Pathogenesis of Hyperbilirubinemia
Occurs when serum bilirubin > 1.2 mg/dl
Pre-hepatic
increased production of bilirubin (hemolysis). Increased indirect bilirubin.
Hepatic (hepatocellular)
impaired uptake or conjugation of bilirubin. Increased indirect (unconjugated) bilirubin. As with liver cell injury caused by hepatitis or toxins. Medications (such as phenothiazines) that interfere with conjugation
Post-hepatic (cholestatic)
decreased excretion of conjugated bilirubin. Increased direct (conjugated) bilirubin. As with common bile duct obstruction
Clinical Characteristics of Hyperbilirubinemia
Jaundice (icterus): yellow sclera / skin, serum bili > 2.0-2.5 mg/dl
Neonatal jaundice
If > 12 mg/dl can result in brain damage, especially in premature infants. > 20 mg/dl definite kernicterus (brain damage caused by excessive jaundice)
Hepatic Injury five general responses
Inflammation - injures the hepatocytes (liver cells) (i.e. hepatitis, toxins), degeneration, cell death, fibrosis, and cirrhosis
Acute hepatitis
anicteric or icteric (jaundice)
Chronic hepatitis
with or without progression to cirrhosis
Carrier State
without apparent disease, or with subclinical chronic hepatitis
Asymptomatic infection
serologic evidence only
Fulminant hepatitis
hepatic necrosis; occurs suddenly, severe to the point of death.
Hepatitis A virus (HAV)
Immunization is available. Usually a benign, self-limited disease. Incubation period 2 to 6 weeks. No chronic or carrier state. Rare fatalities ( about 0.1%)Transmitted orally commonly through contaminated water and food (fecal-oral)
Not shed significantly in saliva, urine, semen; rare transmission of virus through blood
Hepatitis A virus (HAV). Virus does not appear to harm hepatocytes, instead injury results from the immune response
Hepatitis B virus (HBV)
Immunization is available. Transmitted primarily through blood / body fluid contact
Hepatitis C virus (HCV)
Incubation is from 2 to 26 weeks (mean 6-12). Fulminant hepatitis is rare. Higher rate of progression to chronic disease and cirrhosis
May be the leading cause of chronic liver disease in the Western world.
Hepatitis C virus (HCV). Persistent (chronic) infection is the hallmark of HCV infection. Transmitted through inoculations and blood transfusions, with IV drug use accounting for >40% in the US (?)
Hepatitis D virus (HDV)
Arises in two settings: Acute co-infection after exposure to serum with HDV and HBV; super-infection of a chronic carrier of HBV
Is dependent on HBV co-infection for replication
HDV. Most individuals clear the infection and recover. Transmitted through serum and close personal contact
Hepatitis E Virus (HDE)
Incubation period 2 to 8 weeks (ave 6 wks). No chronic or carrier state. Waterborne transmission. Found predominantly in India. Accounts for > 50% of cases of acute hepatitis, epidemics in Asia, Africa, and Mexico
Hepatitis G Virus (HDE)
Incubation period is UNKNOWN. Transmitted by contaminated blood or blood products and possibly via sexual transmission. No pathologic effects (?) BUT might provide protective effects in patients with HIV (so there is that)
Most common liver disorder in western countries (related to insulin resistance - obesity, diabetes, dyslipidemia, metabolic syndrome)
Non-alcoholic fatty liver disease (NAFLD). Build-up of fat in the liver due to increased fatty acid synthesis.
Non-alcoholic steato-hepatitis (NASH)
hepatic inflammation hard to distinguish from alcoholic hepatitis by biopsy. (To distinguish alcoholic liver disease (ALD) from non-alcoholic fatty liver disease (NAFLD))
Alcoholic liver disease
Usually patients have history of heavy alcohol use (more than 100 g/day) for decades and includes alcoholic fatty liver disease (with or without steato-hepatitis), alcoholic hepatitis, and cirrhosis
Rule out chronic viral hepatitis (HCV) as the cause of the chronic liver disease:
Liver biopsy might be needed, but findings are not specific for alcoholic hepatitis.
Low serum albumin
liver does not produce enough
Coagulopathy
liver does not produce enough clotting factors
High MCV (mean corpuscular volume of RBC)
Look for elevated serum Cr and decreased glomerular filtration rate (GFR) to predict hepato-renal syndrome (liver and kidney failure).
