Endocrine Pathophysiology Exam

Understanding Liver Disease ●​ The liver is connected to the digestive tract ●​ Portal venous circulation is a low-pressure system (5 – 10 mmHg) ○​ Increasing portal system pressure will open the non-functioning anastomoses between the portal and systemic circulation ○​ Portal blood enters the systemic (venous) circulation ○​ The liver consumes about 20% of the total body oxygen at rest ■​ Total liver blood flow is about 1.5L/min ●​ Portal HTN ○​ Widens and ruptures anastomoses ■​ Blood is forced into alternate channels by the increased resistance to flow ■​ Blood from the small intestine may bypass the liver; bypassing the processing of substances from the digestive tract ●​ Causes chronic passive congestion in the spleen – splenomegaly ●​ Transudation of fluid into the abdominal cavity leads to ascites ●​ Increased pressure in the venous system leads to hemorrhoids, esophageal varices, and caput medusa Liver Biochemical Tests – liver enzymes ●​ Alanine aminotransferase (ALT, SGPT) ●​ Aspartate aminotransferase (AST, SGOT) ●​ Alkaline phosphatase Functional Patterns of Liver Injury: ➢​ Jaundice ➢​ Caput Medusa Liver Function Tests ●​ Total bilirubin ●​ Albumin ●​ Prothrombin time Bile system ●​ Bile is formed in hepatocytes and secreted into bile canaliculi ○​ 800-1000 ml of bile secreted daily to facilitate fat digestion and absorption ■​ Emulsification of fats and fat-soluble vitamin absorption ■​ 80% of Bile salts are absorbed and recycled in the small intestine ■​ Bile contains bilirubin, cholesterol, salts, water, phospholipids ●​ The canaliculi converge to form larger bile ducts which drain into the common hepatic duct ●​ The cystic duct communicates with the gallbladder ●​ The cystic duct and hepatic duct join to form the common bile duct ○​ Connects the liver to the duodenum ●​ The passage of bile into the duodenum is controlled by the sphincter of Oddi ●​ Common bile duct ○​ Obstruction results in jaundice ○​ Lack of bile adversely affects absorption of fats and fat-soluble vitamins (A,D,E,K) ○​ May provide a site of entry for bacteria or parasites ■​ Ascaris sp. ○​ The terminal portion of the bile duct passes through the head of the pancreas ○​ Diseases of the duodenum and pancreas may obstruct the bile duct ■​ Obstructive jaundice is an important sign of carcinoma involving the head of the pancreas Liver Functions ●​ Bilirubin ○​ The liver is responsible for the uptake and processing of bilirubin released from RBCs ○​ Bilirubin is secreted in bile ○​ Jaundice is the result of excess bilirubin in tissue ●​ Plasma Proteins ○​ Lack of albumin decreases osmotic pressure resulting in edema ○​ Decreased clotting factors (VIII, IX, X, XI, XII) result in bleeding risks ○​ Decreased production of protein C, protein S, and antithrombin — increased clotting risk ●​ Liver Enzymes ○​ AST & ALT most prominent in the liver ○​ Alkaline phosphatase is used as a marker of bile obstruction ●​ Metabolism ○​ The liver is responsible for removing or modifying various blood products ■​ Ig, hormones, drugs, etc. ■​ Accumulation of non-processed products can cause disease ●​ End-stage liver disease ○​ Accumulation of ammonia leads to hepatic encephalopathy ○​ Accumulation of estrogen leads to telangiectasia, testicular atrophy, gynecomastia, palmar erythema ○​ Malabsorption of fats results in steatorrhea and weight loss ●​ Cancer ○​ Primary carcinoma ■​ Especially increased with hepatitis B or C infection ○​ Secondary carcinoma ■​ Common site for metastases due to its rich blood supply ●​ Carbohydrate metabolism ○​ Glycogenesis ■​ Transformation of newly absorbed glucose to storage glycogen ○​ Glycogenolysis ■​ Breakdown of glycogen to release glucose ○​ Glyconeogenesis – gluconeogenesis ■​ Generation of glycogen/glucose from non-glucose components (amino acid precursors) ●​ Protein metabolism ○​ Protein