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yellow discoloration of the sclera due to retention of bilirubin.


Bilirubin metabolism

Reticuloendothelial cells convert heme to bilirubin (85% from breakdown of senescent RBCs, 15% from hepatic heme or marrow RBC precursors).

Bilirubin is transported to the liver complexed to albumin (unconjugated bilirubin).

Bilirubin is conjugated with glucuronic acid in liver cells (conjugated bilirubin).

Conjugated bilirubin is excreted in bile (brown stools).


Unconjugated vs Conjugated bilirubin

Water insoluble
Bound to albumin
Toxic to tissues
Not excreted in urine.

Conjugated bilirubin:
Water soluble
Is not tightly bound to albumin when present in serum
Not toxic to tissues
Excreted in urine when present in serum at high levels (bilirubinuria).


Gilbert’s syndrome

Common (3-10%); autosomal recessive or autosomal dominant inheritance

Due to decreased glucuronyltransferase activity (UGT1A1 30% of normal).

Increased unconjugated bilirubin (


Intrahepatic cholestasis

Bile within hepatocytes
Canalicular bile stasis
Feathery degeneration of hepatocytes


Extrahepatic cholestasis (extrahepatic biliary obstruction)

Canalicular bile stasis
Feathery degeneration of hepatocytes
Bile within distended bile ducts, and occasionally “bile lakes”
Portal tract edema
Bile duct proliferation within portal tracts
Extrahepatic biliary obstruction may promote the development of ascending cholangitis, a secondary bacterial infection of the biliary tree



Virus preferentially infects liver cells (hepatotrophic virus).

HAV infection does not cause chronic hepatitis.

Hepatocellular injury is due to the patients cellular immune response (cytotoxic CD8+ T cells) and subsequent lysis of infected cells.

The viremia (virus in the blood) is transient, and because of this, blood products are rarely at risk and donor screening for HAV is not performed (fecal-oral transmission).

Majority of infections are subclinical (asymptomatic).

Some present clinically with acute hepatitis; .1% will develop fulminant hepatitis (acute liver failure) and may die.

Diagnosis is made by successful interpretation of the serologic profile.

Prevent the disease by vaccination.



Virus preferentially infects liver cells (hepatotrophic virus).

HBV infection has the potential to cause chronic hepatitis.

Hepatocellular injury is due to the patients cellular immune response (cytotoxic CD8+ T cells) and subsequent lysis of infected cells.

Virus is present in blood and body fluids (saliva, semen, vaginal secretions).

Transmission is parenteral, sexual/close contact, perinatal.

Diagnosis is made by successful interpretation of the serologic profile, to include nucleic acid testing if necessary (detecting viral DNA).

Prevent the disease by vaccination.

Majority of patients (70%) have asymptomatic infection (subclinical disease); 30% develop clinical acute hepatitis.

The majority of patients (90%) will have infections that resolve.

0.1-0.5% develop acute fulminant hepatitis with liver failure and may die.

Approximately 5% of exposed adults will develop chronic hepatitis. Some of these patients may eventually recover, but some will develop non-progressive chronic hepatitis B, some will develop progressive disease leading to cirrhosis, and some will develop hepatocellular carcinoma. Some individuals (particularly those exposed at childbirth) will develop an asymptomatic “healthy” carrier state.

Carrier state, defined as persistent HBV infection without significant ongoing necroinflammatory disease, typically occurs as a result of exposure at childbirth (perinatal transmission) or exposure as a young child (immune tolerance to HBV).



Defective single stranded RNA virus that causes hepatitis only in the presence of HBV. In order to replicate and form complete virions, HDV must be encapsulated by HBV.

HDV can infect an individual with chronic HBV (superinfection) or it can be transmitted simultaneously with HBV (acute coinfection). (Hint: to remember the difference, think that superinfection is an infection “superimposed” on an existing chronic infection).

Infection with HDV and HBV is more severe than HBV alone, with increased mortality in acute hepatitis and increased propensity to develop chronic hepatitis.

In USA, HDV largely restricted to IV drug users.

Diagnosis is made by successful interpretation of the serologic profile, to include nucleic acid testing if necessary (detecting viral RNA).

Prevent the disease by vaccination for HBV.

Acute coinfection of HBV and HDV results in acute hepatitis B + D. This entity is clinically indistinguishable from acute hepatitis B alone. While the acute hepatitis occurring in B + D acute coinfection is usually transient and self-limited, the severity of the acute hepatitis is increased, and there is an increased risk of acute liver failure, particularly in IV drug users (3-4%, compared to .1-.5% with HBV alone).

Rate of progression to chronic hepatitis in acute coinfection is no different than with acute HBV infection without HDV.

HDV superinfection may (1) convert mild chronic HBV hepatitis into acute liver failure (7-10%) (2) cause acute hepatitis to erupt in a healthy, inactive HBV carrier (3) lead to chronic hepatitis (80%, compared to 4% with HBV alone). An inactive HDV/HBV carrier state also exists.

In patients with HBV infection, testing for HDV should be considered in those who have risk factors (intravenous drug users and patients from endemic countries) or in those who present with unusually severe or protracted acute hepatitis, as well as those with acute hepatitis of undetermined origin occurring in a chronic HBV carrier.



HCV is a single stranded RNA virus discovered in 1989.

HCV is spread parenterally (blood, IV drug use), by sexual or close contact, rarely perinatally (32% unknown source).

Virus preferentially infects liver cells (hepatotrophic virus).

Hepatocellular injury is due to the patients cellular immune response (cytotoxic CD8+ T cells) and subsequent lysis of infected cells.

