Diseases of the liver

LiverLiver

Maintaining body metabolic homeostasis: Lipid and carbohydrate metabolism: production

and secretion of glucose Protein synthesis: albumin, coagulation factors Detoxification and drug metabolism Excretion of bilirubin Synthesis and excretion of bile salts

Normal liver has smooth brown surface

Weight: 1200-1600 g

Liver anatomy and histology

Patterns of hepatic injury Inflammation Steatosis: accumulation of fat droplets within

hepatocytes Cell death: those cells closer to the central vein are more

susceptible to ischemia, toxins and drugs leading to “centri-lobular” necrosis

Fibrosis: Irreversible, affect blood flow and hepatocyte function

Cirrhosis: End stage liver disease with diffuse fibrosis and regenerating nodules

Steatosis Alcohol, Obesity, Diabetes

Hyperlipidemia

Clinical picture:Silent, or fatigue, malaise, right upper quadrant discomfort

Liver cirrhosis Definition: bridging fibrous septa and parenchymal

nodules with disruption of architecture. End stage for many diseases affecting the liver

Mechanism: cell death, regeneration and fibrosis

Clinical consequences of liver disease

Hepatic dysfunction:

Decrease synthesis capacity leading to :

Hypoalbuminemia: edema, ascitis, muscle

wasting, weight loss

Hypoglycemia: weakness and syncope

Coagulation factor deficiency: bleeding

Decrease detoxification capacity leading to:

Hyperammonemia and increase toxic

metabolites: Encephalopathy (altered behavior

and consciousness that may lead to deep coma

and death)

Injury to other organs by active toxins

Hepato-renal syndrome:

Renal failure without intrinsic or functional

causes of renal failure.

Clinical picture liver diseaseClinical picture liver disease Jaundice: yellow discoloration of skin and sclera due to

accumulation of bilirubin Cholestasis: systemic accumulation of bilirubin, bile salts and

cholesterol (usually secondary to obstruction) Portal hypertension in cirrhosis: increased resistance to portal

blood flow Esophageal varices Ascitis Splenomegaly Hemorrhoids

Malignancy on top of cirrhosis

Jaundice Jaundice Accumulation of bilirubin in tissue leading to yellow

discoloration of skin and sclera

Normal serum level: 0.3-1.2 mg/dl; jaundice appears

with levels above 2.0-2.5 mg/dl

Source of bilirubin: the breakdown of old red blood cells

in the spleen releases heme that changes into bilirubin

by specific enzymes.

Bilirubin

Unconjugated- Albumin

bound- Insoluble in

water, toxic

Conjugated- Loosely bound

to albumin- Water soluble,

non-toxic, excreted in urine

Conjugation is a function of the liver by adding glucuronic acid to bilirubin

Laboratory evaluation of liver disease Hepatocyte function:

Serum albumin Prothrombin time: prolonged in liver cirrhosis Serum ammonia

Hepatocyte injury (enzymes normally present inside the hepatocytes and released with injury): Serum aspartate aminotransferase (AST) Serum alanine aminotransferase (ALT) Serum lactate dehydrogenase

Biliary excretory function: Serum bilirubin Serum alkaline phosphatase Serum gamma-glutamyl transpeptidase

Selected disorders of the liver

Viral hepatitis Drug-induced hepatitis Autoimmune hepatitis Alcoholic hepatitis Hemochromatosis Wilson disease Neoplasms of the liver

Hepatitis A virus RNA virus Mode of transmission: contaminated water and food Incubation period: 2-6 weeks Virus shedding: 2-3 weeks before and 1 week after

appearance of jaundice No carrier state No increase risk for chronic hepatitis, or carcinoma Because viremia is transient, no need to screen

donated blood

Hepatitis B virusHepatitis B virus

Ds-DNA virus

Mode of transmission: parenteral (blood products,

contaminated needles and IV drug abuse), and body

fluids (including saliva)

