18 Hepatobiliary and Pancreatic Disorders

18 Hepatobiliary and Pancreatic Disorders

18 Hepatobiliary and Pancreatic Disorders

Laboratory Evaluation of Liver Cell Injury

Bilirubin metabolism and jaundice

Table 18-1. Causes of Jaundice

Type of HyperbilirubinemiaUrine BilirubinUrine UBGDisorders

Unconjugated

CB 50%AbsentDecreased intrahepatic bile flow Drug-induced (e.g., OCP)Primary biliary cirrhosisDubin-Johnson syndrome: genetic defect in secretion into intrahepatic bile ducts; black pigment in hepatocytesRotor's syndrome: similar to Dubin-Johnson syndrome but without black pigment in hepatocytesDecreased extrahepatic bile flow Gallstone in common bile duct Carcinoma of head of pancreas

CB, conjugated bilirubin; HDN, hemolytic disease of newborn; OCP, oral contraceptive pill; UBG, urobilinogen; UCB, unconjugated bilirubin.

1. Bilirubin metabolism

a. Unconjugated bilirubin (UCB)

i. Senescent red blood cells (RBCs) are phagocytosed by splenic macrophages.

ii. UCB is the end product of heme degradation.

UCB is lipid-soluble.

b. UCB combines with albumin in the blood.

i. UCB is taken up by hepatocytes.

ii. UCB is conjugated to produce conjugated bilirubin (CB).

CB is water-soluble.

c. CB is secreted into the intrahepatic bile ducts.

i. Temporarily stored in the gallbladder

ii. Enters the duodenum via the common bile duct

d. Intestinal bacteria convert CB to urobilinogen (UBG).

i. UBG is spontaneously oxidized to urobilin.

ii. Urobilin produces the brown color of stool.

e. A small amount of UBG is recycled to the liver and kidneys.

Color of urine is due to urobilin.

Jaundice

Jaundice is due to an increase in UCB and/or CB.

Jaundice is first noticed in the sclera.

Classification of causes of jaundice is based on the percentage of CB

Percent CB = CB/total bilirubin

Schematics showing common causes of jaundice

In this discussion, the symbol (+) is used to indicate degrees of magnitude. Normal bilirubin metabolism (A) shows liver uptake of lipid-soluble unconjugated bilirubin (UCB+) and its conjugation to water-soluble conjugated bilirubin (CB+). CB is secreted into the common bile duct (CBD) and is emptied into the bowel. Intestinal bacteria convert CB to urobilinogen (UBG+), which spontaneously oxidizes to the pigment urobilin. Urobilin is responsible for the color of stool. A small percentage of UBG is reabsorbed into the blood. Most of it enters the liver (larger arrow) and a small percentage (smaller arrow) enters the urine (UBG+). Urobilin is responsible for the color of urine. All the normal bilirubin in blood is UCB (CB% AST: viral hepatitis

Serum aspartate transaminase (AST)Present in mitochondriaAlcohol damages mitochondria: AST >ALT indicates alcoholic hepatitis

Cholestasis

Serum -glutamyl transferase (GGT)Intra- or extrahepatic obstruction to bile flowInduction of cytochrome P-450 system (e.g., alcohol): increases GGT

Serum alkaline phosphatase (ALP)Normal GGT and increased ALP: source of ALP other than liver (e.g., osteoblastic activity in bone)Increased GGT and ALP: liver cholestasis

Bilirubin Excretion

CB 50%Conjugated hyperbilirubinemia (e.g., liver cholestasis)

Urine bilirubinBilirubinuria: viral hepatitis, intra- or extrahepatic obstruction of bile ducts

Urine UBGIncreased urine UBG: extravascular hemolytic anemias, viral hepatitisAbsent urine UBG: liver cholestasis

Hepatocyte Function

Serum albuminAlbumin is synthesized by the liverHypoalbuminemia: severe liver disease (e.g., cirrhosis)

Prothrombin time (PT)Majority of coagulation factors are synthesized in the liverIncreased PT: severe liver disease

Blood urea nitrogen (BUN)Urea cycle is present in the liverDecreased serum BUN: cirrhosis

Serum ammoniaAmmonia is metabolized in the urea cycleIncreased serum ammonia: cirrhosis, Reye syndrome

Immune Function

Serum IgMIncreased in primary biliary cirrhosis

Antimitochondrial antibodyPrimary biliary cirrhosis

Anti-smooth muscle antibodyAutoimmune hepatitis

Antinuclear antibodyAutoimmune hepatitis

Tumor Marker

-Fetoprotein (AFP)Hepatocellular carcinoma

CB, conjugated bilirubin; UBG, urobilinogen; UCB, unconjugated bilirubin

Viral Hepatitis

Phases of acute viral hepatitis

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1. Prodrome

a. Fever, painful hepatomegaly

b. Serum transaminases increase steadily.

Peak just before jaundice occurs

c. Atypical lymphocytosis

2. Jaundice

a. Variable finding depending on the type of hepatitis

b. Increased urine bilirubin and urine UBG

3. Recovery

Jaundice resolves

Phases of acute viral hepatitis

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1. Prodrome

a. Fever, painful hepatomegaly

b. Serum transaminases increase steadily.