Alcoholic hepatitis Clinical presentation: History
fever, anorexia, jaundice
Alcoholic hepatitis Clinical presentation: Physical
RUQ or epigastric pain, tender hepatomegaly, many have bruit over the liver; some have ascites. Other signs of advanced liver disease - spider angiomata, palmar erythema, gynecomastia, (due to increased estrogen). Proximal muscle wasting due to malnutriti
Acute or chronic liver failure characterized by
jaundice, encephalopathy, sometimes renal failure.
Hepato-renal syndrome
hepatic and renal failure. Probably due to decreased GFR (glomerular filtration rate). Hypo-albuminemia leads to loss of fluid from intravascular space into peritoneal cavity and eventually ascites
Cirrhosis
end stage of chronic liver disease. Deposition of fibrous septa (scar) around regenerated nodules of hepatocytes. Liver becomes firm, maybe shrunken.
Alcoholic Cirrhosis Incidence:
In most people, it takes 80-160 grams / day of EtOH (ethanol) for 10 - 20 years to result in some form of hepatic injury. Only 10% of alcoholics will develop cirrhosis
Alcoholic Cirrhosis Pathogenesis:
Hepato-cellular (liver cell) necrosis, followed by fibrosis (scarring) surrounding nests of living hepatocytes (liver cells). Portal hypertension is a result. Liver failure follows
If cirrhosis has not developed and EtOH intake is stopped, the liver can
fully recover normal function
Primary Biliary Cirrhosis
Chronic cholestatic liver disease - immune destruction of intra-hepatic bile ducts impairs bile flow
Primary Biliary Cirrhosis Incidence:
most are women ages 30-65
Primary Biliary Cirrhosis Clinical Characteristics:
Most patients already have another auto-immune disease. Most have circulating anti-mitochondrial antibodies. Obstructive jaundice
Sclerosing cholangitis
Cell-mediated immune destruction of bile ducts (intra- and extra-hepatic)
Primary Biliary Cirrhosis Incidence:
most are men < 40
Primary Biliary Cirrhosis Pathogenesis:
Segmental narrowing beading of larger bile ducts
Primary Biliary Cirrhosis Clinical Characteristics:
Many have inflammatory bowel disease (ulcerative colitis). Obstructive jaundice. Risk of cholangio-carcinoma (cancer of bile ducts). Candidate for liver transplant
Gilbert Syndrome
autosomal dominant disorder of bilirubin metabolism
Gilbert Syndrome Pathogenesis:
Mild chronic unconjugated hyperbilirubinemia due to defect in bilirubin conjugation.
Gilbert Syndrome Clinical Characteristics:
Causes intermittent jaundice. Begins after puberty, more common in males. Mostly asymptomatic, found incidentally
Pathogenesis of primary hemochromatosis
autosomal recessive condition leading to excess iron (Fe) deposition in liver, pancreas, pituitary.
Hemochromatosis Clinical Characteristics:
Bronze pigmentation of skin. Often found with DM - "Bronze Diabetes". Diagnosed by high serum Fe, high saturation of transferrin. Fe deposits in cirrhotic liver
Pathogenesis of secondary hemochromatosis
hemolysis
Secondary hemochromatosis
chronic Fe overload such as with hemolysis.
Wilson's Disease
autosomal recessive disorder of copper metabolism
Wilson's Disease Pathogenesis:
Copper is not eliminated from the body, therefore it accumulates.
Wilson's Disease Clinical Characteristics:
Kayser-Fleischer rings around irises. Neurologic disorders, large liver
Alpha1- antitrypsin deficiency
Deficiency results in damage to pulmonary alveoli leading to emphysema. Deficiency also results in more liver cell damage. 20% can progress to cirrhosis. Common cause of childhood cirrhosis
Pathophysiology of cirrhosis When liver is damaged, these cells are "activated" to proliferate and secrete collagen (scar) which "squeezes" the sinusoids. Increased pressure in the liver vessels
backs up into the portal vein branches, this leads to portal hypertension.
Portal Hypertension
Increased pressure in portal venous system (portal vein and its braches). Due to obstruction of blood flow through liver, often due to cirrhosis.
Portal Hypertension
can lead to dilation of vessels feeding the portal vein, resulting in splenomegaly, dilation of veins of abdominal wall, and esophageal varices. Eventually ascites forms
Pre hepatic Portal Hypertension
Problem is before portal blood reaches the liver.