by-product (urea) is excreted by the kidneys ○​ Deamination of proteins produces ammonia (also produced bycolonic bacteria and absorbed) which is converted to urea Condition Overview Jaundice ●​ ●​ ●​ ●​ A symptom – not a disease • Yellow discoloration of the skin and mucosa secondary to bilirubin accumulation Icterus – yellow discoloration of the sclera Becomes apparent with bilirubin > 2.5mg/dL Infectious Hepatitis ●​ Infectious agents that cause hepatitis ○​ Hepatitis A (HAV) ○​ Hepatitis B & D (HBV)+/- (HDV) ○​ Hepatitis C (HCV) ○​ Hepatitis E (HEV) ○​ Yellow fever virus ○​ Epstein-Barr virus (infectious mononucleosis) ○​ Lassa, Marburg, Ebola viruses ○​ Herpes simplex virus ○​ Cytomegalovirus ○​ Enteroviruses other than HAV ○​ Leptospirosis ○​ Entamoeba histolytica Pathogenesis ●​ Pre-hepatic (hemolytic) ○​ Malaria – hemolytic jaundice ●​ Hepatic (hepatocellular) ○​ Gilbert disease – autosomal recessive genetic defect in the hepatic conjugation of bilirubin ○​ Viral hepatitis, drug-induced hepatitis, cirrhosis ○​ Newborn jaundice – liver conjugation enzymes may not be completely functional for the first 7-14 postnatal days ●​ Post-hepatic (cholestatic) ○​ Biliary atresia ○​ Obstructive jaundice – bile does not reach the intestines ■​ Acholic stool – pale/clay-colored Viral Hepatitis Two major pathophysiologic mechanisms of liver injury: ⇒ Direct cellular injury by the virus ⇒ Induction of the immune response against foreign viral proteins Hepatitis B ●​ Associated with a rare form of acute fulminating hepatitis ●​ Presents with a variety of symptoms which may include hives, arthritis, localized edema, glomerulonephritis, polyarteritis nodosa Hepatitis A ●​ The only type of viral hepatitis that presents with a high-grade fever Infectious etiology IgM Anti-HAV antibodies A non-encapsulated RNA virus Transmission via the oral-fecal route Incubation period 15-50 days Hepatitis C ●​ Unique features include polyarteritis nodosa and glomerulonephritis ●​ Most likely to develop chronic hepatitis Viral Hepatitis - Hep A ●​ ●​ ●​ ●​ ●​ Viral Hepatitis - Hep B ●​ Infectious Etiology ●​ Hepatitis B – HBV ○​ Encapsulated DNA virus ○​ Incubation 40-180 days ○​ Transmission via body fluids or sexual contact ■​ Maternal-fetal transmission rate – 85% ●​ Infants are at an increased risk because the immune system is not active enough to fight the virus ●​ Infant infections are associated with progressive disease ●​ Phases: preicteric, icteric; chronic ○​ Preicteric: Weakness, N/V, mild liver enlargement and tenderness, measles-like rash ○​ Icteric: Jaundice, elevated bilirubin, AST, ALT ■​ ***10% of patients will progress to chronic hepatitis ○​ Hepatocellular carcinoma and cirrhosis are long-term complications Viral Hepatitis - Hep D ●​ An incomplete RNA virus that requires HBV for its own replication ●​ Co-infection produces more prominent symptoms and greater risk of fulminant disease ○​ Transmitted via blood or sexual contact ●​ S/S similar to hepatitis B Diagnoses ●​ Diagnosis is based on symptoms, physical findings, serum liver enzymes, and the presence of specific viral proteins and viral antibodies ●​ Fulminant Infection ●​ Characterized by acute, mild enteric illness, fever, N/V, anorexia, jaundice, elevated serum aminotransferases ●​ Recovery w/in days w/o LT consequences ●​ NO long term sequelae ●​ Vaccine prevention ●​ Screen ○​ Persons from endemic areas (SE Asia, Alaska, Africa), MSM, pregnant women ●​ Hepatitis B vaccination ○​ Various schedules depending on age and product ●​ HBsAg – hepatitis B surface antigen ○​ Appears in serum weeks before the onset of clinical findings ○​ Gradually persists for 3-4 months; persistence > 6 months denotes a carrier state ●​ Anti-HBsAg – anti-hepatitis B surface antigen (antibodies) or Anti-HBs ○​ May be seen with infection or vaccination ○​ The vaccine consists of recombinantly produced