Acute liver failure is rare, developing in only 0.2%. 20% will develop acute hepatitis, which is usually asymptomatic, that resolves. Unfortunately, 80% will develop chronic hepatitis, with 20-30% developing cirrhosis if untreated. Chronic HCV infection accounts for almost half of all chronic liver disease in the USA and the number of cases are expected to triple in the next 20 years. Most patients with chronic viral hepatitis C are asymptomatic, and 30% may have a normal serum ALT.

Virus consists of 6 distinct genotypes and over 50 subtypes; in the USA, infection with genotype 1a is most common, followed by genotypes 1b, 2a, and 2b.

Some patients develop extrahepatic autoimmune manifestations/syndromes (cryoglobulinemia, membranoproliferative glomerulonephritis, thyroiditis).

Antibodies (anti-HCV) develop approximately 10 weeks following infection. Unfortunately, antibodies do not confer recovery or immunity in most patients (virus has a high mutation rate, enabling divergent strains in a single patient to escape from neutralizing antibodies). There is no vaccine.

Presence of antibodies does not distinguish between acute, chronic, or past infection. Diagnosis is established by antibody detection using immunoassays as a screening test, and if positive, active infection is confirmed by measuring viral load using tests that detect and quantitate HCV RNA by PCR; this test can also be used to assess response to therapy. Genotype testing is also performed, as it is used to guide therapy, as well as predict response to therapy. Liver biopsy may also be performed to assess extent of liver damage.

Treatment regimens are in flux, with some very promising therapies that will be “game changing” in terms of clearing the infection. Therapy is based on the genotype, and certain genotypes appear to be more responsive to treatment. Response to treatment can also be dependent on genetic variations near the IL-28B gene in the patient, and also on the presence of certain mutations in the HCV virus. The goal of therapy is to achieve clearance of the infection with a sustained virological response (undetected HCV virus 24 weeks following therapy).

CDC estimates that the prevalence of HCV infection for individuals born between 1945 and 1965 is five times that of other age groups, and that 75% are unaware they are infected because of a lack of symptoms. As a result, the CDC has recommended that all individuals in this age group (aka “baby boomers”) be tested for HCV infection. Initial testing includes HCV antibody screen with reflex to HCV RNA by PCR if the antibody screen is positive.



Virus preferentially infects liver cells (hepatotrophic virus).

Hepatocellular injury is due to the patients cellular immune response (cytotoxic CD8+ T cells) and subsequent lysis of infected cells.

HEV is very prevalent in underdeveloped countries, very rare in the USA.

HEV does not cause chronic hepatitis or a carrier state (remember, the viral hepatitis that are “vowels”, A and E, do not cause chronic hepatitis).

While acute viral hepatitis E is generally self-limited, 0.5-3% develop acute liver failure. For reasons that are unknown, pregnant women have high mortality (20%).

Diagnosis is made by considering HEV as a possible cause of acute hepatitis, and successful interpretation of the serologic profile.

According to UpToDate, a vaccine has been developed for HEV but is not commercially available.



Incubation phase: variable, dependant on viral type.

Preicteric prodrome: nonspecific, constitutional symptoms (malaise, fatigue, nausea, loss of appetite, arthralgias etc.); elevated serum levels of liver enzymes (ALT: alanine aminotransferase; AST: aspartate aminotransferase).

Icteric (jaundice) phase: jaundice is not always present (anicteric hepatitis); conjugated hyperbilirubinemia mainly; dark urine (bilirubinuria).

Convalescence (recovery) vs. acute liver failure vs. chronic hepatitis (with or without progression to cirrhosis) vs. “healthy” carrier.



In general, same pathology regardless of viral type. Patients with acute viral hepatitis seldom undergo liver biopsy.

Major finding is that of lobular hepatitis, which includes:

Diffuse liver cell degeneration (cellular swelling - ballooning degeneration) with focal hepatocellular necrosis and apoptosis (with apotosis, one can see so called councilman bodies, and with necrosis, get loss and disappearance of hepatocytes, so called “dropout necrosis”). In severe cases, confluent necrosis can be seen.

Kupffer cell hyperplasia and hepatocellular regeneration.

Mononuclear inflammation (predominantly lymphocytes) within portal tracts and lobules (hence the term lobular hepatitis).

"Lobular disarray"

Variable hepatocellular and canalicular cholestasis.



Massive acute hepatocellular necrosis, with or without lobular and portal inflammation, can be caused by a variety of agents such as acute viral hepatitis, drug or toxin induced hepatitis (acetaminophen overdose causes 50%), vascular liver diseases, autoimmune hepatitis, Wilson's disease.

Patients clinically suffer acute liver failure; if the patient survives, they may not get cirrhosis (the acute toxic agent causes no fibrosis, and as the reticulin framework of the liver is intact, the liver can regenerate without much architectural distortion).

Pattern of necrosis may suggest etiology:

Focal random necrosis, inflammatory infiltrate: viral hepatitis, autoimmune hepatitis.

Zonal necrosis, non-inflammatory: drugs, ischemia.



Infants born to mothers with an active HBV infection (positive for HBsAg and HBeAg) have a 70-90% chance of acquiring perinatal HBV infection.

More than 90% of infected infants will become chronic HBV carriers.

25% of these carriers will eventually die of cirrhosis or hepatocellular carcinoma.

All pregnant women should be screened for HBsAg.

Treatment of newborns born to HBsAg positive mothers with hepatitis B immune globulin (HBIG) and hepatitis B vaccine is 85-95% effective in preventing the development of the HBV chronic carrier state, when administered within 2-12 hours after birth.



Liver injury due to a T-cell-mediated autoimmune pathogenesis; there is a female predominance, with negative viral hepatitis markers, elevated serum IgG and gamma globulin levels, and characteristic autoantibodies.