Peak just before jaundice occurs

c. Atypical lymphocytosis

2. Jaundice

a. Variable finding depending on the type of hepatitis

b. Increased urine bilirubin and urine UBG

3. Recovery

Jaundice resolves

Microscopic findings in acute viral hepatitis

1. Lymphocytic infiltrate with destruction of hepatocytes

Apoptosis of hepatocytes (Councilman bodies)

2. Persistent inflammation and fibrosis is an unfavorable sign.

Sign of chronic hepatitis progressing to postnecrotic cirrhosis

Epidemiology of viral hepatitis

Table 18-3. Viral Hepatitis: Transmission and Clinical Findings

VirusTransmissionClinical Findings

Hepatitis AFecal-oralNo carrier stateDoes not lead to chronic hepatitisOccurs in day care centers, prisons, travelers to developing countries, and male homosexuals (anal intercourse)

Hepatitis BParenteral, sexual, vertical (pregnancy, breast feeding)Carrier state may occurChronic hepatitis in 10% of immunocompetent patientsSerum sickness prodrome (5-10%): vasculitis (PAN), polyarthritis, membranous GNIncreased incidence of hepatocellular carcinoma

Hepatitis CParenteral, sexualCarrier state may occurMild hepatitis; jaundice uncommonChronic hepatitis in >70% of casesAssociated with posttransfusion hepatitis, type I MPGN, alcohol excess, PCTIncreased incidence of hepatocellular carcinoma

Hepatitis DParenteral, sexualCarrier state may occurRequires HBsAg to replicateChronic state less likely with coinfection (HBV and HDV exposure at same time) than superinfection (HBV carrier exposed to blood containing HBV and HDV)

Hepatitis EFecal-oral (waterborne)No carrier state or chronic hepatitisFulminant hepatitis may develop in pregnant womenOccurs in developing countries

Hepatitis GParenteralCarrier stateNo chronic hepatitis

GN, glomerulopathy; MPGN, membranoproliferative glomerulonephritis; PAN, polyarteritis nodosa; PCT, porphyria cutanea tarda.

Serologic studies in viral hepatitis

Table 18-4. Serologic Studies in Hepatitis B

HBsAgHBeAg HBV DNAAnti-HBc-IgMAnti-HBc-IgGAnti-HBsInterpretation

+----Earliest phase of acute HBV

+++--Acute infection

--+--Window phase, or serologic gap

---++Recovered from HBV

----+Immunized

+--+-"Healthy" carrier if HBsAg >6 months

++-+-Chronic infective carrier if >6 months

Anti-HBc, core antibody; anti-HBs, surface antibody; HBeAg, e antigen; HBsAg, surface antigen.

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1. Hepatitis A virus (HAV)

a. Anti-HAV-IgM indicates active infection.

b. Anti-HAV-IgG indicates recovery from infection or vaccination.

Protective antibody

2. Hepatitis B virus (HBV)

a. Hepatitis B surface antigen (HBsAg)

. Appears within 2 to 8 weeks after exposure

. First marker of infection

i. Persists up to 4 months in acute hepatitis

i. HBsAg longer than 6 months defines chronic HBV.

i. Hepatitis B e antigen (HBeAg) and HBV-DNA

. Infective particles

i. Appear after HBsAg and disappear before HBsAg

i. Anti-HBV core antibody IgM (anti-HBc-IgM)

. Nonprotective antibody

. Remains positive in acute infections

i. Persists during "window phase" or "serologic gap"

i. HBsAg, HBV DNA, and HBeAg are absent.

ii. Converts to anti-HBc-IgG in 6 months

i. Anti-HBV surface antibody (anti-HBs)

. Protective antibody

i. Marker of immunization after HBV vaccination

i. Chronic HBV

. Persistence of HBsAg longer than 6 months

. Anti-HBc-IgM converts to anti-BHc-IgG.

i. "Healthy" chronic carrier

i. Presence of HBsAg and anti-HBc-IgG

i. Absence of DNA and e antigen

ii. Infective chronic carrier

ii. Presence of HBsAg, anti-HBc-IgG, and infective particles (DNA and e antigen)

ii. Increased risk for postnecrotic cirrhosis and hepatocellular carcinoma

i. Hepatitis C virus (HCV)

i. Screen with enzyme immunoassay

. Presence of anti-HCV-IgG indicates infection or recovery.

i. It is not a protective antibody.

i. Confirmatory tests

. Recombinant immunoblot assay (RIBA)

i. HCV RNA using polymerase chain reaction

ii. Positive RIBA and HCV RNA indicate infection.

iii. Positive RIBA and negative HCV RNA indicate recent recovery.

i. Hepatitis D virus (HDV)

i. Presence of anti-HDV-IgM or IgG indicates active infection.

i. IgG is not a protective antibody.

i. Hepatitis E virus (HEV)

i. Presence of anti-HEV-IgM indicates active infection.

i. Anti-HEV-IgG indicates recovery (protective antibody).

Other laboratory test findings

1. CB 20% to 50% (mixed hyperbilirubinemia)

a. Decreased uptake/conjugation of UCB

b. CB gains access to blood via damaged bile ductules.

2. Increased urine UBG and urine bilirubin

a. CB is water-soluble and is filtered in the kidneys.

b. UBG recycled back to inflamed liver is redirected to the kidneys.

3. Increased serum transaminases

a. Serum ALT greater than AST

b. Serum ALT is the last liver enzyme to return to normal.

Other Inflammatory Disorders

Summary of important infectious diseases

Table 18-5. Infectious Diseases of the Liver

DiseasePathogen(s)Characteristics

AmebiasisEntamoeba histolyticaUsually right lobe abscess

Ascending cholangitisEscherichia coliInflammation of bile ducts (cholangitis) from concurrent biliary infection and duct obstruction (e.g., stone)Triad of fever, jaundice, right upper quadrant painMost common cause of multiple liver abscesses

ClonorchiasisClonorchis sinensis (Chinese liver fluke)Contracted by ingesting encysted larvae in fish; larvae enter common bile duct and become adultsMay produce cholangiocarcinoma

EchinococcosisEchinococcus granulosus (sheepherder's disease)Single or multiple cysts containing larval formsDog is definitive host; human is intermediate hostRupture of cysts can produce anaphylaxis

Granulomatous hepatitisMycobacterium tuberculosis,Histoplasma capsulatumSign of miliary spread

SchistosomiasisSchistosoma mansoniEggs incite a fibrotic response in the portal vein ("pipestem cirrhosis")Complications of cirrhosis: portal hypertension, ascites, and esophageal varices