Budd-Chiari Syndrome
occlusion of the intrahepatic and/or hepatic veins. (may be considered both intra- and/or post-hepatic). Polycythemia vera, hepatocellular carcinoma, pregnancy, trauma , tumor metastasis from the adrenals / kidney
Post-hepatic Portal Hypertension
Problem is blood flow AFTER the liver. Blood "tries" to leave the liver via hepatic veins, to drain into the IVC, but is impeded due to:
Budd-Chiari Syndrome hepatic vein thrombosis.
Obstruction of inferior vena cava above the liver, chronic heart failure, and constrictive pericarditis
Polycystic liver disease
congenital, autosomal dominant. Problems develop as adult
Polycystic liver disease
If cysts replace much functioning hepatic tissue leading to liver failure
Hemangioma
Common benign hepatic tumor of blood vessels; usually no harm to the patient. Low risk of rupture, even when large
Focal nodular hyperplasia (FNH)
Not a true neoplasm but rather represents a response to abnormal vascular flow through a congenital or acquired vascular anomaly
Hepatic adenoma
Young women, especially those on OCP. Also with anabolic androgens & glycogen storage disease. May be symptomatic. Can rupture (especially if > 4 cm)
Hepatocellular Carcinoma
Associated with chronic liver disease. Higher rates with cirrhosis and chronic Hepatitis B, C. May be a large solitary tumor or many small ones
Hepatocellular Carcinoma patients may present with
Painful enlarging mass in the liver, ascites, portal vein thrombosis, and hemorrhage from esophageal varicies
cholangio
bile ducts in general
choledocho
common bile duct
choledocholithiasis
stones in common duct
Choledocholithiasis can cause
obstructive jaundice, cholangitis, or pancreatitis
Cholelithiasis
Presence of stones in gall gallbladder or in extrahepatic biliary ducts
Cholesterol Stones
Most common; formed in bile that is supersaturated with cholesterol AND with decreased bile acids and lecithin
Cholesterol Stones Risk Factors:
female, fat, forty, fertile" or not! Often occur in obese persons or with metabolic disorders (diabetes) - or in skinny people without diabetes!
Black Pigmentary Stones Major components:
Calcium bilirubinate, cholesterol, calcium soaps of fatty acids
Black Pigmentary Stones Risk factors:
hemolysis, cirrhosis. Formation due to increased concentration of unconjugated bilirubin in the bile.
Chronic hemolytic processes increase the likelihood, including in children
Black Pigmentary Stones. Thalassemia, sickle cell disease, others
Brown Stones Risk factors:
INFECTION. Associated with inflammation of the gall bladder due to E. coli or by liver flukes endemic in Asia
Chronic Cholecystitis ("biliary colic")
Periodic pain associated with gall stones, concentrated bile and stones irritate the mucosal lining of gallbladder. RUQ or epigastric pain is self-limiting. Often with nausea and vomiting. Not an acute infection: no fever or leukocytosis
Acute Cholecystitis Pathogenesis:
Inflammation of gallbladder, usually due to obstruction of cystic duct (not CBD) by stone. Infection with Gram neg rods (E-coli, Klebsiella).
Acute Cholecystitis Clinical Characteristics:
Pain in the RUQ, often after a high fat meal. May have associated fever, nausea, vomiting, leukocytosis.
Acute Cholecystitis Physical exam findings May be associated with "Murphy sign
patient exhales, you palpate the RUQ, then have patient inhale; it will hurt! Jaundice is NOT common (not obstruction of CBD).
Extrahepatic Biliary Obstruction
Decreased outflow of bile from the liver due to blockage of bile ducts outside the liver: Gall stones lodged in common bile duct (CBD), tumor of other structures surrounding the CBD, and (Less commonly) tumor of CBD; congenital abnormality
Common bile duct (CBD) obstruction Clinical Characteristics:
Patient might not notice JAUNDICE, but others do. Might not have pain
CBD obstruction with infection
cholangitis Serious, life-threatening!
Cholangitis Pathogenesis:
infection in obstructed CBD
Cholangitis Clinical Characteristics:
Very ill! - may be in septic shock
Cholangitis Physical exam findings Charcot's triad:
Fever/chills, JAUNDICE, and RUQ pain. Palpable gallbladder in RUQ
Cholecystectomy
removal of the gallbladder (usually for symptomatic stones)