AIH is subclassified into subtypes based on positive titers to various autoantibodies:

Type 1 is defined by anti-nuclear (ANA), anti-smooth muscle actin (SMA), and anti-soluble liver antigen/liver-pancreas (anti-SLA/LP) antibodies.

Type 2 is defined by anti-liver/kidney microsome-1 (anti-ALKM-1) and/or antibodies to a liver cytosol antigen (ALC-1).

Type 1 is usually seen in middle age females, type 2 is usually seen in children and adolescents. Type 1 is the most common type seen in the USA, and is associated with HLA DR3.

Liver pathology demonstrates chronic hepatitis with increased plasma cells in the periportal lymphocytic inflammatory infiltrate along with lobular inflammation; patients may also present with a “flare” of fulminant acute hepatitis (acute liver failure).

Diagnosis of AIH is a diagnosis of exclusion with other liver diseases; quantitative “scoring systems” have been developed based on female gender, ratio of alkaline phosphatase to ALT, total serum globulin, autoantibody titers, level of alcohol consumption, lack of markers for other liver diseases such as PBC and viral hepatitis, and findings on liver biopsy.

Treatment of autoimmune hepatitis is with immunosuppressive agents (e.g. steroids).

Some patients with AIH may also exhibit cholangitis (autoimmune cholangitis).



Hepatic disease of varied etiology characterized by widely distributed (diffuse, not focal) interconnecting fibrous scars with nodular parenchymal regeneration.

Many causes:
Alcoholic liver disease 60-70%
Viral hepatitis (B, D, C) 10%
Biliary diseases 5-10%
Hereditary hemochromatosis 5%
Wilson's disease, A1AT def. rare
Cryptogenic cirrhosis (Non-Alcoholic Fatty Liver Disease) 10-15%

Stellate cells in the space of Disse proliferate as a result of injury and become activated into fibrogenic myofibroblasts; other fibrocytic cells (such as portal fibroblasts) also cause fibrosis.

Cirrhosis was once thought to be irreversible, when there were no reliable ways to cure any of the chronic liver diseases, and thus there were no opportunities to see if cirrhosis could regress. Although it is uncommon, fully established cirrhosis may regress (hepatocytes secrete metalloproteinases which can break apart fibrotic scars – “remodeling of the fibrous scars”).

Many patients with chronic liver disease and cirrhosis are asymptomatic until late in the course of the disease. Patients with cirrhosis may die from progressive liver failure, complications of portal hypertension, or hepatocellular carcinoma.


Hepatic failure

fibrosis destroys and impairs the normal vascular interconnections in the liver, resulting in decreased hepatic perfusion.

Hepatic failure may be the result of acute liver failure, or more commonly, chronic liver failure.

Acute liver failure is defined as an acute liver illness associated with encephalopathy and coagulopathy that occurs within 26 weeks (half a year) of the initial liver injury in the absence of pre-existing liver disease.

Acute liver failure is typically secondary to massive hepatic necrosis (usually acute viral hepatitis A or B, drug, toxin, AIH). Acute liver failure may also occur without overt necrosis (Reye’s syndrome, acute fatty liver of pregnancy). Most common cause of acute liver failure is acetaminophen overdose (50% of cases).

Chronic liver failure is most commonly due to chronic liver disease associated with cirrhosis; however, not all cases of cirrhosis lead to chronic liver failure and not all end-stage chronic liver disease is cirrhotic. Some individuals with compensated advanced liver disease can develop acute liver failure (this is called acute-on-chronic liver failure).


Portal hypertension

due to increased resistance to portal blood flow as a result of fibrosis of sinusoids and central veins, as well effects from parenchymal nodules. Arterial to portal anastomoses also occur within the fibrotic liver, increasing portal pressure. Hyperdynamic splanchnic circulation is also present.

Posthepatic, intrahepatic, and prehepatic causes, but cirrhosis is the most common cause (see next slide).

Key manifestations/complications may include:

Ascites (fluid in peritoneal cavity, most common cause is cirrhosis)

Portosystemic shunts, occurring in areas where systemic and portal circulation share similar capillary beds (e.g. bleeding Esophageal Varices)

Splenomegaly (congestive)

Hepatic Encephalopathy



Reye’s syndrome is rare acute postviral illness characterized by liver injury (microvesicular steatosis) and encephalopathy.

In addition to microvesicular steatosis, widespread mitochondrial injury is present. It is believed that some patients with Reye’s syndrome actually have inborn errors of metabolism (fatty acid oxidation disorder).

Reye’s syndrome usually occurs in children and teenagers following a viral infection, with 90-95% having received salicylates (aspirin); 25% of patients with Reye's syndrome will suffer profound encephalopathy and less commonly liver failure.

Incidence of Reye’s syndrome has dramatically decreased following discontinuation of aspirin for febrile illness.



Extrahepatic causes:

Intra-abdominal sepsis leading to pylephlebitis (septic thrombophlebitis of the portal vein, often caused by acute appendicitis, acute diverticulitis, or other intrabdominal infection).
Inherited or acquired hypercoagulable disorders (e.g. post surgical thrombosis, myeloproliferative syndromes).
Pancreatitis or pancreatic cancer (propagation of splenic vein thrombosis).

Intrahepatic causes:

Invasion of portal vein by hepatocellular carcinoma.

Complications of portal vein thrombosis include portal hypertension. As the obstruction is often presinusoidal (i.e. before the liver), ascites does not typically occur.


Hepatic stellate cells

Hepatic stellate cells are storage sites of lipids, especially esterified vitamin A. When stellate cells are activated, they lose vitamin A stores and deposit collagen in the Space of Disse.