Spontaneous peritonitisEscherichia coli in adultsStreptococcus pneumoniae in childrenDevelops in ascites (e.g., cirrhosis, nephrotic syndrome)

Summary of important infectious diseases

Table 18-5. Infectious Diseases of the Liver

DiseasePathogen(s)Characteristics

AmebiasisEntamoeba histolyticaUsually right lobe abscess

Ascending cholangitisEscherichia coliInflammation of bile ducts (cholangitis) from concurrent biliary infection and duct obstruction (e.g., stone)Triad of fever, jaundice, right upper quadrant painMost common cause of multiple liver abscesses

ClonorchiasisClonorchis sinensis (Chinese liver fluke)Contracted by ingesting encysted larvae in fish; larvae enter common bile duct and become adultsMay produce cholangiocarcinoma

EchinococcosisEchinococcus granulosus (sheepherder's disease)Single or multiple cysts containing larval formsDog is definitive host; human is intermediate hostRupture of cysts can produce anaphylaxis

Granulomatous hepatitisMycobacterium tuberculosis,Histoplasma capsulatumSign of miliary spread

SchistosomiasisSchistosoma mansoniEggs incite a fibrotic response in the portal vein ("pipestem cirrhosis")Complications of cirrhosis: portal hypertension, ascites, and esophageal varices

Spontaneous peritonitisEscherichia coli in adultsStreptococcus pneumoniae in childrenDevelops in ascites (e.g., cirrhosis, nephrotic syndrome

Autoimmune hepatitis

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1. Occurs most often in young women

2. Clinical findings

Fever, jaundice, hepatosplenomegaly

3. Laboratory findings

. Positive serum antinuclear antibody (ANA) test

a. Anti-smooth muscle antibodies

Neonatal hepatitis

1. Epidemiology

a. Idiopathic

b. Associated with infections (e.g., cytomegalovirus)

c. Associated with inborn errors of metabolism (e.g., 1-antitrypsin deficiency)

2. Biopsy shows multinucleated giant cells

"Giant cell" hepatitis

Reye syndrome

1. Usually develops in children younger than 4 years of age

Often follows a chickenpox or influenza infection

2. Mitochondrial damage (? virus, salicylates)

. Disruption of the urea cycle

. Increase in serum ammonia

a. Defective -oxidation of fatty acids

a. Microvesicular type of fatty liver

Small cytoplasmic globules without nuclear displacement

Clinical findings

. Encephalopathy

. Cerebral edema, coma, convulsions

a. Hepatomegaly

a. Laboratory findings

. Transaminasemia

a. Normal to slight increase in total bilirubin

b. Increased serum ammonia

Acute fatty liver of pregnancy

1. Abnormality in -oxidation of fatty acids

2. Fatal to mother and fetus unless the baby is delivered

Preeclampsia

1. Hypertension, proteinuria, dependent pitting edema in third trimester

2. Liver cell necrosis around portal triads

Increased serum transaminases

3. HELLP syndrome

. Hemolytic anemia with schistocytes

a. Elevated serum transaminases

b. Low platelets

b. Due to disseminated intravascular coagulation

Fulminant hepatic failure

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Acute liver failure with encephalopathy within 8 weeks of hepatic dysfunction

1. Causes

a. Viral hepatitis (most common overall cause)

b. Drugs (e.g., acetaminophen most common cause)

c. Reye syndrome

2. Gross and microscopic findings

a. Wrinkled capsular surface due to loss of hepatic parenchyma

b. Dull red to yellow necrotic parenchyma with blotches of green (bile)


Hepatic encephalopathy (see section VII), jaundice

Laboratory findings

. Decrease in transaminases

. Liver parenchyma is destroyed.

a. Increase in PT and ammonia

Circulatory Disorders

Prehepatic obstruction to blood flow

Obstruction of blood flow to the liver (i.e., hepatic artery, portal vein)

1. Hepatic artery thrombosis with infarction

a. Liver infarction is uncommon because of a dual blood supply.

Hepatic artery and portal vein tributaries normally empty blood into the sinusoids.

b. Causes

. Liver transplant rejection

i. Vasculitis due to polyarteritis nodosa

i. Portal vein thrombosis

i. Causes

. Pylephlebitis (inflammation of portal vein)

. Most often due to acute appendicitis

. Air in biliary tree from bacterial gas

i. Polycythemia vera

ii. Hepatocellular carcinoma

ii. Tumor invasion of the portal vein

i. Clinical findings

. Portal hypertension, ascites, splenomegaly

i. No hepatomegaly

Prehepatic obstruction to blood flow

Obstruction of blood flow to the liver (i.e., hepatic artery, portal vein)

1. Hepatic artery thrombosis with infarction

a. Liver infarction is uncommon because of a dual blood supply.

Hepatic artery and portal vein tributaries normally empty blood into the sinusoids.

b. Causes

. Liver transplant rejection

i. Vasculitis due to polyarteritis nodosa

i. Portal vein thrombosis

i. Causes

. Pylephlebitis (inflammation of portal vein)

. Most often due to acute appendicitis

. Air in biliary tree from bacterial gas


ii. Hepatocellular carcinoma

ii. Tumor invasion of the portal vein


. Portal hypertension, ascites, splenomegaly

i. No hepatomegaly

Intrahepatic obstruction to blood flow

Intrahepatic obstruction to sinusoidal blood flow

1. Causes

a. Cirrhosis (see Section VII)

b. Centrilobular hemorrhagic necrosis

c. Peliosis hepatis, sickle cell disease

2. Centrilobular hemorrhagic necrosis

a. Most often due to left-sided heart failure (LHF) and right-sided heart failure (RHF)

i. LHF decreases cardiac output causing hypoperfusion of the liver.