HBV surface antigen alone ●​ Anti-HBcAg – anti-hepatitis B core antigen (antibodies) ○​ Appears about 4 weeks after the appearance of HBsAg ○​ Present during the acute illness and may remain elevated for several years ●​ HBV DNA ○​ Can be detected in serum and is used as an index of infectivity ●​ Anti-HBV = hepatitis B antibodies ○​ Hepatitis B vaccination will also protect against hepatitis ●​ D Anti-HDV = hepatitis D antibodies Viral Hepatitis - Hep C ●​ Viral Etiology ●​ RNA virus – HCV ●​ Transmission via body fluids - blood (primarily) or sexual contact ○​ 10% of transmissions are idiopathic ●​ Progresses to chronic hepatitis in 50% of patients*** ○​ May lead to cirrhosis and hepatic cancer - Increased risk of hepatocellular carcinoma ○​ More likely to present with necrosis, steatosis, and portal bridging – chronic pattern findings ●​ No vaccine protection ○​ 6 genotypes ○​ Genotype 1 is the most prominent in the US and most severe ●​ USPSTF 2020 screening recommendations – all adults ages 18-79 ●​ Anti-HCV = hepatitis C antibodies​ Hepatitis E ●​ RNA virus ○​ Similar to HAV ○​ Transmission via the oral – fecal route ○​ Not usually seen in the US (but as close as Mexico) ○​ High incidence in India ○​ High mortality rate in pregnant woman ■​ 20% Condition Metabolic-dysfunction Associated Steatotic Liver Disease (MASLD) Overview ●​ Formerly known as non-alcoholic fatty liver disease (NAFLD) ●​ Fatty accumulations in the liver ○​ Most common liver disease in the US ○​ 1:4 adults have fatty liver buildup ●​ Underlying diseases ○​ Established associations ■​ Affecting 70% of patients with obesity or T2DM ○​ Emerging associations ■​ Hypothyroidism, obstructive sleep apnea, hypopituitarism, hypogonadism, psoriasis ●​ May progress to fibrosis and steatosis if not arrested ○​ Metabolic-dysfunction associated steatohepatitis ○​ Formerly known as NASH Nonalcoholic steatohepatitis (a more aggressive form of MASLD) 1:7 patients with MAFLD will have MASH Pathophysiology ●​ Increased hepatic mitochondrial oxidation of free fatty acids, increased oxidative stress and lipid peroxidation ●​ MASLD is considered the hepatic manifestation of metabolic syndrome ●​ MASLD and fibrosis increase risk for cardiovascular events ○​ CV disease ●​ Medications that can produce a fatty liver ○​ Amiodarone, methotrexate, tamoxifen, corticosteroids, diltiazem, valproic acid, antiretroviral therapy (NRTI, PI) Signs/Symptoms ●​ ●​ ●​ ●​ Many patients are asymptomatic Fatigue, weakness Weight loss Upper abdominal pain Cirrhosis ●​ Severe Fibrosis ●​ Common endpoint of all chronic liver diseases characterized by loss of normal liver structure and function ●​ Synonymous with Late end-stage-liver disease ●​ Irreversible and incurable ●​ Alcohol abuse and hepatitis virus account for 60+% of cirrhosis cases in the US ●​ Metabolites from alcohol metabolism are toxic to hepatocytes Ascites ●​ ●​ Histology: Fibrotic and nodular ●​ Main process ○​ Necrosis repaired by fibrocytes with nodule formation ○​ Impedes blood flow causing portal HTN ●​ 2 basic patterns ○​ Portal – liver disease etiology ○​ Biliary – biliary tract disease ●​ Clinical features ○​ Alcohol abuse ■​ Fatty, yellow, enlarged liver, Mallory bodies ○​ Other etiologies ■​ The liver shrinks to ½ its normal size ●​ Histological classifications ○​ Micronodular, macronodular and mixed forms ●​ “Hydroperitoneum” – accumulation of fluid in the abdominal cavity ●​ Increased risk of spontaneous bacterial peritonitis due to translocation of intestinal bacteria (E. coli, Klebsiella) ●​ Develops secondary to increased portal pressure and hypoalbuminemia ○​ Transduction of fluid out of the circulation ○​ Deceased osmotic pressure ●​ The resulting decrease in plasma volume triggers the release of aldosterone, ADH, and the activation of the RAAS ●​ Ascites, splenomegaly, esophageal varicose, hemorrhoids, ammonia