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1. Recognize common liver chemistry tests and their clinical implications when abnormal, including AST and ALT, Alkaline phosphatase, and Bilirubin.

AST: hepatocellular damage. ALT: hepatocellular damage. Bilirubin: cholestasis, impaired conjugation or biliary obstruction. Alkaline phosphatase: cholestasis, infiltrative disease or biliary obstruction.


prothrombin time

•Assesses the extrinsic clotting pathway. When combined with serum albumin can assess synthetic function aka hepatic function.


Causes of Prothrombin time prolongation

hepatocellular dysfunction or Vitamin K deficiency


Non hepatic causes of low albumin levels

poor nutrition, nephrosis, malabsorption, severe illness with catabolism


Non hepatic causes of elevated prothrombin time

malabsorption, genetic causes


compare half lives of albumin and coagulation factors

albumin half life is 19-21 days. Coag factors half lives may be less than a day. These tests can be used to determine acute vs chronic components of hepatic function


Test to assess hepatic dysfunction vs Vit K deficiency with prolonged prothrombin time

Administer subcutaneous vitamin K and assess response. No correction indicates liver dysfunction. Normalization indicates vitamin K deficiency


2. Characterize patterns of liver chemistry test abnormalities for hepatocellular and cholestatic liver diseases.

Hepatocellular injury or necrosis: predominantly AST and ALT elevation. Cholestatic pattern: predominantly alk phos elevation. Can also have a mixed pattern which indicates synthetic dysfunction


Function of AST and ALT

Both are aminotransferases which catalyze transfer of aa groups to form hepatic metabolites.


compare location in hepatocyte and organ expression of AST and ALT

AST: cytosol and mitochondria, liver, heart, muscle and blood. ALT: cytosol, liver only


AST:ALT ratio

normally 1 b/c impaired plasma clearance of AST by sinusoidal cells. Alcoholic liver disease is >2 b/c hepatic deficiency of B6 which is cofactor for ALT activity and alcohol induced injury to mitochondria enriched in AST.


hepatic causes of mild (< 5X) AST and ALT elevations

Chronic HBV and HCV, acute viral hepatitis (A-E, EBV, CMV), steatohepatitis, alcohol related liver injury, hemochromatosis, autoimmune hepatitis, alpha1- antitrypsin deficiency, Wilsons dz, celiac dz and cirrhosis


NON hepatic causes of mild (< 5X) AST and ALT elevations

hemolysis, myopathy, thyroid dz, strenous exercise


Causes of severe (>15X) AST and ALT elevations

acute viral hepatitis (A-E, herpes), meds/toxins, ischemic hepatitis, autoimmune hepatitis, Wilsons dz, acute Budd-Chiari syndrome, hepatic artery ligation or thrombosis


Alkaline phosphatase function

•Hydrolase enzyme responsible for removing phosphate groups from nucleotides, proteins and alkaloids


Tissue location of alk phos

Nearly all tissues: liver (microvilli of bile canaliculus), bone, placenta, intestine.


Causes of elevated alk phos

Cholestatic or infiltrative diseases of liver, Obstruction of biliary system, Bone disease, Pregnancy, renal failure, CHF


List infiltrative dz of liver that cause elevation in alkaline phosphatase

sarcoidosis, tuberculosis, fungal, granulomatous dz, amyloidosis, lymphoma, metastatic malignancy, hepatocellular carcinoma


How do you differentiate hepatobiliary vs nonhepatobiliary origin of elevated alk phos?

1. 5'-nucleotidease: Significantly elevated only in liver disease, highest levels in cholestatic diseases. 2. gamma-glutamyltransferase (GGT): Not present in bone, Elevated after alcohol consumption and almost all types of liver disease


Bilirubin metabolism

Normal heme degradation product. Requires conjugation (glucuronidation) into water soluble forms before biliary excretion. Heme > heme oxygenase converts to biliverdin in kupffer cells of liver > biliverdin reductase converts to bilirubin > UDP glucuronyl transferase conjugates bilirubin into water soluble form in hepatocytes > bile canaliculus


Indirect vs direct bilirubin

indirect: measures unconjugated bilirubin before entering hepatocyte. Direct: measures conjugated bilirubin that has exited hepatocyte


hemolytic jaundice

overwhelmed conjugation: indirect bilirubin increases


Biliary obstruction- effect on direct and indirect bilirubin

obstruction leads to conjugated hyperbilirubinemia


Gilberts syndrome

dimished bilirubin-UGT (enzyme that conjugates bilirubin) leads to unconjugated hyperbilirubinemia with normal AST, ALT and alk phosph


Crigler-Najjar syndrome

rare autosomal recessive UDP-GT deficiency causes impaired bilirubin conjugation. Leads to unconjugated hyperbilirubinemia. Type I: severe jaundice, neuro impairment. Type 2: lower serum bilirubin, no neuro problems


Dubin-Johnson syndrome

defective secretion of conjugated bilirubin due to mutation of MRP-2 gene (responsible for transporting conjugated bilirubin from hepatocyte into bile canaliculus). Leads to conjugated hyperbilirubinemia


bilirubin levels in cirrhosis

conjugated hyperbilirubinemia- impairment of hepatocellular bilirubin secretion into bile, but bilirubin conjugation is preserved. Also, increased peripheral RBC destruction occurs


sites of cholestasis, detection method and examples

1. lesion in canaliculus/ biliary ductules: detected by labs or liver biopsy. Includes cholestatic drugs, PBC and pregnancy. 2. intra/extra hepatic bile duct lesion: detected by imaging (US, ERCP, MRCP). Includes biliary atresia, PSC, gallstones, malignancy of pancreas or bile duct.