Causes ischemic necrosis of hepatocytes located around central vein

ii. RHF causes a back-up of systemic venous blood into the central veins and sinusoids.

b. Enlarged liver with a mottled red appearance ("nutmeg" liver)

i. Congestion of central veins and sinusoids

ii. Necrosis of hepatocytes around the central vein

c. Clinical findings

i. Painful hepatomegaly with or without jaundice

ii. Increased transaminases caused by ischemic necrosis

iii. May progress to cardiac cirrhosis

Fibrosis around central veins

3. Peliosis hepatis

a. Sinusoidal dilation due to blood

b. Causes

i. Anabolic steroids

ii. Bartonella henselae causing bacillary angiomatosis

Occurs in AIDS

c. Potential for intraperitoneal hemorrhage

Posthepatic obstruction to blood flow

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Obstruction of blood flow out of the liver (e.g., hepatic vein)

1. Causes

a. Hepatic vein thrombosis

b. Veno-occlusive disease

2. Hepatic vein thrombosis

a. Causes


ii. Oral contraceptive pills

iii. Hepatocellular carcinoma

Invades hepatic vein

b. Clinical findings

i. Enlarged, painful liver

ii. Portal hypertension, ascites, splenomegaly

iii. High mortality rate

c. Laboratory findings

i. Increased transaminases

ii. Increased PT

3. Veno-occlusive disease

a. Complication of bone marrow transplantation

b. Collagen develops around the central veins.

Hematobilia

Blood in the bile in patients with trauma to the liver

Alcohol-Related and Drug- and Chemical-Induced Liver Disorders

Alcohol-related disorders

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1. Risk factors for alcohol-related liver disease

2. Pathways for alcohol metabolism

3. Types of liver disease

a. Fatty change is the most common type of disease

i. Substrates of alcohol metabolism are used to synthesize liver triglyceride.

ii. Clinical findings

Tender hepatomegaly without fever or neutrophilic leukocytosis

b. Alcoholic hepatitis

i. Pathogenesis

Due to acetaldehyde damage to hepatocytes

Stimulation of collagen synthesis around the central vein

Perivenular fibrosis

ii. Microscopic findings

Fatty change with neutrophil infiltration

Mallory bodies

Damaged cytokeratin intermediate filaments in hepatocytes


iii. Clinical findings

Painful hepatomegaly

Fever, neutrophilic leukocytosis, ascites, hepatic encephalopathy

May progress to alcoholic cirrhosis

c. Cirrhosis (see section VII)


Alcohol-related disorders

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1. Risk factors for alcohol-related liver disease

2. Pathways for alcohol metabolism

3. Types of liver disease

a. Fatty change is the most common type of disease

i. Substrates of alcohol metabolism are used to synthesize liver triglyceride.

ii. Clinical findings

Tender hepatomegaly without fever or neutrophilic leukocytosis

b. Alcoholic hepatitis

i. Pathogenesis

Due to acetaldehyde damage to hepatocytes

Stimulation of collagen synthesis around the central vein


ii. Microscopic findings

Fatty change with neutrophil infiltration

Mallory bodies

Damaged cytokeratin intermediate filaments in hepatocytes (see


iii. Clinical findings

Painful hepatomegaly

Fever, neutrophilic leukocytosis, ascites, hepatic encephalopathy

May progress to alcoholic cirrhosis

c. Cirrhosis (see section VII)


Chemical- and drug-induced liver disease

Table 18-6. Drug- and Chemical-Induced Liver Diseases

DiseaseCause

Tumors

AngiosarcomaVinyl chloride, arsenic, thorium dioxide (radioactive contrast material)

CholangiocarcinomaThorium dioxide

Hepatocellular carcinomaAflatoxin (due to Aspergillus mold)

Liver cell adenomaOral contraceptive pills

Other Liver Diseases

Acute hepatitisIsoniazid (caused by toxic metabolite), halothane, acetaminophen, methyldopa

CholestasisOral contraceptive pills (estrogen interferes with intrahepatic bile secretion), anabolic steroids

Fatty changeAmiodarone (resembles alcoholic hepatitis; Mallory bodies and progression to cirrhosis), methotrexate

FibrosisMethotrexate, retinoic acid, amiodarone

Obstructive (Cholestatic) Liver Disease

Types of cholestatic liver disease

1. Intrahepatic cholestasis

a. Blockage of the intrahepatic bile ducts

b. Causes

i. Drugs (e.g., oral contraceptive pills, anabolic steroids)

ii. Neonatal hepatitis

iii. Pregnancy-induced cholestasis (estrogen)

2. Extrahepatic cholestasis

a. Blockage of common bile duct (CBD)

b. Causes

i. Stone usually originating from the gallbladder

ii. Primary sclerosing pericholangitis

iii. Extrahepatic biliary atresia

iv. Carcinoma head of pancreas

Types of cholestatic liver disease

1. Intrahepatic cholestasis

a. Blockage of the intrahepatic bile ducts

b. Causes

i. Drugs (e.g., oral contraceptive pills, anabolic steroids)

ii. Neonatal hepatitis

iii. Pregnancy-induced cholestasis (estrogen)

2. Extrahepatic cholestasis

a. Blockage of common bile duct (CBD)

b. Causes

i. Stone usually originating from the gallbladder

ii. Primary sclerosing pericholangitis

iii. Extrahepatic biliary atresia

iv. Carcinoma head of pancreas

Gross and microscopic

1. Enlarged, green-colored liver

2. Bile ducts distended with bile, bile lakes, bile infarcts

Clinical findings

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1. Jaundice with pruritus

Pruritus due to bile salts deposited in skin

2. Malabsorption

Bile salts do not enter the small intestine.