accumulation, portal HTN, estrogen accumulation, bleeding abnormalities, hepatorenal syndrome ●​ Treatment ○​ Na+/fluid restriction, diuretics abdominocentesis (ST treatment – fluid will return) Associated Signs ●​ Caput Medusae: Dilated periumbilical veins ●​ Splenomegaly ○​ Very common in cirrhosis ○​ Secondary to portal hypertension Enlargements of 3-6X the normal size (normal 150g) ○​ Pain ○​ The enlarged spleen is likely to sequester and destroy blood cells ■​ Anemia, leukopenia, thrombocytopenia ●​ Esophageal varices & Hemorrhoids ○​ Anastomoses between the portal and systemic circulations move blood into the lower esophageal and hemorrhoidal plexi forming varices ●​ Asterixis ○​ A characteristic flapping tremor of the hand when the arm is extended; seen in patients with hepatic encephalopathy ●​ Gynecomastia, impotence, loss of libido, palmar erythema, spider angiomas, testicular atrophy ○​ Estrogen accumulation ●​ Bleeding and bruising ○​ Decreased clotting factor production ○​ Bone marrow suppression – thrombocytopenia ○​ DIC ●​ Hepatic Encephalopathy Four Stages ○​ Stage I: Sleep disturbance, irritability, and personality changes ○​ Stage II: Lethargy and disorientation ○​ Stage III: Deep somnolence ○​ Stage IV: Coma ●​ Cryptococcal infection – disseminated ○​ High risk due to immune dysregulation, high mortality ○​ Monitor cryptococcal antigen levels ■​ Patient may be asymptomatic ●​ Cardiopulmonary function ○​ HF, HTN due to fluid overload ●​ Hepatorenal Syndrome ○​ Hypoperfusion, oliguria, azotemia = RAAS activation ●​ Endocrine symptoms ○​ Gynecomastia, anovulation ●​ Anemia ●​ Osteodystrophy ○​ Abnormal vitamin D and calcium homeostasis ○​ The liver is important in activation of vitamin D ○​ Calcium is bound to albumin as a carrier protein ●​ Hypothyroidism ○​ Decrease in thyroid binding globulins for transport Portal HTN ●​ The superior mesenteric and splenic veins meet to make the hepatic portal vein – the major venous drainage of the GI tract ●​ Increased portal pressure causes opening of portal-systemic collateral channels resulting in gastroesophageal varices, ascites, splenomegaly, renal and pulmonary disease ●​ Fibrosis distorts sinusoids. Nodules impinge on hepatic veins obstructing blood flow ●​ Progressive portal hypertension parallels mesenteric arterial vasodilation. ●​ Mesenteric arterial vasodilation is driven by increased NO production in response to increased resistance to portal blood flow ○​ This results in ascites, hepatorenal syndrome, and hepatopulmonary syndrome Hepatic Encephalopathy Liver Transplant MELD ●​ ●​ ●​ (Model for End-stage Liver Disease) score Estimates mortality of liver disease during the next three months MELD of < 15 cut off for transplantation Basis for liver allocation in the US since 20022 Factors ○​ Blood type ○​ Body size relative to donor’s ○​ Geographic considerations ○​ Current supply of livers ○​ INR, SCr, Bilirubin, serum Na+, albumin, gender Condition Acetaminophen Toxicity Condition Neonatal (Physiologic) Jaundice ●​ Shunting of blood prevents the liver from performing normal detoxification ●​ Accumulation of ammonia ●​ Confusion, altered consciousness, coma, death ●​ Fetor hepaticus due to mercaptans (breakdown of sulfur-containing amino acids in saliva) ●​ Lactulose will bind ammonia in the GI tract; lactulose is not absorbed and is excreted via the feces ○​ Antibiotics (to alter GI flora; decrease GI accumulation of ammonia) have been studied ■​ neomycin, metronidazole, vancomycin, rifaximin Overview ●​ Dose-related injury ○​ Most common cause of acute liver toxicity in the US ○​ Results from the accumulation of toxic metabolites ■​ Damages hepatocytes ●​ Liver necrosis is commonly seen with doses of 15g+ ●​ Cumulative damage ○​ Toxicity can occur when multiple smaller doses within 24 hours exceed recommended levels ○​ Adult max daily dose – 4g –- 1000mg Q6h