Hepatic pit cells

Hepatic pit cells are liver associated lymphocytes. These natural killer cells protect against viruses and tumor cells.


Hepatic endothelial cells

Hepatic endothelial cells are “leaky”: perforated by fenestrae and no basement membrane.


Kupffer cells

Kupffer cells are endocytic, phagocytic macrophages. Source of inflammatory mediators that contribute to liver injury.


What does the liver convert?

The liver converts excess protein and carbohydrates to blood proteins, glucose, and VLDL.


Phase I and II reactions

Phase I reactions add hydroxyl groups to substrates.

Phase II reactions add sulfate, methyl groups, glutathione, or glucuronate to the hydroxyl group.


Cytochomre P450

Cytochomre P450 enzymes are important phase I metabolizing enzymes.
all use NADPH; all use O2
overlapping substrate specificity
expression induced by their substrates


Sulfotransferases use ______ as a sulfur donor.

Sulfotransferases use PAPS as a sulfur donor.


Ethanol and Cyp2E1

Ethanol incudes Cyp2E1


alcohol damage to the liver

Acetaldehyde angers kupffer cells, which set off stellate cells


Glycogen storage diseases labs

Glycogen storage diseases: Fasting hypoglycemia.



interconverts glucose 1-phosphate and glucose 6-phosphate.


What does the liver do with excess carbohydrates?

Excess carbohydrate is converted to fatty acids and packaged as triacylglycerol in VLDL particles by the liver. IDL and LDL particles can be recycled by the liver.


What does the liver do with excess nitrogen?

Excess nitrogen that results from amino acid catabolism must be converted to urea for excretion. One of urea’s nitrogens comes from free ammonia and the other comes from aspartate.
Excess nitrogen is transported from peripheral tissues to the liver in the form of the amino acid glutamine.
The liver has a high requirements for products of the pentose phosphate pathway.
NADPH powers biosynthetic and detoxification reactions. Nucleotides are used for nucleic acids and cofactors.



central vein endothelial cells secrete Wnt
Differences in Wnt regulated gene expression create a ‘safe zone’ for free ammonia to be a substrate for the urea cycle, without free ammonia being released into the general circulation.


How do you maintain blood glucose while fasting?

Maintaining blood glucose while fasting is dependent on the urea cycle.



Ketone bodies are synthesized from fatty acids during extended fasting / starvation. They serve as an alternative fuel source to reserve glucose for tissues that are dependent on it, e.g. red blood cells.



Glycosylation occurs in the lumen of the endoplasmic reticulum. The chain begins assembly on a molecule of dolichol.
Many secreted proteins are modified by branched sugar chains.
The glycosyl chain is transferred from dolichol to the protein. It is modified further as it is transferred through the Golgi.



fatty liver



An autoimmune cholangiopathy characterized by progressive inflammatory destruction of small and medium sized intrahepatic bile ducts, which may lead to cirrhosis. Extrahepatic bile ducts are spared.

Largely a disorder of middle-age females (9:1 F:M, peak age 40-50, range 30-70). This disease is most prevalent in individuals of Northern European ancestry.

PBC is believed to have an autoimmune pathogenesis, and 90-95% of patients have circulating antimitochondrial antibodies (often abbreviated as AMA, these antibodies target the E2 component of the mitochondrial pyruvate dehydrogenase complex); CD8+ T cells are also present directed at this complex.

Patients can present with insidious onset of fatigue and anicteric pruritis, or be discovered incidentally as a result of laboratory testing for another disorder. As the disease evolves over several decades, patients develop increasing bilirubin levels or in some patients, portal hypertension. In advanced cases, secondary features emerge, such as xanthomas and xanthelasmas (impaired biliary elimination of cholesterol), steatorrhea (decreased excretion of bile acids), and vitamin D malabsorption-related osteomalacia and osteoporosis. Eventually, patients can develop liver failure with cirrhosis, and are at increased risk for hepatocellular carcinoma.

Key laboratory findings are elevated alkaline phosphatase and GGT (cholestatic injury pattern), along with positive test for AMA (antimitochondrial antibodies, particularly AMA-M2). Liver biopsy is also used to demonstrate loss of bile ducts and to stage the disease.

Treatment is with ursodeoxycholic acid, as well as liver transplant for end stage liver disease.



Cirrhosis secondary to any disorder causing prolonged extrahepatic bile duct obstruction (stones, tumor, biliary atresia, cystic fibrosis, choledochal cysts).

Extrahepatic bile duct obstruction produces bile stasis, which damages intrahepatic bile ducts. Subsequent inflammation leads to periportal hepatitis and fibrosis, which if untreated, can eventually progress to bridging fibrosis and cirrhosis. Ascending cholangitis (secondary bacterial infection) may also contribute to liver damage.



An autoimmune cholangiopathy characterized by progressive, random, uneven fibroinflammatory obliteration of extrahepatic and intrahepatic bile ducts (fibrosing cholangitis).

Etiology is believed to be autoimmune (atypical p-ANCA is found in 80% of patients), and 70% of cases are associated with IBD, usually ulcerative colitis (4% of patients with ulcerative colitis get PSC). Most patients are male with a mean age of 40 years, and laboratory evaluation shows a cholestatic injury pattern with elevated alkaline phosphatase and GGT.

A key diagnostic test is cholangiography, which demonstrates strictures and dilations of extrahepatic and intrahepatic bile ducts (beaded appearance on cholangiogram). Liver biopsy can also be diagnostic, demonstrating focal fibrosing cholangitis. Liver biopsy is also used to stage the liver disease.