3. Cholesterol deposits in skin

Due to cholesterol in bile

4. Light-colored stools

Due to a lack of urobilin

Laboratory findings

1. CB >50%

2. Bilirubinuria

3. Absent urine UBG

4. Increase in serum ALP and GGT

Benign intrahepatic cholestasis of pregnancy

1. Due to estrogen inhibition of intrahepatic bile secretion

2. Not dangerous to the fetus or mother

Extrahepatic biliary atresia

1. Cause of jaundice in newborns

2. Inflammatory destruction of all or part of the extrahepatic bile ducts

3. Bile duct proliferation in the triads

4. Common indication for liver transplantation in a child

Primary sclerosing pericholangitis

1. Epidemiology

a. Obliterative fibrosis of intrahepatic and extrahepatic bile ducts

b. Male dominant

c. Associated with ulcerative colitis


a. Jaundice

b. Cirrhosis

c. Increased incidence of cholangiocarcinoma

Cirrhosis

Irreversible diffuse fibrosis of the liver with formation of regenerative nodules

Regenerative nodules

1. Hepatocyte reaction to injury

2. Lack normal liver architecture

Lack of portal triads and sinusoids

3. Surrounded by bands of fibrosis

4. Compress sinusoids and central veins

. Intrasinusoidal hypertension

a. Reduction in the number of functional sinusoids

b. Increase in hydrostatic pressure in portal vein

Causes

1. Alcoholic liver disease (most common)

2. Postnecrotic cirrhosis (HBV, HCV)

3. Autoimmune disease (primary biliary cirrhosis)

4. Metabolic disease:

a. Hemochromatosis, Wilson's disease

b. 1-Antitrypsin deficiency, galactosemia

Complications associated with cirrhosis

Ammonia derives from metabolism of amino acids and from the release of ammonia from amino acids by bacterial ureases in the bowel. Ammonia (NH3) is diffusible and is reabsorbed into the portal vein for delivery to the urea cycle where it is metabolized into urea. Ammonium (NH4+) is not reabsorbed in the bowel and is excreted in stool. Methods for reducing the synthesis of ammonia in the colon include restriction of protein intake (most cost effective) and the use of oral neomycin, which destroys the colonic bacteria. Oral administration of lactulose results in the release of hydrogen ions causing NH3 to be converted to NH4+, which is excreted in the feces.

1. Hepatic failure

End point of progressive damage to the liver

b. Multiple coagulation defects

b. Due to inability to synthesize coagulation factors

b. Produces a hemorrhagic diathesis

c. Hypoalbuminemia from decreased synthesis of albumin

c. Produces dependent pitting edema and ascites

d. Hepatic encephalopathy

d. Reversible metabolic disorder

d. Increase in aromatic amino acids (e.g., phenylalanine, tyrosine, tryptophan)

d. Converted into false neurotransmitters (e.g., gamma aminobutyric acid)

d. Increase in serum ammonia

d. Due to a defective urea cycle that cannot metabolize ammonia

d. Clinical findings

d. Alterations in the mental status

d. Somnolence and disordered sleep rhythms

d. Asterixis (i.e., inability to sustain posture, flapping tremor)

d. Coma and death in late stages

a. Portal hypertension

. Pathogenesis

. Resistance to intrahepatic blood flow due to intrasinusoidal hypertension

. Anastomoses between portal vein tributaries and the arterial system

a. Complications

a. Ascites (see below)

a. Congestive splenomegaly

a. Increased hydrostatic pressure in splenic vein

a. Hypersplenism with various cytopenias may occur

a. Esophageal varices

a. Hemorrhoids, periumbilical venous collaterals (caput medusae)

a. Ascites

. Pathogenesis

. Portal hypertension

. Increase in portal vein hydrostatic pressure

. Hypoalbuminemia

. Decreases oncotic pressure

. Secondary hyperaldosteronism; causes:

. Decreased cardiac output

. Activates the renin-angiotensin-aldosterone system (retention of Na+ and water)

. Liver unable to metabolize aldosterone

a. Clinical findings

a. Abdominal distention with a fluid wave

a. Increased risk for spontaneous bacterial peritonitis

a. Hepatorenal syndrome

. Renal failure without renal parenchymal disease

a. Due to decreased renal blood flow

b. Preservation of renal tubular function

a. Hyperestrinism in males

. Pathogenesis

. Liver cannot degrade estrogen and 17-ketosteroids (e.g., androstenedione).

. Androstenedione is aromatized into estrogen in the adipose cell.

a. Clinical findings

a. Gynecomastia

a. Spider telangiectasia

a. Female distribution of hair

Postnecrotic cirrhosis

1. Most often caused by chronic hepatitis due to HBV and HCV

2. Increased incidence of hepatocellular carcinoma

Primary biliary cirrhosis (PBC)

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1. Epidemiology

a. Autoimmune disorder

Granulomatous destruction of bile ducts in portal triads

b. Occurs more often in women between 40 and 50 years of age

c. Progresses from a chronic inflammatory reaction to cirrhosis


a. Pruritus

. Deposition of bile salts in skin

i. Early finding well before jaundice appears

i. Hepatomegaly

i. Jaundice

Late finding after most of the bile ducts have been destroyed

Cirrhosis with portal hypertension

Increased risk for hepatocellular carcinoma

Laboratory findings

Antimitochondrial antibodies (>90% of cases)

Increase in IgM

Secondary biliary cirrhosis

1. Complication of chronic extrahepatic bile duct obstruction

Example-cystic fibrosis, where bile is dehydrated

2. No increase in antimitochondrial antibodies or IgM

Hereditary hemochromatosis

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The normal function of the HFE gene product is to facilitate the binding of plasma transferrin (binding protein of iron) with its mucosal cell transferrin receptor so that transferrin can be endocytosed by intestinal cells. The amount of endocytosed transferrin iron determines how much mucosal cell iron is released into the plasma. In hemochromatosis, when there is a mutated HFE gene, mucosal cell transfer of iron to plasma transferrin is always at a maximum resulting in iron overload.

Hemosiderosis (secondary hemochromatosis) is caused by multiple blood transfusions (e.g., sickle cell anemia, thalassemia major); alcohol abuse (alcohol increases iron reabsorption); and well water (iron pipes). Iron deposits are more prevalent in macrophages than in parenchymal tissue.