Incubation period: 4-26 weeks

Carrier state: yes

Hepatitis Hepatitis BB infection: infection: Possible outcomesPossible outcomes

Possible outcomes of infection:Possible outcomes of infection: Subclinical or acute hepatitis with recovery Subclinical or acute hepatitis with recovery

and clearance (85%); 1% of those may and clearance (85%); 1% of those may develop fulminant hepatitis and deathdevelop fulminant hepatitis and death

Healthy carriers (10%)Healthy carriers (10%) Persistent infection (5%): 80% recover and Persistent infection (5%): 80% recover and

20% develop chronic hepatitis20% develop chronic hepatitis 20% of chronic hepatitis patients develop 20% of chronic hepatitis patients develop

cirrhosis and 10% of those develop cirrhosis and 10% of those develop hepatocellular carcinomahepatocellular carcinoma

Hepatitis CHepatitis C Ss-RNA virus

Mode of transmission: parenteral, sexual, 40%

unknown source. It is present in the saliva.

Incubation period: 2-26 weeks

HCV is the leading cause for chronic liver disease

Outcomes of infection:

Hepatitis DHepatitis D Defective RNA virus that needs Hep B capsule to

replicate

Mode of transmission: Parenteral

Coinfection of B and D: mild disease with recovery in

most cases, <5% chronic hepatitis

Superinfection by D after B: accelerated more severe

hepatitis; 80% chronic hepatitis

Hepatitis EHepatitis E ssRNA virus Mode of transmission: water-borne Incubation period: 2-8 weeks Endemic in certain populations; 40% in Indian

population Self-limited infection but with higher mortality in

pregnant females

The points to remember

Hepatitis A Hepatitis B Hepatitis C

Transmission Oral-fecal Parenteral Parenteral

Carrier state None Present Present

Chronic hepatitis

None 5-10% >70%

Fulminant hepatitis

0.1% 0.1-1.0% Rare

Carcinoma No Yes Yes

Drug-indued hepatitis Predictable or unpredictable (idiosyncrasy)

Mechanisms: direct toxicity, conversion of drug to an

active toxin, immune-mediated

A long list of drugs can cause different forms of injury:

hepatitis, fibrosis, granulomas, necrosis, cholestasis,

vascular disorders and neoplasia

Example: Acetaminophen overdose induces

centrilobular necrosis

Autoimmune hepatitisAutoimmune hepatitis More in females (70%) The absence of serologic markers for viral hepatitis Elevated serum IgG levels High titers of autoantibodies (antinuclear, anti-smooth

muscle, and anti-microsomal) Associated with other forms of autoimmune disorders

such as rheumatoid arthritis and ulcerative colitis Risk for cirrhosis is 5% Respond to immunosuppressive drugs

Alcoholic liver diseaseAlcoholic liver disease 100,000 death annually related to alcohol; 20,000 are

related directly to end-stage liver cirrhosis

Effects on liver:

80% fatty liver (steatosis)

10% alcoholic hepatitis

10% cirrhosis

Hereditary hemochromatosis

Autosomal recessive disease characterized by increased

body iron, most of which is deposited in the liver and

pancreas.

Mostly due to increased iron absorption and accumulation

over the years.

Due to mutations in the hemochromatosis gene (HFE); a

gene that regulates iron absorption.

Excess iron damages DNA, lipids and stimulates collagen formation (fibrosis)

Clinical picture: Males are more affected; 50-60 years old Liver cirrhosis, skin pigmentation, diabetes

(pancreatic fibrosis), risk for hepatocellular carcinoma.

Diagnosis: elevated serum and tissue iron. Early detection and therapy by phlebotomy and iron

chelators lead to normal life expectancy

Wilson disease Autosomal recessive disorder characterized by accumulation of

copper in liver, brain and eyes, among other organs

Less common than hemochromatosis

The mutated gene is located on chromosome 13; the mutation leads

to failure to excrete copper into bile, and its accumulation in tissue

Clinical picture: neuropsychiatric manifestations, acute and

chronic liver disease

Diagnosis: Clinical picture, increased hepatic and urinary copper,

and decreased serum copper binding protein.