List diseases that cuase indirect hyperbilirubinemia

gilberts syndrome (nl LFTs), hemolysis (nl LFTs) , and crigler-Najjar syndrome


list diseases that cause direct hyperbilirubinemia

extrahepatic obstruction of bile flow, intrahepatic cholestasis, hepatitis, cirrhosis


Chronic Hepatitis B diagnosis

hepatitis B surface antigen (HBsAg) for >6 months


When is treatment considered in chronic hep B

1) HBsAg positive >6 months, 2) serum HBV DNA >10^5 copies/mL and 3) persistent or intermittent elevation in ALT and AST levels. OR if cirrhosis and positive HBV DNA (regardless of AST/ALT)


Benefits of chronic Hep B treatment

reduces the risk of progressive chronic liver disease and long-term complications of cirrhosis and hepatocellular carcinoma (HCC). prevent decompensation of liver disease (development of jaundice, ascites, variceal bleeding).


Hep B treatment results/goal

Although treatment can lead to viral suppression in HBeAg positive patients with normal ALT, the likelihood of HBeAg seroconversion (loss of HBeAg and developemend of HBeAb) is low. Goal is HBeAg seroconversion which is associated with negative HBV DNA when treatment is stopped. Goal is NOT to achieve loss of HBsAg


Chronic Hep B treatment

1. Interferon (standard and pegylated): finite duration of treatment, absence of resistant mutants and more durable response. Interferon should not be used in patients with advanced liver disease. 2. nucleoside/tide analogs (lamivudine, adefovir, entecavir or tenofovir): less side effects


compare the Hep B antigens

HBsAg: surface antigen, marker of active infection. HBeAg: e antigen, surrogate marker of high viral load. HBcAg: core antibody, marker of active infection


Diagnosis of chronic Hep C

HCV RNA in the blood


Goal of HCV therapy

sustained virological response: eradicate HCV RNA and to remain HCV RNA negative 12 weeks after antiviral therapy is stopped


HCV standard of care

The current standard of care for treating HCV genotype 1 has been pegylated interferon, ribavirin and an NS3/4a protease inhibitor (boceprevir or telaprevir) for 24-48 weeks. Patients with other genotypes are currently treated with pegylated interferon and ribavirin


Unfavorable and favorable predictors of sustained virological response with HCV therapy

unfavorable: high baseline HCV RNA, genotype 1. black/hispanic, age, body weight, insulin resistance, more severe liver histology or steatosis. Favorable: low baseline HCV RNA, genotype 2/3, white


New Hep C treatments

target HCV encoded proteins vital to replication and life cycle of virus


Hereditary hemochromatosis benefits of treatment

prevent major causes of death in HH including decompensated cirrhosis, hepatocellular carcinoma, diabetes and cardiomyopathy. Survival is normal in patients in whom treatment is initiated before the development of cirrhosis or diabetes


Hereditary hemochromatosis treatment

Therapeutic phlebotomy (Each 500 mL of whole blood removed contains 200-250 mg of iron) once per week for one year then once every 2-4 months for maintenance. OR chelation with desferoxamine if anemic patient


Hereditary hemochromatosis treatment endpoint

serum ferritin of 50 ng/mL


Autoimmune hepatitis treatment

primary: Prednisone to suppress overactive immune system. Secondary: azathioprine, allows for lower doses of prednisone to be used. Stopping therapy results in a flair


Azathioprine side effects

reduction in the white blood cell count, nausea and rarely pancreatitis


corticosteroids side effects

weight gain, anxiety, osteoporosis, diabetes, high blood pressure and cataracts.


Primary biliary cirrhosis diagnosis

anti-mitochondrial antibody


Primary biliary cirrhosis treatment

Ursodiol (ursodeoxycholic acid)- a secondary bile acid which is a metabolic byproduct of intestinal bacteria. Improves bile acid transport/detox, cytoprotection and anti-apoptosis


Primary sclerosing cholangitis treatment

stent strictures with endoscopic retrograde cholangioscopy, treat cholangitis with antibiotics. Liver transplant is only long term treatment


Wilson disease treatment

general chelators that induce cupria (loss of copper in the urine) such as D-penicillamine and trientine, then zinc which interferes with uptake of copper from GI tract and induces enterocyte chelation of metals.


how do you monitor treatment of Wilson disease

24-hour urinary copper excretion. With chronic (maintenance) treatment, urinary copper excretion should run in the vicinity of 200-500 mcg per day on treatment. Values of urine copper excretion <200 mcg/day may indicate either non-adherence to theapy or overtreatment and excess copper removal


Non-alcoholic steatohepatitis treatment

Modifying risk factors for NASH: 1) Obesity, 2) Type II diabetes mellitus, and 3) Dyslipidemia. Investigational therapies have included use of diabetes drugs (even if not associated with diabetes) and vitamin E – an antioxidant.


what causes syphilis and what happens

treponema pallidum- causes demyelination of posterior columns in spinal cord and sclerosing of posterior roots. Results in decreased reflexes, decreased pain and proprioception.


microglia develop from what

monocytes- mesoderm derived


structures arising from surface ectoderm

lens of eye, epidermis and anterior pituitary


structures from neuroectoderm

CNS neurons, oligodendrocytes, astrocytes, ependymal cells,


internuclear ophthalmoplegia

seen in MS- demyelination of ipsilateral medial longitudinal fasciculus results innormal lateral rectus movement of eyes, but contralateral CN III does not stimulate medial rectus to fire. Abducting eye gets nystagmus