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1. Epidemiology

a. Autosomal recessive disorder

b. Male dominant disorder

c. In women, symptoms develop after menopause.

Due to menses causing loss of iron

2. Pathogenesis

a. Unrestricted reabsorption of iron in the small intestine

b. Mutations involving hereditary hemochromatosis gene (HFE)

There is a 1:10 carrier rate in the population.

c. Iron stimulates the production of hydroxyl free radicals

Free radicals damage tissue and cause fibrosis.

3. Iron deposits in multiple organs

Liver, pancreas, heart, joints, skin, pituitary

Clinical and laboratory findings

. Cirrhosis

. Iron deposits primarily in hepatocytes

. Increased risk of hepatocellular carcinoma

a. "Bronze diabetes"

a. Type I diabetes mellitus

a. Destruction of -islet cells

a. Hyperpigmentation

a. Iron deposits in skin and increases melanin production

b. Malabsorption

b. Destruction of exocrine pancreas

c. Restrictive cardiomyopathy, degenerative joint disease

d. Increased serum iron, percent saturation, and ferritin

e. Decreased total iron-binding capacity

e. Transferrin synthesis is decreased when iron stores are increased

Wilson's disease (hepatolenticular degeneration)

Ceruloplasmin, the binding protein for copper, is secreted into the plasma where it represents 90% to 95% of the total serum copper concentration. The remaining 5% to 10% of copper is free copper that is loosely bound to albumin. Ceruloplasmin is eventually taken up and degraded by the liver. The copper that was bound to ceruloplasmin is excreted into the bile. The gene defect in Wilson's disease affects a copper transport system that produces a dual defect-decreased synthesis of ceruloplasmin in the liver and decreased excretion of copper into bile. Accumulation of copper in the liver increases the formation of free radicals causing damage to hepatocytes. In a few years, unbound copper is released from the liver into the circulation (increased in blood and urine) where it damages the brain, kidneys, cornea, and other tissues.

1. Epidemiology

Autosomal recessive disorder

2. Pathogenesis

. Gene mutation

. Defective hepatocyte transport of copper into bile for excretion

. Decreased synthesis of ceruloplasmin (binding protein for copper in blood)

a. Unbound copper eventually accumulates in blood

a. Loosely attached to albumin

a. Copper deposits in other tissues causing a toxic effect.

a. Clinical and laboratory findings

. Liver disease progresses from acute hepatitis to cirrhosis.

a. Kayser-Fleischer ring

a. Due to free copper deposits in Descemet's membrane in the cornea

b. Central nervous system disease

b. Copper deposits in the putamen

b. Produces a movement disorder resembling parkinsonism

b. Copper deposits in the subthalamic nucleus

b. Produces hemiballismus

b. Copper is toxic to neurons in the cerebral cortex

b. Produces dementia

c. Decreased total serum copper

c. Due to decreased ceruloplasmin

d. Decreased serum ceruloplasmin

d. Useful in diagnosing Wilson's disease in its early stages

e. Increased serum and urine free copper

e. Useful in diagnosing Wilson's disease in the later stages

1-Antitrypsin (AAT) deficiency

1. Autosomal recessive disorder

2. Pathogenesis

a. Alleles are inherited codominantly (each allele expresses itself).

b. Normal genotype is PiMM.

c. Most common abnormal allele is Z.

d. PiZZ variant has decreased AAT levels in serum.

i. Production of a mutant protein that cannot be secreted into blood

ii. Accumulation of AAT in hepatocytes causes liver damage.

Periodic acid-Schiff stains show red cytoplasmic granules.

3. Clinical findings in children with PiZZ variant

a. Neonatal hepatitis with intrahepatic cholestasis

b. Most common cause of cirrhosis in children

c. Increased risk for hepatocellular carcinoma

4. Young adults with panacinar emphysema

PiZZ variant where there is no synthesis of AAT in the liver

Laboratory test abnormalities in cirrhosis

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1. Decreased serum blood urea nitrogen (BUN) and increased serum ammonia

Due to disruption of the urea cycle

2. Fasting hypoglycemia

Defective gluconeogenesis and decreased glycogen stores

3. Chronic respiratory alkalosis

Toxic products from hepatic dysfunction overstimulate respiratory center

4. Lactic acidosis

Liver dysfunction in converting lactic acid to pyruvate

5. Hyponatremia

6. Hypokalemia

Secondary aldosteronism increases renal exchange of Na+ for K+

7. Increased PT

Decreased synthesis of coagulation factors

8. Hypoalbuminemia

Decreased synthesis of albumin

9. Hypocalcemia

. Hypoalbuminemia decreases the total serum calcium.

. Approximately 40% of the total calcium is calcium bound to albumin.

a. Vitamin D deficiency

a. Decreased liver 25-hydroxylation of vitamin D.

a. Mild transaminasemia

Enzymes are not markedly increased due to the loss of parenchymal cells.

Liver Tumors

Benign tumors

1. Cavernous hemangioma

a. Most common benign tumor

b. Rare cause of intraperitoneal hemorrhage

2. Liver (hepatic) cell adenoma

a. Benign tumor of hepatocytes

b. Usually occur in women of childbearing age

Associated with the use of oral contraceptive pills

c. Highly vascular tumors

. Tendency to rupture during pregnancy

i. Produce intraperitoneal hemorrhage

Benign tumors

1. Cavernous hemangioma

a. Most common benign tumor

b. Rare cause of intraperitoneal hemorrhage

2. Liver (hepatic) cell adenoma

a. Benign tumor of hepatocytes

b. Usually occur in women of childbearing age

Associated with the use of oral contraceptive pills

c. Highly vascular tumors

. Tendency to rupture during pregnancy

i. Produce intraperitoneal hemorrhage

Malignant tumors

1. Metastasis

a. Most common liver cancer

b. Primary cancers of lung (most common), gastrointestinal tract, breast

c. Multiple nodular masses

2. Hepatocellular carcinoma

a. Epidemiology

i. Most common primary liver cancer

ii. Male dominant

Peaks around 60 years of age

iii. Causes

Chronic HBV and HCV

Aflatoxins (from Aspergillus mold in grains and peanuts)

Hereditary hemochromatosis, alcoholic cirrhosis, PBC, AAT deficiency

b. Pathogenesis

i. Most often associated with preexisting cirrhosis

ii. Postnecrotic cirrhosis HBV/HCV most common risk factors

c. Gross findings

i. Focal, multifocal, or diffusely infiltrating cancer

With or without preexisting cirrhosis (usually with preexisting cirrhosis)

ii. Portal and hepatic vein invasion is common.

d. Microscopic findings

Characteristic finding is the presence of bile in neoplastic cells.