Patients may present with fatigue, pruritis, and jaundice. Some are detected by biochemical abnormalities only (e.g. persistent alkaline phosphatase elevation in a patient with UC). There is no effective therapy, and patients can develop biliary cirrhosis and liver failure; as in PBC, treat end stage liver disease with liver transplant.



Several gene defects have been identified, which result in decreased synthesis of hepcidin, a protein produced in the liver that regulates intestinal iron absorption. A deficiency of hepcidin leads to excessive intestinal iron absorption.

The adult form of hemochromatosis is almost always caused by mutations of a gene called HFE, which is located on the short arm of chromosome 6. This gene encodes a protein that regulates hepcidin synthesis. The most common HFE mutation (C282Y) accounts for 80% of all hemochromatosis in adults; another mutation, H63D, results in more mild iron accumulation.

The M:F ratio is 5-7:1, with a peak incidence at age 40-60. Hemochromatosis is one of the most common inherited metabolic disorders, with one 1 of 220 individuals of northern European extraction homozygous for C282Y. The penetrance of the disorder is low, so not all individuals homozygous for C282Y mutation express disease.



Classic clinical triad is cirrhosis, diabetes, and skin pigmentation (so called bronze diabetes); however, this triad is not seen in many patients.

Patients may present with arthralgias, lethargy, hypogonadism, abdominal pain, cardiomyopathy (CHF).

Best screening test is fasting transferrin saturation if transferrin saturation is elevated (>45%), repeat transferrin saturation with serum ferritin; if both elevated, order HFE gene test.

Liver biopsy is used in those cases where there is uncertainty about the diagnosis or concern about the presence of cirrhosis; biopsy demonstrating increased iron confirms the diagnosis

Treatment is to clear excessive iron from the tissues, using phlebotomy or iron chelating agents.

If treatment starts before permanent liver damage has occurred (e.g. precirrhotic), the patient has a normal life expectancy.

Major causes of death are hepatocellular carcinoma, cardiac disease, and liver failure.

Once a case has been identified, perform genetic screening of blood relatives.



Autosomal recessive disorder of copper metabolism, resulting in the accumulation of toxic levels of copper in tissues (liver, brain, eye).

Defect on chromosome 13; incidence 1:30,000.

Disorder is caused by mutations of the ATP7B gene, which produces defects in a liver copper-transporting ATPase protein. This results in impaired secretion of copper as ceruloplasmin as well as impaired excretion of copper into bile. Over 200 different disease causing mutations of the gene have been identified (most patients are compound heterozygotes).



Copper is an essential heavy metal required for many enzymes to be active.

Copper is absorbed in the duodenum and proximal small intestine, and transported to liver cells complexed to albumin.

Hepatocellular copper is then complexed to a protein called apoceruloplasmin and secreted into blood as ceruloplasmin (90 to 95% of plasma copper).

Ceruloplasmin is recycled to the liver, and copper is excreted in the bile.

In Wilson's disease, due to the defective copper-transporting ATPase, hepatocellular copper fails to enter circulation as ceruloplasmin, hence ceruloplasmin levels are typically low (DX test).

Copper accumulates in the liver, and "spills over" into the blood loosely bound to albumin. The loosely bound copper is then deposited in other tissues. The excess copper in tissues is directly toxic. Urinary 24 hour copper excretion is typically increased (DX test).

Overall serum copper levels are usually low, due to the lack of ceruloplasmin. (DX test).

As ceruloplasmin is an acute phase reactant, one may see normal levels in Wilson’s disease as a result of liver disease.

Genetic tests for Wilson’s disease mutations are now available.

Many patients present with liver disease (either acute or chronic) in childhood, adolescence, or young adulthood.

Liver pathology is not distinctive

Consider Wilson's disease in the differential diagnosis of liver disease in anyone



Autosomal codominant disorder characterized by abnormally low levels of alpha-1-antitrypsin, a protease inhibitor (proteases are lysosomal enzymes capable of degrading extracellular tissue proteins; A1AT primarily inhibits neutrophil elastase).

A1AT is a glycoprotein produced by the liver (small amounts produced by macrophages).

The pair of A1AT genes are codominantly expressed (chromosome 14).

In most mutations an abnormal A1AT protein is produced by the liver cells but there is impaired secretion (null variants produce no A1AT); dysfunctional mutations also exist.

Depending on the A1AT levels as well as the patient's A1AT genotype, respiratory disease (emphysema) or various forms of liver disease may develop.

Emphysema in A1AT deficiency is due to the imbalance between A1AT and neutrophil elastase; A1AT levels of 80 mg/dl or greater appear to protect the lung from emphysema.

2% of all emphysema is secondary to A1AT deficiency (panlobular).

Cigarette smoking increases the risk of emphysema. Variation in levels of neutrophil elastase may explain why some patients develop emphysema and others do not.

Only 10-15% of PiZZ individuals develop clinical liver disease.

Liver disease is usually associated with homozygous Z and MMALTON genotypes. Null-Null individuals do not develop liver disease.

Liver disease is related to the accumulation of A1AT in hepatocytes, and not secondary to anti-protease/protease imbalance (Null-Null do not accumulate A1AT in hepatocytes).

In PiZZ individuals, the defective A1AT protein cannot fold correctly and thus hepatocellular secretion is diminished. The accumulated A1AT protein induces an unfolded protein response, causing a signaling cascade that can lead to apoptotic cell death. As only 10-15% of PiZZ individuals develop clinical liver disease, other genetic factors or environmental factors must be present for liver disease to develop.

Liver disease of A1AT deficiency ranges from asymptomatic individuals with elevated LFT's to cirrhosis; overall, 3% of PiZZ individuals will develop cirrhosis.

