What are the main etiologies of steatosis?
(Recall, steatosis = fat in liver)
- Diabetes mellitus
- Drugs, e.g., corticosteroids
- Hepatitis C
Describe alcoholic liver disease: prevalence/epidemiology
- Alcoholic liver disease is the 3rd largest health problem in the US (1. heart disease, 2. cancer)
- Alcoholism is the 8th leading cause of death globally
What are liver biopsy findings in alcoholic liver disease?
In decreasing order:
- Increased iron in hepatocytes
- Alcoholic steatohepatitis
Describe the process of steatosis in liver disease
- Initially Zone 3 or centrilobular
- Entire lobule involved in severe cases
- Hepatomegaly with soft yellow greasy liver
- Steatosis reversible if abstain from alcohol
What is Nonalcoholic fatty liver disease (NAFLD)?
- Potentially progressive liver disease
- Global problem (1 billion worldwide)
- Most common cause of chronic liver function test elevation in US
- Spectrum ranges from steatosis to steatohepatitis, fibrosis, and cirrhosis
What is steatohepatitis?
- What causes it
- Classic form associated with alcohol abuse - alcoholic hepatitis
- Nonalcoholic steatohepatitis (NASH) develops in 10-20% of those with nonalcoholic fatty liver disease
- NASH tends to be more clinically indolent and less florid histologically than alcoholic hepatitis
What is nonalcoholic steatohepatitis (NASH)?
- Obesity, especially morbid obesity, in adults and children
- Diabetes mellitus
- Metabolic syndrome
- Develops in 10-20% of those with nonalcoholic fatty liver disease: steatohepatitis
What are the diagnostic criteria for metabolic syndrome?
At least two of these:
- Central obesity or BMI > 30
- Hypertension, BP > 140/90 mmHg
- Dyslipidemia: hypertriglyceridemia and low HDL cholesterol
Plus one of these:
- Type 2 diabetes mellitus
- Insulin resistance
- Impaired glucose tolerance
- Impaired fasting glucose
What can cause Nonalcoholic steatohepatitis?
Not all patients are obese...
- Jejunoileal bypass surgery
- Intestinal resection
- Total parenteral nutrition (TPN)
What is the natural history of NAFLD (Non Alcoholic Fatty Liver Disease)
- Simple steatosis usually not progressive
- 10-20% with NAFLD develop NASH
- Up to 50% with NASH develop fibrosis
- Fibrosis may be stable, progress or regress
- About 20% with NASH develop cirrhosis
- 35-50% of patients with alcoholic hepatitis who continue to drink develop cirrhosis
- Most cryptogenic cirrhosis now thought to represent “burned-out” NAFLD
- Patients with NASH who develop cirrhosis at increased risk for HCC
What are histological features of steatohepatitis?
- Ballooning degeneration
- Mallory-Denk bodies (Mallory hyaline)
- Lobular neutrophils
- Nonspecific portal and lobular inflammation
- Fibrosis around terminal hepatic veins and perisinusoidal fibrosis, “chicken wire” pattern
- Very characteristic of steatohepatitis, not seen with Hep B/C
What lab tests are used for evaluation of liver disease?
- Measure liver excretion
- Measure synthetic function
- Assess hepatocellular damage
- Assess biliary obstruction
- Measure ability to detoxify
- Tumor markers
- Biopsies are done in minority
What are lab tests that measure liver excretion?
- Serum bilirubin
- Urine bilirubin
Describe serum bilirubin
- What does the test evaluate
- Suggests what conditions
- What is measured
- Specific test of hepatobiliary dysfunction
- Except... Also elevated with hemolysis
- Not sensitive for liver damage
- Functional reserve of liver is over 2-3x daily pigment load
- Total bili = unconjugated + conjugated
- When you order "serum bilirubin" you get total; could order direct as well if total is elevated or if jaundiced
- Direct = conjugated + small fraction unconjugated*
T/F: There is no conjugated bilirubin in normal serum
- BUT small amount is reported because of test methodology
Describe urine bilirubin
- Normal values
- Suggests what conditions
- From conjugated bilirubin
- Not normally present on urine dipstick
- Presence confirms clinically suspected jaundice
- Absence with jaundice suggests unconjugated hyperbilirubinemia (unconjugated bilirubin not water-soluble)
What are lab tests of liver synthetic capability?
Liver is the site of synthesis of most proteins. How is it assessed in lab?
Measure globulins by serum protein electrophoresis
What do low levels of albumin mean?
Low albumin levels correlate with severity of hepatocellular dysfunction
What do PT/INR depend on?
- What is INR?
Coagulation factors (proteins) synthesized in the liver
- Factors I, II, V, VII, and X, as well as Vitamin K (1, 2, 5, 7, 10) INR used because PT varies depending on what reagents are used in the assay
- INR is the ratio of pts PT to normal control raised to the sensitivity index of the tissue factor used in the assay
- INR is a standard unit can be compared regardless of reagent used
When are INR/PT elevated?
- Severe acute and advanced liver disease
- Prognostic value
- Assess safety of medical procedures
What are lab tests to assess hepatocellular damage?
- Describe what each is measuring/function of that substance
- Where is each found (macro and micro)
- Which is best marker
Transaminases- transform alpha-ketoacids into amino acids
- Aspartate aminotransferase (AST)
- Serum glutamic oxaloacetic (SGOT)
- Found in liver, heart, skeletal muscle, brain, pancreas, lung, RBCs
- > 80% in mitochondria and ER
- Alanine aminotransferase (ALT)
- Serum glutamate pyruvate transaminase (SGPT)
- Mainly in liver
- Low in kidney, heart, skeletal muscle
- Mainly cytoplasmic
- Usually better index of liver injury than AST
Serum transaminases are sensitive indicators of ________
Serum transaminases are sensitive indicators of liver cell damage
- Also a measure of continued hepatocyte damage in chronic hepatitis
What is the best early index of acute viral hepatitis and recurrent activation?
