Diseases of the liver

Liver
Normal liver has smooth brown surface

Weight: 1200-1600 g

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

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

Unconjugated - Albumin bound - Insoluble in water, toxic

Conjugated - Loosely bound to albumin - Water soluble, non-toxic, excreted in urine

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 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 B infection: Possible outcomes

Possible outcomes of infection:
Subclinical or acute hepatitis with recovery and clearance (85%); 1% of those may develop fulminant hepatitis and death Healthy carriers (10%) Persistent infection (5%): 80% recover and 20% develop chronic hepatitis 20% of chronic hepatitis patients develop cirrhosis and 10% of those develop hepatocellular carcinoma

Hepatitis 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 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 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 Transmission Carrier state Chronic hepatitis Fulminant hepatitis Carcinoma Oral-fecal None None 0.1% No Hepatitis B Parenteral Present 5-10% 0.1-1.0% Yes Hepatitis C Parenteral Present >70% Rare 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 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 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 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 adenoma

Significance of this benign tumor:
It may be mistaken for carcinoma

Subcapsular adenomas are at risk for rupture,

especially during pregnancy leading to lifethreatening 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 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 Pancreas
85% exocrine: enzymes for digestion Acute and chronic pancreatitis Cystic fibrosis Tumors 15% endocrine: insulin, glucagon and others Diabetes Tumors

Pancreatic exocrine enzymes

Acute pancreatitis

Acute 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 adenocarcinoma
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

Gall stones
Cholesterol
Western > others Advancing age Female sex Obesity Hyperlipidemia and bile stasis

Pigmented
Asian > Western Hemolytic anemia Biliary infection

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

Acute 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

Almost always associated with gallstones