Clinical findings

. Fever due to liver cell necrosis

i. Rapid enlargement of the liver

ii. Increased ascites, blood present in ascitic fluid

iii. Laboratory findings

iv. Increased -fetoprotein (AFP)

v. Production of ectopic hormones

v. Erythropoietin (secondary polycythemia)

v. Insulin-like factor (hypoglycemia)

i. Lung most common metastatic site

i. Angiosarcoma

Exposure to vinyl chloride (most common cause), arsenic, or thorium dioxide

Gallbladder and Biliary Tract Disease

Cystic diseases

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1. Choledochal cyst

a. Most common cyst in biliary tract in children younger than 10 years old


i. Abdominal pain with persistent or intermittent jaundice

ii. Increased incidence of cholelithiasis, cholangiocarcinoma, and cirrhosis

2. Caroli disease

a. Autosomal recessive disease

b. Segmental dilatation of intrahepatic bile ducts


i. Association with polycystic kidney disease

ii. Increased incidence of cholangiocarcinoma

Cystic diseases

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1. Choledochal cyst

a. Most common cyst in biliary tract in children younger than 10 years old


i. Abdominal pain with persistent or intermittent jaundice

ii. Increased incidence of cholelithiasis, cholangiocarcinoma, and cirrhosis

2. Caroli disease

a. Autosomal recessive disease

b. Segmental dilatation of intrahepatic bile ducts


i. Association with polycystic kidney disease

ii. Increased incidence of cholangiocarcinoma

Cholangiocarcinoma

1. Most common malignancy of bile ducts

2. Causes of cholangiocarcinoma

a. Primary sclerosing pericholangitis (see section VI)

Most common cause in United States

b. Clonorchis sinensis (Chinese liver fluke)

c. Thorotrast (thorium dioxide)

d. Choledochal cyst and Caroli disease


a. Obstructive jaundice

b. Palpable gallbladder (Courvoisier's sign)

Gallstones (cholelithiasis)

1. ypes

a. Cholesterol stones (80% of cases)

They are radiolucent.

b. Pigment stones

. Black and brown pigment stones

i. Some are radiopaque.

i. Pathogenesis

i. Cholesterol stones

. Supersaturation of bile with cholesterol

i. Decreased bile salts and lecithin

i. Both normally solubilize cholesterol in bile

ii. Risk factors

ii. Female over 40 years old

ii. Obesity

ii. Cholesterol is increased in bile.

ii. Use of oral contraceptive pills

ii. Estrogen increases cholesterol in bile.

ii. Rapid weight loss, use of lipid-lowering drugs

ii. Native Americans (e.g., Pima and Navajo Indians)

i. Pigment stones

. Black pigment stones

. Sign of chronic extravascular hemolytic anemia (e.g., sickle cell anemia)

. Excess bilirubin in bile produces calcium bilirubinate

i. Brown pigment stones

i. Sign of infection in the CBD

i. Complications associated with stones

i. Cholecystitis (most common)

i. CBD obstruction

i. Gallbladder cancer

i. Acute pancreatitis

Acute cholecystitis

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1. Pathogenesis

a. Obstruction of cystic duct by a stone (90% of cases)

i. Causes increased intraluminal pressure and ischemia to gallbladder wall

Mucosal ulceration predisposes to infection (usually E. coli).

ii. Chemical irritation from conversion of lecithin to lysolecithin (toxic)

b. Other causes not associated with stones

i. AIDS

Infection with cytomegalovirus (CMV) or Cryptosporidium

ii. Severe volume depletion

2. Clinical and laboratory findings

a. Fever with nausea and vomiting

Usually 15 to 30 minutes after eating

Initial midepigastric colicky pain

Pain eventually shifts to the right upper quadrant.

. Pain is constant and dull

i. Pain may radiate to right scapula

i. Jaundice suggests a stone in the CBD.

i. Neutrophilic leukocytosis with left shift

i. Tests to identify stones

. Ultrasound is the gold standard

i. Radionuclide scan identifies stone(s) in cystic duct.

Chronic cholecystitis

1. Pathogenesis

a. Cholelithiasis with repeated attacks of minor inflammation

b. Chemical inflammation (infection is uncommon)


a. Severe, persistent pain 1 to 2 hours postprandially

b. Recurrent epigastric distress, belching, and bloating

Cholesterolosis

1. Excess cholesterol in bile

a. Cholesterol deposits in macrophages

b. Produces a yellow, speckled mucosal surface

2. No clinical significance

Gallbladder adenocarcinoma

1. Epidemiology

a. Dominant in elderly women

b. Poor prognosis

2. Pathogenesis

a. Cholelithiasis (95% of cases)

b. Porcelain gallbladder

Gallbladder with dystrophic calcification

Pancreatic Disorders

Embryologic abnormalities of the pancreas

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1. Annular pancreas

a. Dorsal and ventral buds form a ring around the duodenum.

