suggest the presence of cirrhosis. Findings may include
a liver that appears shrunken, irregular, and nodular. Imaging studies may also show evidence of
varices and ascites in patients with portal hypertension.
A liver biopsy is required to definitively confirm the diagnosis of cirrhosis. However, it is generally
not necessary if the clinical, laboratory, and radiologic data strongly suggest the presence of
cirrhosis and the results would not alter the patient's management.

Major complications of cirrhosis include:

 Variceal hemorrhage
 Ascites
 Spontaneous bacterial peritonitis
 Hepatic encephalopathy
 Hepatocellular carcinoma
 Hepatorenal syndrome
 Hepatopulmonary syndrome

Variceal hemorrhage — Patients with variceal hemorrhage typically present with hematemesis
and/or melena. It is typically treated with endoscopic variceal band ligation.
Ascites — Ascites is the accumulation of fluid within the peritoneal cavity. It is the most common
complication of cirrhosis. The first step leading to fluid retention and ultimately ascites in patients
with cirrhosis is the development of portal hypertension. Patients without portal hypertension do not
develop ascites or edema. Ascites is typically treated with a combination of diuretics and sodium
restriction, though some patients require repeated therapeutic paracenteses.
Hepatic encephalopathy — Hepatic encephalopathy describes the spectrum of potentially
reversible neuropsychiatric abnormalities seen in patients with liver dysfunction.
Treatments for hepatic encephalopathy include addressing any predisposing conditions (eg,
infection or gastrointestinal bleeding), synthetic disaccharides (eg, lactulose).

NONALCOHOLIC FATTY LIVER DISEASE (NAFLD)

Nonalcoholic fatty liver disease refers to the presence of hepatic steatosis when no other causes for
secondary hepatic fat accumulation (eg, heavy alcohol consumption) are present. NAFLD may
progress to cirrhosis.
NAFLD is subdivided into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis
(NASH).
Most patients with NAFLD are asymptomatic, although some patients with NASH may complain of
fatigue, malaise, and vague right upper abdominal discomfort. Patients are more likely to come to
attention because laboratory testing revealed elevated liver aminotransferases or hepatic steatosis
was detected incidentally on abdominal imaging.
Patients with NAFLD may have mild or moderate elevations in the aspartate aminotransferase and
alanine aminotransferase, although normal aminotransferase levels do not exclude NAFLD.
Radiographic findings in patients with NAFLD include increased echogenicity on ultrasound,
decreased hepatic attenuation on computed tomography, or an increased fat signal on magnetic
resonance imaging.
A definitive diagnosis of NAFLD requires all of the following:
 Demonstration of hepatic steatosis by imaging or biopsy
 Exclusion of significant alcohol consumption
 Exclusion of other causes of hepatic steatosis
 Absence of coexisting chronic liver disease
Radiologic findings are often sufficient to make a diagnosis of NAFLD, provided other causes of
hepatic steatosis have been excluded. However, liver biopsy may be indicated if the diagnosis is not
clear or to assess the degree of hepatic injury.

DRUG-INDUCED LIVER INJURY (DILI)

Liver injury can develop following the use of many drugs. The most common drug implicated in
DILI-associated acute liver failure is acetaminophen, followed by antibiotics,
Worldwide, amoxicillin-clavulanate is one of the most commonly reported causes of DILI. DILI
can be classified in several ways, including by its clinical presentation (hepatocellular injury,
cholestatic injury, or mixed injury), the mechanism of hepatotoxicity (predictable or idiosyncratic),
and the histologic findings (eg, hepatitis, cholestasis, and steatosis).
Many patients with DILI are asymptomatic and are only detected because of laboratory testing.
Patients with acute DILI who are symptomatic may report malaise, low-grade fever, anorexia,
nausea, vomiting, right upper quadrant pain, jaundice, acholic stools, or dark urine. In addition,
patients with cholestasis may have pruritus. In severe cases, hepatic encephalopathy may develop,
indicating acute liver failure. Patients with chronic DILI may go on to develop significant fibrosis
or cirrhosis and have signs and symptoms associated with cirrhosis or hepatic decompensation (eg,
jaundice, ascites).
Patients with DILI-associated hepatocellular injury have a disproportionate elevation of their
aminotransferases, whereas patients with cholestatic injury predominantly have an elevation of their
alkaline phosphatase (ALP). Serum bilirubin may be elevated both with hepatocellular and
cholestatic injury.
The primary treatment for DILI is withdrawal of the offending drug and monitoring to ensure the
liver tests normalize. Recovery will occur in the majority of patients with DILI once the offending
medication is stopped. Patients with acetaminophen poisoning can be treated with antidote - N-
acetylcysteine.