Biliary disease

Secondary biliary cirrhosis: secondary to extrahepatic

bile obstruction by stones, atresia or tumors

Primary biliary cirrhosis: immune-mediated destruction

of intrahepatic bile ducts, more in females

Primary sclerosing cholangitis: chronic fibrosis of intra-

and extra-hepatic bile ducts; more in men, association

with ulcerative colitis

Tumor of the liverTumor of the liver Liver cell adenoma

Occurs in women of childbearing age in relation to oral contraceptives; it regresses on discontinuation of hormones

Well circumscribed mass Sheets of hepatocytes with no portal tracts

Liver cell adenomaLiver cell adenoma

Significance of this benign tumor:

It may be mistaken for carcinoma

Subcapsular adenomas are at risk for rupture,

especially during pregnancy leading to life-

threatening intraabdominal hemorrhage

Hepatocellular carcinoma (HCC)

Risk factors: Strongly associated with hepatitis B and C infection.

The carrier state for hepatitis B carries 200-fold

increased risk for HCC

Chronic liver disease (e.g. alcohol)

Hepatotoxins

Clinical picture:

Often patient already has liver cirrhosis, with rapid increase in liver size, worsening ascites, fever and pain; elevated serum alpha fetoprotein levels

Median survival is 7 months (death from bleeding, liver failure, or profound cachexia)

Metastatic carcinomaMetastatic carcinoma The most common malignant tumors in the liver Usually multiple lesions The most common primary sites are colon, lung,

breast, pancreas and stomach

The Pancreas

The PancreasThe Pancreas85% exocrine: enzymes

for digestion Acute and chronic

pancreatitis Cystic fibrosis Tumors

15% endocrine: insulin, glucagon and others

Diabetes Tumors

Pancreatic exocrine Pancreatic exocrine enzymes enzymes

Acute pancreatitisAcute pancreatitis

Acute pancreatitisAcute pancreatitis Clinical presentation: abdominal pain radiating to the

back, elevated serum amylase and lipase, hypocalcemia

Rise in serum lipase is more specific for pancreatitis.

Complications: infections, abscess, pseudocyst

Mortality is high: 20-40%, from shock, sepsis or acute

respiratory failure, acute renal failure, disseminated

intravascular coagulation

Chronic pancreatitis Progressive destruction of pancreatic parenchyma and

its replacement by fibrosis Predisposing factors: alcohol, hypercalcemia or

idiopathic 30% of idiopathic cases have been found to have

mutation in CFTR gene Complications: Pseudocyst, malabsorption, 2ry diabetes Diagnosis: abdominal pain, malabsorption, calcifications

on X-ray

Pancreatic Pancreatic adenocarcinomaadenocarcinoma

The 5th most frequent cause of death from cancer

Risk factors: smoking

CP: symptoms are late; pain and jaundice

Prognosis is poor: 5% survive for 5 years

Islet cell tumors

Rare compared to adenocarcinoma

Insulinomas: secrete insulin hypoglycemia

behavioral changes, confusion and coma. Over

90% are benign

Gastrinomas: secrete gastrin increase acid

production duodenal and gastric ulcers

Gallbladder Gallstones

Afflict 10% of adult population in Western countries

Costs of management: $6 billion a year

20 million patients are estimated to have gallstones totalling several tons

Made of cholesterol, bilirubin and calcium salts with different concentrations

Two types: cholesterol and pigmented stones

GallstonesGallstones

Cholesterol Western > others Advancing age Female sex Obesity Hyperlipidemia and

bile stasis

PigmentedPigmented Asian > WesternAsian > Western Hemolytic anemiaHemolytic anemia Biliary infectionBiliary infection

Complications: empyema, perforation, fistula, inflammation, obstruction, pancreatitis

Acute cholecystitisAcute cholecystitis Calculous: acute inflammation of a gallbladder that has

stones. It may represent a medical emergency; no

associated infection initially

Acalculous: no stones, in severely ill patients, severe

trauma, burns and sepsis

Chronic cholecystitis AlmostAlmost always associated with gallstones