b. Associated with small bowel obstruction

2. Aberrant pancreatic tissue (i.e., heterotopic rest, choristoma)

Locations-wall of stomach, duodenum, jejunum, or in a Meckel diverticulum

Major pancreatic duct

. Major pancreatic duct and CBD are confluent in their terminal part

. Both empty their contents into the duodenum via the ampulla of Vater

a. Important in the pathogenesis of acute pancreatitis

a. Stone(s) obstruct terminal part of the CBD

a. Increased back-pressure refluxes bile into the major pancreatic duct

a. Bile activates pancreatic proenzymes causing acute pancreatitis

Embryologic abnormalities of the pancreas

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1. Annular pancreas

a. Dorsal and ventral buds form a ring around the duodenum.

b. Associated with small bowel obstruction

2. Aberrant pancreatic tissue (i.e., heterotopic rest, choristoma)

Locations-wall of stomach, duodenum, jejunum, or in a Meckel diverticulum

Major pancreatic duct

. Major pancreatic duct and CBD are confluent in their terminal part

. Both empty their contents into the duodenum via the ampulla of Vater

a. Important in the pathogenesis of acute pancreatitis

a. Stone(s) obstruct terminal part of the CBD

a. Increased back-pressure refluxes bile into the major pancreatic duct

a. Bile activates pancreatic proenzymes causing acute pancreatitis

Acute pancreatitis

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An increase in amylase is not specific for pancreatitis. Other causes of hyperamylasemia include mumps, small bowel infarction, and a ruptured ectopic pregnancy.

1. Epidemiology and pathogenesis

a. Alcohol abuse and gallstones are the major causes

b. Must be activation of pancreatic proenzymes (inactive enzymes)

Activation leads to autodigestion of the pancreas

c. Mechanisms of activation of proenzymes

. Obstruction of the main pancreatic duct or terminal CBD

. Gallstones (see section IX)

. Alcohol thickens ductal secretions

. Also increases duct permeability to enzymes

i. Chemical injury of acinar cells

i. Examples-thiazides, alcohol, triglyceride (>1000 mg/dL)

ii. Infectious injury of acinar cells

ii. Examples-CMV, mumps, coxsackievirus

iii. Mechanical injury of acinar cells

iii. Examples-seat belt trauma, posterior penetration of duodenal ulcer

iv. Metabolic activation of proenzymes (e.g., hypercalcemia, ischemia, shock)

i. Trypsin is important in the activation of proenzymes.

. Proteases damage acinar cell structure.

i. Lipases and phospholipases produce enzymatic fat necrosis.

ii. Elastases damage vessel walls and produce hemorrhage

iii. Activated enzymes also circulate in the blood.


i. Fever, nausea and vomiting

i. Severe, boring midepigastric pain with radiation into the back

Radiation into back is due to its retroperitoneal location.

Shock

Due to hemorrhage and loss of enzyme-rich fluid around the pancreas (called "third spacing")

Hypoxemia

. Circulating pancreatic phospholipase destroys surfactant.

. Loss of surfactant produces atelectasis and intrapulmonary shunting.

i. Acute respiratory distress syndrome (ARDS) may occur.

i. Grey-Turner's sign (flank hemorrhage), Cullen's sign (periumbilical hemorrhage)

i. Tetany

. Hypocalcemia is caused by enzymatic fat necrosis.

i. Calcium binds to fatty acids leading to a decrease in ionized calcium.

i. Laboratory findings

i. Increased serum amylase

. Increased in 2 to 12 hours

i. Returns to normal in 2 to 3 days

i. Increased renal clearance

ii. Present in urine for 1 to 14 days

i. Increased serum lipase

. More specific for pancreatitis

i. Serum levels return to normal in 3 to 5 days.

ii. Is not excreted in urine

i. Neutrophilic leukocytosis

i. Hypocalcemia, hyperglycemia (destruction of -islet cells)

i. Computed tomographic (CT) scan is the gold standard for pancreatic imaging.

i. Plain abdominal radiograph

. Sentinel loop in subjacent duodenum or transverse colon (cut-off sign)

. Localized ileus, where the bowel does not demonstrate peristalsis

i. Left-sided pleural effusion containing amylase (10% of cases)

i. Complications

i. Pancreatic pseudocyst

. Collection of digested pancreatic tissue around pancreas

i. Abdominal mass with persistence of serum amylase longer than 10 days

i. Amount of amylase in the fluid surpasses renal clearance of amylase.

i. ARDS, pancreatic abscess, disseminated intravascular coagulation

Chronic pancreatitis

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1. Epidemiology

a. Majority of cases are idiopathic.

b. Known causes

i. Alcohol abuse is the most common known cause.

ii. Cystic fibrosis is the most common cause in children.

iii. Malnutrition is the most common cause in developing countries.

2. Pathogenesis

a. Repeated attacks of acute pancreatitis produce duct obstruction.

b. Calcified concretions occur as well as dilation of the ducts.

Radiographic dyes show a "chain of lakes" appearance in the major duct.

Clinical findings

Severe pain radiating into the back

Malabsorption

Type 1 diabetes mellitus

Pancreatic pseudocyst

Laboratory and radiographic findings

Increased amylase and lipase

Pancreatic calcifications (CT scan best study)

Exocrine pancreatic cancer

1. Epidemiology

a. Adenocarcinoma

Varying degrees of differentiation

b. Causes

. Smoking (most common cause)

i. Chronic pancreatitis

ii. Hereditary pancreatitis

i. Pathogenesis

i. Association with K-RAS gene mutation

i. Mutation of suppressor genes (TP16 and TP53)

i. Location

i. Most occur in the pancreatic head (65% of cases)

Often blocks CBD causing jaundice

Remainder occur in the body and tail

Clinical and laboratory findings

Epigastric pain with weight loss

Signs of CBD obstruction (carcinoma of head of pancreas)

. Jaundice (CB > 50%)

i. Light-colored stools (absent UBG)

ii. Palpable gallbladder (Courvoisier's sign)

i. Superficial migratory thrombophlebitis

i. Increased CA19-9

Gold standard tumor marker

Poor prognosis

Documents

18 Hepatobiliary and Pancreatic Disorders