CHOLEDOCHOLITHIASIS
Choledocholithiasis refers to the presence of gallstones within the common bile duct. Most patients
with choledocholithiasis are symptomatic, although occasional patients are asymptomatic.
Symptoms associated with choledocholithiasis include right upper quadrant or epigastric pain,
nausea, and vomiting.
On physical examination, patients with choledocholithiasis often have right upper quadrant or
epigastric tenderness. Patients may also appear jaundiced.
ALT and AST are typically elevated early in the course of biliary obstruction. Later, liver tests are
typically elevated in a cholestatic pattern, with elevations in serum bilirubin, alkaline phosphatase,
and gamma-glutamyl transpeptidase being more pronounced than those in ALT and AST.
Patients suspected of having choledocholithiasis are diagnosed with a combination of laboratory
tests and imaging studies. The first imaging study obtained is typically a transabdominal ultrasound.
Patients at high risk for having common bile duct stones and with an intact gallbladder generally
proceed to endoscopic retrograde cholangiopancreatography (ERCP) with stone removal, followed
by cholecystectomy.

PRIMARY BILIARY CHOLANGITIS

Primary biliary cholangitis (PBC) is rare condition. The vast majority of patients are women, and
most patients are diagnosed between the ages of 30 and 65 years (often in their 40s or 50s).
Patients with PBC may be asymptomatic, or they may present with symptoms such as fatigue and
pruritus. Other clinical manifestations include jaundice, cholestatic liver enzymes,
antimitochondrial antibodies (AMA), and signs and symptoms of cirrhosis.
Approximately 50 to 60 percent of patients with PBC are asymptomatic at diagnosis and are
detected because of abnormalities in liver biochemical tests obtained for other reasons. Among
patients with symptoms, fatigue and pruritus are most commonly seen.
The findings on physical examination in patients with PBC vary widely and depend on the stage of
the disease at time of presentation. The physical examination is often normal in patients who are
asymptomatic. Skin findings are common, such as hyperpigmentation, excoriations, xanthelasmas,
jaundice, dermatographism and fungal infections of the feet or nails.
Common laboratory test abnormalities in patients with PBC included an elevated alkaline
phosphatase, AMA, antinuclear antibodies (ANA), and hyperlipidemia.
A diagnosis of PBC is established if there is no extrahepatic biliary obstruction and at least two of
the following are present:
 An alkaline phosphatase at least 1.5 times the upper limit of normal
 Presence of AMA at a titre of 1:40 or higher
 Histologic evidence of PBC (nonsuppurative destructive cholangitis and destruction of
interlobular bile ducts)
While a liver biopsy is often not required to make the diagnosis, it provides useful information with
regard to staging and prognosis.
Ursodeoxycholic acid (UDCA) is a first-line therapy. Liver transplantation is an option for patients
with progressive disease despite medical therapy.

PRIMARY SCLEROSING CHOLANGITIS

Primary sclerosing cholangitis (PSC) is usually a progressive disorder that ultimately leads to
complications of cholestasis and hepatic failure. Median survival without liver transplantation after
diagnosis is 10 to 12 years.
Patients with PSC may be asymptomatic and diagnosed as part of the evaluation of abnormal
laboratory tests, or they may have symptoms such as fatigue and pruritus. Physical examination
may reveal jaundice, hepatomegaly, splenomegaly, and excoriations, though it is often normal.
Liver biochemical tests usually demonstrate a cholestatic pattern, with elevation of the serum
alkaline phosphatase predominating in most patients.
Radiographic findings include abnormal appearing bile ducts with wall thickening, dilations, and
strictures.
PSC should be considered in patients with a cholestatic pattern of liver test abnormalities
(particularly an elevated alkaline phosphatase), especially those with underlying inflammatory
bowel disease. The diagnosis is then made by showing cholangiographic evidence of characteristic
bile duct changes (multifocal strictures, segmental dilations). A percutaneous liver biopsy may
support the diagnosis of PSC, but it is rarely diagnostic. In patients with characteristic findings on
cholangiography, a liver biopsy is typically not required.
Ursodeoxycholic acid is a first-line medical therapy. Liver transplantation is now the treatment of
choice for patients with advanced liver disease secondary to PSC.

WILSON DISEASE
Wilson disease is a genetic disorder of copper metabolism with an autosomal recessive pattern of
inheritance.Impaired biliary copper excretion leads to accumulation of copper in several organs,
most notably the liver, brain, and cornea.
The clinical manifestations of Wilson disease are predominantly hepatic, neurologic, and
psychiatric, with many patients having a combination of symptoms.
The majority of patients with Wilson disease are diagnosed between the ages of 5 and 35.
Hepatic manifestations include acute liver failure with a Coombs-negative hemolytic anemia, acute
hepatitis, chronic hepatitis, cirrhosis, steatosis, and asymptomatic liver biochemical abnormalities.
The reported neurologic manifestations of Wilson disease are broad, and diagnosing neurologic
Wilson disease can be challenging because patients present in many different ways. The majority of
patients with neurologic Wilson disease have dysarthria and/or movement disorders. Behavioral and
psychiatric symptoms are more common in patients with neurologic involvement than in patients
with hepatic involvement. The most common behavioral and psychiatric symptoms include
depression, personality change, incongruous behavior, and irritability.
Other clinical manifestations of Wilson disease include Coombs-negative hemolytic anemia and
Kayser-Fleischer rings.
In patients with clinical features suggestive of Wilson disease, liver biochemical tests, a complete
blood count, serum ceruloplasmin and copper levels, an ocular slit-lamp examination, and a 24-hour
urinary copper excretion should be made.
Untreated, Wilson disease is universally fatal. Copper accumulation in the liver eventually leads to
the development of cirrhosis, and among patients with neurologic Wilson disease, the neurologic
disease may progress until the patient becomes severely dystonic, akinetic, and mute. The majority
of patients will die from liver disease (cirrhosis or acute liver failure).
The prognosis for patients who receive and are adherent to treatment for Wilson disease is
excellent.