In infants, the liver disease usually presents as neonatal hepatitis and cholestasis (can mimic biliary atresia). A1AT deficiency is the most commonly diagnosed inherited hepatic disorder in infants and children.

In adults, cirrhosis can occur without preceding history of childhood liver disease; if liver failure occurs, treat with liver transplant.

Best first-line diagnostic test is to measure A1AT level, and if low, determine phenotype.


Hepatic vein thrombosis (Budd-Chiari syndrome)

defined as thrombosis of two or more
hepatic vein branches, with the classic clinical triad of hepatomegaly, ascites, and
abdominal pain.

Most often, it is caused by conditions that make blood clots more likely to form, including: myeloproliferative disorders, intra-abdominal malignancy, chronic inflammatory disease, infection, inherited or acquired disorders of blood clotting, oral contraceptives, pregnancy; 10% are idiopathic.

Can also have thrombosis of inferior vena cava (obliterative hepatocavopathy, endemic
in Nepal, possibly infectious etiology).

Diagnosis is confirmed by imaging studies (Doppler ultrasound, MRI scan, CT scan)
demonstrating thrombosis.

Pathology: centrilobular hemorrhagic necrosis, cardiac sclerosis.


Sinusoidal obstruction syndrome (hepatic veno-occlusive disease)

defined by the presence of obstructive, nonthrombotic lesions of the small (central) hepatic veins in patients exposed to radiation and/or hepatoxins. Pathology demonstrates marked narrowing and obliteration of central vein lumens by subendothelial swelling and fibrosis.

Usually occurs in allogeneic bone marrow (hematopoietic stem cell) transplant patients; can also occur in cancer patients receiving chemotherapy. Pathogenesis is due to toxic damage to hepatic sinusoidal endothelium, secondary to the cytoreductive agents (e.g. chemotherapy) used in these patients.

In the acute form patients develop painful hepatomegaly, sudden weight gain, increased serum bilirubin. Chronic more indolent form occurs associated with toxic effects of pyrrolizidine alkaloids found in certain herbal teas and these patients have clinical symptoms of Budd-Chiari syndrome.

Diagnosis confirmed by clinical features, imaging studies (no thrombosis of hepatic vein), liver biopsy (chronic form).


Biliary atresia

defined as complete or partial obstruction of the lumen of the extrahepatic biliary tree within the first 3 months of life. The etiology may be inflammatory (viral infection or autoimmune injury) or due to anomalous embryologic development affecting the biliary tree. Untreated, most cases will progress to destruction of the intrahepatic bile ducts, resulting in neonatal hepatitis and possibly secondary biliary cirrhosis. Biliary atresia accounts for 50% of pediatric liver transplant cases.


Neonatal hepatitis

defined as hepatitis occurring in early infancy (1-2 months), it can be caused by many types of disorders, such as biliary atresia (20%), inherited metabolic disorders (e.g. alpha-1 antitrypsin deficiency (15%), tyrosinemia, cystic fibrosis), infectious agents (e.g. CMV, many others), and toxic effects of drugs (this list of causes by no means complete). In 10-15% of cases the cause is unknown (idiopathic neonatal hepatitis).



Characterized by maternal hypertension, proteinuria, peripheral edema, and coagulation abnormalities. When convulsions and hyper-reflexia are also present, the condition is called eclampsia. Rarely, in this condition the liver may develop hemorrhagic ischemic necrosis, associated with DIC and platelet fibrin thrombi. The HELLP syndrome of Hemolysis, Elevated Liver enzymes, and Low Platelets may be present.


Acute fatty liver of pregnancy

Disorder of pregnancy characterized by acute onset of liver dysfunction, and severe cases can result in acute hepatic failure and death. Liver biopsy shows microvesicular steatosis. Defect in mitochondrial fatty acid oxidation has been implicated in some cases (long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD).


Intrahepatic cholestasis of pregnancy

Characterized by mild increase in serum conjugated bilirubin (usually


Liver allograft

liver may be affected by preservation injury (oxygen radicals in hypoxic organ damage sinusoidal endothelium), anastomotic problems, and acute and chronic rejection. In acute rejection one can see portal hepatitis with lymphocytic cholangitis, as well as endotheliitis involving portal and hepatic vein branches. In chronic rejection there can be inflammatory damage to both bile ducts and arteries (get "vanishing bile duct syndrome" and obliterative arteritis with ischemic necrosis).



do not measure hepatic function; elevations of these enzymes reflect hepatocellular damage.
Present in the liver as well as heart, skeletal muscle, brain, and kidneys. Elevation is not specific for the liver.


Alkaline Phosphatase

reflect injury to the bile duct epithelium/canalicular membrane and are markers of cholestasis.
Consists of various isoenzymes found in bone, liver, placenta, intestine, and leukocytes.

Increase is usually due to bone or liver disease.

Increase of ALP in liver disease is due to increased synthesis of hepatic ALP, which is found in the canalicular membrane of hepatocytes.

The primary stimulus for ALP production is bile duct obstruction, so ALP is an indicator of intrahepatic or extrahepatic cholestasis.

Measurement of gamma-glutamyl transferase (GGT, associated with biliary epithelium) can assist in determining if ALP rise is due to bone or liver.

Patients with disease processes that result in hepatocellular injury have a disproportionate increase in the serum transaminases compared with ALP, and those patients with a cholestatic disease process have the opposite findings.



reflect global hepatic synthesis (function).


prothrombin time

reflect global hepatic synthesis (function).



reflect injury to the bile duct epithelium/canalicular membrane and are markers of cholestasis.



do not measure hepatic function; elevations of these enzymes reflect hepatocellular damage.
Only small amounts are found in tissues other than the liver, so ALT is a more specific indicator of hepatocyte injury than AST.