In acute hepatitis, which comes first, symptoms are serum transaminases?
Serum transaminases rise before clinical symptoms in acute hepatitis
- Typ > 1000 U/L
- ALT > AST
What conditions have:
- Lower transaminases than acute hepatitis
- AST > ALT
- Alcoholic liver disease
- Congestive heart failure
Recall: AST is in cytosol and mitochondria while ALT is mainly in cytosol; alcoholic hepatitis involves mainly mitochondrial damage and thus AST > ALT
How can serum transaminase levels help in DDx of obstructive vs. parenchymal liver disease?
- Transaminases > 400 U/L: usually parenchymal disease
- Transaminases < 300 U/L: not as helpful in differential diagnosis
- High alkaline phosphatase and bilirubin: obstruction
What are tests to assess biliary obstruction or infiltrative disease?
- Alkaline phosphatase
- Direct bilirubin
Describe alkaline phosphatase as a lab value
- What diseases
- Function of enzyme
- Not specific
- Sensitive indicator of:
- Intrahepatic cholestasis
- Extrahepatic cholestasis
- Function: catalyzes hydrolysis of phosphate esters
- Derived from: bone, liver, placenta
- Physiological significance unclear
- Present on bile duct epithelium and canalicular membrane of hepatocytes
- Association with membranes -> physiological theories of plasma membrane importance
How does liver respond to biliary obstruction?
Synthesizing more alkaline phosphatase
- Released into circulation because of detergent action of retained bile salts on hepatocyte membranes
With jaundice, what is indicated by:
- High alkaline phosphatase levels
- Low alkaline phosphatase levels
- High: obstruction
- Low: hepatocellular injury
Does rise in alkaline phosphatase precede, accompany, or follow jaundice?
- May rise before onset of jaundice
- May persist after jaundice
When may alkaline phosphatase be elevated without jaundice?
T/F: Alkaline phosphatase rises in cholestasis and to a lesser extent, when liver cells are injured
What causes the highest increase in alkaline phosphatase?
Large duct obstruction
What should be considered if alkaline phosphatase is increased out of proportion to bilirubin?
- Bilirubin under 1 mg/dL
- Alkaline phosphatase > 1000 U/L
- Granulomatous disease
- Infiltrative disease (with large duct obstruction , bilirubin usually also rises)
What is gamma-glutamyl transferase (GGT)?
- Indicates what
- Sensitive but nonspecific screen for liver disease; elevated in many liver diseases
- Present in kidney, liver, pancreas, and small amounts other organs
- Most of enzyme in blood from hepatobiliary system
Describe the levels of GGT in various liver disease conditions... when:
- Highest in intra- and posthepatic biliary obstruction
- More sensitive than alkaline phosphatase
- Milder elevations in hepatitis
- Elevated with primary and metastatic neoplasms
- Elevated with alcohol abuse
When is GGT useful?
In children who have higher alkaline phosphatase (from bone) due to active growth
In adults, if high alkaline phosphatase and normal GGT, what should be considered?
Bone as a source of high alkaline phosphatase
What does blood ammonia evaluate?
- When elevated
Test for ability to detoxify
- Diffuse hepatocellular injury or portal blood bypasses liver
- Hepatic encephalopathy
May be elevated in pts without hepatic encephalopathy
What is serum alpha fetoprotein (AFP)?
- Normal levels
- Cause of elevation What is suggested by:
- AFP > 1000 mg/L - AFP > 3000 mg/L
- Only small amounts present in normal individuals
- Increased levels seen with regeneration, almost never > 500 mg/L
- AFP > 1000 mg/L suggestive of hepatocellular carcinoma or germ cell neoplasm
- AFP > 3000 mg/L very suggestive
- Rarely made by other tumors, and if so, usually mg/l
Describe techniques/types of liver biopsy
- Percutaneous “blind” core needle biopsy
- Radiographically - guided core needle biopsy or fine needle aspiration (FNA)
- Transjugular liver biopsy
- Endoscopic ultrasound-guided FNA or core needle biopsy
- Laparoscopic needle core or wedge biopsy
- Open surgical needle core or wedge biopsy
What are indications for liver biopsy?
- Evaluate mass lesions
- Diagnosis when clinical and lab studies equivocal
- Assess cause of hepatomegaly
- Evaluate asymptomatic patients with persistently abnormal LFTs
- Distinguish whether jaundice secondary to hepatitis, obstruction
- Grading and staging of chronic hepatitis
- Monitor course of disease and response to treatment
- Assess degree of injury; e.g., with toxin exposure
- Evaluate for adverse effects of therapy, e.g., methotrexate
- Evaluate for alcoholic liver disease and nonalcoholic fatty liver disease
- Assess for steatohepatitis and fibrosis
- Determine if liver involvement in systemic disease, e.g., sarcoidosis, lymphoma, etc
What are indications for liver biopsy in liver transplant patients?
- Evaluate for acute or chronic allograft rejection
- Assess whether abnormal LFTs due to rejection, recurrent disease (esp. HCV), CMV infection, other infection, biliary obstruction, post-transplant lymphoproliferative disorder, other
- Assess grade, stage of recurrent hepatitis
- Evaluate response to anti-rejection or antiviral therapy