HEREDITARY HEMOCHROMATOSIS
Hereditary hemochromatosis (HH) is a genetic (autosomal recessive) disorder in which increased
intestinal iron absorption can lead to total-body iron overload.
Clinical manifestations of HH generally do not occur until after the age of 40 years in men and after
menopause in women. Nonspecific symptoms such as fatigue, lethargy, and apathy are common, as
are symptoms attributable to iron overload in specific organs. The liver, heart, and pituitary gland
are common sites of iron overload. Untreated, patients can develop cirrhosis, hepatocellular cancer,
heart failure, arrhythmias, type 2 diabetes, hypogonadism, cognitive changes, arthropathy, and
bronze-colored skin.
Evaluation and diagnosis – In most cases, the initial test is serum iron studies (elevated transferrin
saturation, serum ferritin, iron). For those with evidence of iron overload, liver function tests
and HFE mutation testing are appropriate. Magnetic resonance imaging is generally used
determining both hepatic as well as cardiac iron deposition.
Management - Removing excess iron, typically by phlebotomy, is the mainstay of treatment for
individuals with HH who have iron overload.

CHOLANGIOCARCINOMA
The term cholangiocarcinoma is used to designate bile duct cancers arising in the intrahepatic or
extrahepatic biliary tree, exclusive of the gallbladder or ampulla of Vater.
Most patients with extrahepatic cholangiocarcinoma present with painless jaundice, right upper
quadrant abdominal pain, and weight loss. Patients with intrahepatic cholangiocarcinoma are less
likely to be jaundiced. The development of cholangiocarcinoma in a patient with primary sclerosing
cholangitis (PSC) is often heralded by rapid clinical deterioration with declining performance
status, in addition to jaundice, weight loss, and abdominal pain.
The initial study is usually a contrast-enhanced magnetic resonance imaging (MRI) scan/magnetic
resonance cholangiopancreatography (MRCP) or a multiphasic contrast-enhanced multidetector-
row computed tomography (MDCT).
All patients with suspected cholangiocarcinoma should have tumor markers (CA 19-9, CEA, alpha-
fetoprotein) checked. Elevated tumor markers may support a diagnosis of cholangiocarcinoma or, in
the case of an elevated AFP, suggest an alternative diagnosis (hepatocellular carcinoma). A tissue
diagnosis can be obtained by a variety of means in patients suspected of having cholangiocarcinoma
(brush cytology, FNA, computed tomography/MRI-guided biopsy).
HEPATOCELLULAR CARCINOMA
Hepatocellular carcinoma (HCC) is a primary tumor of the liver that usually develops in the setting
of chronic liver disease, particularly in patients with cirrhosis due to alcohol use, chronic hepatitis B
or C virus infections, or nonalcohol-associated steatohepatitis.
There is a range of clinical presentations for patients with HCC, from being asymptomatic to
presenting with a life-threatening illness such as variceal hemorrhage. Previously stable patients
with cirrhosis may develop features of decompensation (eg, variceal bleeding or ascites) due to the
extension of HCC into the hepatic or portal veins. Patients with HCC may develop a paraneoplastic
syndrome that can manifest as hypoglycemia, erythrocytosis, hypercalcemia, or severe diarrhea.
HCC can be diagnosed on contrast-enhanced CT, MRI, or US. HCC can sometimes be diagnosed
on imaging alone, obviating the need for biopsy.

PANCREATIC CANCER
More than 95 percent of malignant neoplasms of the pancreas arise from the exocrine elements and
are referred to as exocrine pancreatic cancers.Cancer of the exocrine pancreas is a highly lethal
malignancy.
The most common presenting symptoms in patients with exocrine pancreatic cancer are pain,
jaundice, and weight loss.
All patients presenting with jaundice or epigastric pain should have an assay of serum
aminotransferases, alkaline phosphatase, and bilirubin to determine if cholestasis is present. In
addition, patients with epigastric pain should be evaluated for acute pancreatitis with a serum lipase.
Patients who present with jaundice, or epigastric pain and weight loss often undergo right upper
quadrant transabdominal ultrasound initially to evaluate for dilated bile ducts or a pancreatic mass.
However, while transabdominal US has high sensitivity for detecting tumors >3 cm, it is much
lower for smaller tumors. For this reason abdominal computed tomography is often performed.
Endoscopic retrograde cholangiopancreatography is a highly sensitive tool for visualization of the
biliary tree and pancreatic ducts in patients with jaundice. An alternative approach is magnetic
resonance cholangiopancreatography. Given the limited sensitivity and specificity CA 19-9 should
not be used as a diagnostic test for pancreatic cancer. Histologic confirmation is required to
establish a diagnosis of pancreatic cancer.