80% of AST is found in mitochondria, and since ETOH is a mitochondrial toxin, AST:ALT ratio of greater than 2.0 suggests alcoholic liver disease.


Serum bilirubin

Serum bilirubin can be elevated in both hepatocellular injury and cholestatic disease and is often not helpful in differentiating between the two conditions.



the most common benign neoplasm of the liver. Lesion consists of discrete red-blue hemorrhagic nodules composed of dilated (cavernous) endothelial lined blood filled channels. These lesions are often an incidental discovery.


Choledochal cyst

congenital dilatation of the common bile duct. Usually occurring in children, this lesion may result in biliary obstruction, stones, or bile duct carcinoma (cholangiocarcinoma).


Caroli's disease/syndrome

refers to several congenital disorders resulting in intrahepatic biliary dilatations, which communicate with the biliary tree. These patients may suffer bouts of cholangitis. There are several forms, and when this disorder is associated with congenital hepatic fibrosis, it is called Caroli’s syndrome.
Both Caroli’s disease and Congenital Hepatic Fibrosis have increased risk of cholangiocarcinoma (bile duct carcinoma).


Congenital Hepatic Fibrosis

non-cirrhotic fibrotic liver disease of children, with an autosomal recessive inheritance. The liver exhibits fibrous septa surrounding islands of normal liver (not cirrhosis). Bile duct proliferation is also present, which communicates with the biliary tree. These patients may develop portal hypertension. A spectrum exists between this disorder and Caroli's disease, and there is also an association with polycystic kidney disease.
Both Caroli’s disease and Congenital Hepatic Fibrosis have increased risk of cholangiocarcinoma (bile duct carcinoma).



Well-demarcated lesion composed of a proliferation of all liver parenchymal elements (central veins, hepatocytes, portal triads). This lesion may represent a hyperplastic response to a localized vascular occlusive event, and has no known malignant potential.

Lesion characteristically forms a mass with a central fibrous scar with a stellate configuration.

More common in young adult (age 20-40) females, but can occur in men. These lesions are usually asymptomatic and discovered incidentally.

Angiography shows a distinctive peripheral filling pattern, and the central scar may be seen with imaging studies.



Diffuse nonfibrosing nodular hyperplasia of the liver.

Easier to see grossly than microscopically.

Patients may develop portal hypertension, but most are asymptomatic.

Occurs in association with conditions affecting intrahepatic blood flow, such as solid organ (renal) transplants, bone marrow (hematopoietic stem cell) transplantation, and vasculitis.



Well-circumscribed benign neoplasm composed of well differentiated hepatocytes (no portal triads or central veins).

Most often occurs in young reproductive aged women, associated with prolonged use of oral contraceptives containing high estrogen content. Can also be seen in individuals using anabolic steroids.

Compared to FNH, more likely to be symptomatic (abdominal pain from rapid growth). These lesions can cause massive bleeding due to hemorrhagic necrosis.

It can sometimes be difficult to distinguish a hepatocellular adenoma from a well differentiated hepatocellular carcinoma on small biopsies. Hepatocellular adenomas can be subclassified based on their genetic profile, and this can also assist in distinguishing hepatocellular adenoma from hepatocellular carcinoma, as well as from focal nodular hyperplasia.



Grossly appear as single or more commonly multiple small white nodules; mimics metastatic carcinoma.

Microscopic: disordered collection of ectatic bile ducts in a fibrous stroma.



Usually solitary, consisting of a benign proliferation of bile ducts; as with bile duct hamartoma, may grossly confuse with metastatic carcinoma.




Liver is more commonly involved by metastatic tumors than by primary liver carcinoma.

Usually metastases are multiple tumors but one can have solitary metastases.

Lung, GI tract (colon), breast, and pancreas are the carcinomas most commonly metastatic to the liver.

Despite extensive metastases, liver function is often not impaired.



Relatively rare carcinoma in USA, quite common in Africa and S.E. Asia.

In USA, usually occur in patients over the age of 60 years. In areas with high endemic HBV infection, this malignancy occurs at a younger age (age 20-40).

Male predominance (M:F ratio ranges from 3:1 to 8:1).

Chronic liver diseases are the most common setting for the emergence of hepatocellular carcinoma (HCC). The most important predisposing factors include chronic viral hepatitis infections and exposure to toxins.

Hepatotrophic viruses: HBV carriers and chronic hepatitis due to HBV and HCV increases the risk of HCC (in Africa and S.E. Asia, HCC occurs in younger patients due to high carrier rate). HBV carriers have 200x risk of HCC vs noncarriers.

Hepatocarcinogens: aflatoxin produced by Aspergillus flavus, especially in the setting of chronic viral hepatitis B (and also possibly chronic viral hepatitis C), is a risk factor for HCC. Alcohol is also a risk factor.

Cirrhosis: chronic hepatitis due to HBV infection, HCV infection, alcoholic cirrhosis, hereditary hemochromatosis, AIAT deficiency, NAFLD/NASH, and other causes of cirrhosis increase the risk of HCC (repeated cycles of cell death and regeneration lead to damaged DNA). In the USA, 85-90% of HCC is associated with cirrhosis.

Gross pathology: can present as a solitary large mass, or with multiple nodules. In some cases the tumor can be diffusely infiltrative. The tumor is typically soft and hemorrhagic.

Microscopic: ranges from well differentiated to anaplastic; trabecular, solid, or tubular patterns can be seen. Vascular invasion is often present.

HCC can metastasize to regional lymph nodes, diaphragm, lung, and bone

Clinical manifestations of HCC (such as fatigue, malaise, ill-defined RUQ pain) are often "masked” by the patient’s underlying cirrhosis or chronic hepatitis. Suspect HCC in any cirrhotic patient suffering sudden clinical deterioration.

Elevated serum alpha-fetoprotein may be present (levels >200 ng/ml are strongly suggestive of HCC, levels



HCC composed of polygonal oncocytic tumor cells in nests and cords separated by lamellar fibrous stroma.

Occurs predominantly in young adults without cirrhosis or chronic viral hepatitis. In the USA, 50% of HCC in patients



Cholangiocarcinomas are carcinomas arising from intrahepatic or extrahepatic bile ducts. Cholangiocarcinomas are virtually always adenocarcinomas.

Intrahepatic as well as extrahepatic cholangiocarcinomas typically exhibit tumor nodules that are usually white and hard, in contrast to HCC (due to sclerosing fibrous reaction to tumor cells).

There is an association of cholangiocarcinoma with those conditions resulting in chronic cholangitis, such as infection with liver flukes (Opisthorchis and Clonorchis), PSC, Caroli’s disease, Congenital Hepatic Fibrosis, and choledochal cysts. Patients with viral hepatitis B and C and NAFLD also have an increased risk for intrahepatic cholangiocarcinoma. Many cholangiocarcinomas have no pre-existing conditions.

Most cases occur age >60 years. These tumors typically have a poor prognosis.

Mixed hepatocholangiocarcinomas do occur, but most are HCC with ductular proliferation.


Hepatocellular VS Cholestatic labs

AST/ALT elevation > bilirubin or alk phos
Suggests parenchymal inflammation

Elevation of bilirubin or alk phos > AST/ALT
Intrahepatic vs extrahepatic obstruction


Gilbert’s Syndrome

Autosomal dominant inborn error of metabolism
5% of the population
Benign unconjugated (indirect) bilirubinemia
Increases with: illness, fasting, stress, fatigue, ethanol, nicotinic acid intake and in the premenstrual period in some women



Unconjugated (indirect) hyperbilirubinemia
Gilbert’s syndrome

Conjugated (direct) hyperbilirubinemia
Intrinsic liver disease
Biliary tract obstruction


Risk Factors for Cholesterol Gallstones

Increasing age
Female gender
Rapid weight loss
Native –American heritage
Hyperalimentation (gallbladder stasis)
Elevated triglyceride levels
Medications (fibric acid derivatives, estrogens, octreotide)
Ileal disease, resection or bypass


Risk Factors for Pigment Gallstones

Increasing age
Chronic hemodialysis
Alcoholic liver disease
Biliary infection
Asian heritage
Hyperalimentation (gallbladder stasis)
Duodenal diverticulum
Truncal vagotomy primary biliary cirrhosis


Acute Cholecystitis

Abdominal pain
Fever and
90-95% of patients have gallstones and previous biliary colic

Acalculous cholecystitis (5%)
Critically ill patients
Major surgery, trauma / burn

Murphy sign - RUQ tenderness on inspiration, inspiratory arrest
Palpable gallbladder is present in 33%
Gallbladder wall thickening > 4mm
Pericholecystic fluid
Cholescintigraphy – non-visualization of the gallbladder

Hepatic profile can be normal but mild elevations are common
WBC usually elevated
Bilirubin levels are usually


Management of Acute Cholecystitis

Broad spectrum antibiotics
Pain management
Cholecystectomy within 96 hours of onset of symptoms


Acalculous Cholecystitis

5-10% are acalculous cholecystitis
Hospitalized, critically ill patients after major surgery, trauma or severe burns
Gallbladder stasis and ischemia
Broad spectrum antibiotics
Cholecystostomy tube



Stone or stones in the CBD

Secondary stones – Migrate from GB

Primary stones - Form in CBD
Dilated CBD post cholecystectomy
Duodenal reflux
Parasitic cholangitis (clonorchiasis, fascioliasis, ascariasis)

Cholangitis: Charcot’s triad

Treatment: ERCP with stone removal



85% of cases are gallstones
other causes are neoplasms, strictures (PSC), parasitic infections and congenital bile ducts abnormalities of the that lead to bile stasis

Biliary pathogens: E coli, Klebsiella, Pseudomonas, enterococci, and Proteus;
B fragilis and Clostridium perfringens in 15%

Broad spectrum antibiotics
ERCP for bile duct decompression


Gallstone Pancreatitis

Gallstones cause 40% of acute pancreatitis in US

Stone passage
Stone obstruction
Biliopancreatic reflux

Hydration, bowel rest, pain control
Antibiotics if cholangitis or necrotizing pancreatitis

20% of cases are severe with a mortality rate of 2-10%

Necrotizing pancreatitis
Organ failure
Walled off pancreatic necrosis
Infected pancreatic necrosis
Disconnected tail
Exocrine dysfunction



Adenocarcinoma of biliary epithelium
Ampullary Gallbladder are different
CA 19-9 tumor marker
Extrahepatic vs. Intrahepatic
Presents as obstructive jaundice or mets

PSC have a 15% lifetime risk
Poor prognosis – Less than 30% 5 year survival for localized disease.
Surgical resection (transplant for hilar tumor) is the only potential for cure
5 year transplant survival: 50-80%



(endoscopic retrograde cholangiopancreatography)
Diagnostic and therapeutic
Complication rate of 7-9%
Cholangitis / liver abscess

30 day procedure related mortality 0.6%


CholescintigraphyHIDA Scan

IV Technetium labeled
Taken up and excreted by hepatocytes
Visualization of the common bile duct, gallbladder and small bowel occurs within 30 to 60 minutes
Nonvisualization of the gallbladder is a positive test
Sen 97% and spec 90% for acute cholecystitis