Overview ●​ Neonatal hyperbilirubinemia occurs in the absence of any specific disorder ●​ Hepatic clearance of bilirubin in the fetus is minimal ○​ Bilirubin crosses the placenta and is conjugated and excreted by the mother’s liver Diagnosis: ●​ ALT, AST – high, normal or low based on the degree of liver cell damage ●​ Decreased albumin, clotting factors ●​ Increased bilirubin, ammonia ●​ Ascites, splenomegaly, anastomoses – varices ●​ Biopsy Living Donor ●​ For adult recipients, use the right lobe (2/3 mass of liver) ●​ For pediatric recipients, use the left lobe Treatment ●​ Gastric lavage ●​ Acetylcysteine – accelerates metabolism Pathophysiology Signs/Symptoms ●​ Glucuronyl transferase activity is less than 1% of that in adults ○​ The newborn’s liver becomes responsible for clearing bilirubin before the conjugation and excretion are fully developed ○​ Increased erythrocyte destruction in the postnatal period adds to the liver’s duties in the newborn ■​ Increased Hemolysis ○​ Therefore, 70% of normal infants have transient unconjugated hyperbilirubinemia ○​ Hepatic bilirubin-conjugating capacity reaches adult levels at about 2 weeks ○​ Absorption of light by unconjugated bilirubin generates water-soluble bilirubin – phototherapy is now routinely used to treat neonatal jaundice Gilbert Disease ●​ Causes intermittent/Transient jaundice ●​ Usually mild or asymptomatic ○​ More likely seen during exertion, stress, fasting, and infections ○​ Presents during times of stress ●​ Usually begins after puberty ○​ However may be seen in neonates and requires strict monitoring of bilirubin levels to prevent kernicterus ●​ More common in males ●​ ●​ ●​ ●​ Autosomal recessive disorder of bilirubin metabolism Resulting in mild, chronic, unconjugated hyperbilirubinemia (< 6 mg/dL) Low production of glucuronyl transferase Patients may be predisposed to develop gallstones Crigler-Najjar syndrome ●​ A severe familial disorder characterized by unconjugated hyperbilirubinemia ●​ Caused by a deficiency of glucuronyl transferase ●​ Type I – leads to early death from kernicterus w/o intervention ●​ Type II - a less severe form that responds to phenobarbital therapy – which decreases the serum concentration of unconjugated bilirubin Hemochromatosis Type I ●​ An autosomal recessive defect of iron absorption ○​ Defect if iron accumulation ●​ HFE gene on chromosome 6 ●​ Alteration of hepcidin function ●​ Results in excessive accumulation of iron stores ○​ Iron circulation is prohibited ○​ Iron levels can be 50X normal levels ○​ Damaged liver cells; progressing to cirrhosis ●​ Symptoms of Type I become shortly after birth affected infants ●​ Develop severe, persistent jaundice these symptoms persist after the first three weeks of life ●​ S/S of kernicterus ○​ Early signs of kernicterus may include lethargy, vomiting, fever, and/or poor feedings ○​ Other symptoms that may follow include absence the Moro reflex; mild to severe muscle spasms, hypotonia ●​ Triad – cirrhosis, skin pigmentation, DM (secondary Fe accumulation in the pancreas) ●​ “Bronze diabetes” ●​ HF, fatigue, impotence, decreased libido, arthralgia, memory loss ●​ Most often seen in males 40-60 years old​ ​ Iron Regulation ●​ The normal total body iron content or iron is 3-4 g – most is bound to hemoglobin ●​ Iron enters the body through the duodenal mucosa; however, there is no appreciable mechanism for iron excretion ○​ Men and postmenopausal women eliminate 1-2 mg daily in desquamated cells ●​ Proteins involved in iron regulation ○​ Hepcidin, ferroportin, transferrin, ferritin ●​ Wilson disease ●​ aka hepatolenticular degeneration ●​ An autosomal recessive disorder of copper metabolism ●​ Treatment ○​ penicillamine (PO) – chelating agent ○​ Low copper diet – no chocolate, ●​ Caused by mutations in the ATP7B gene which encodes for copper- transporting ATPase2 (Ceruloplasmin) ○​ Ceruloplasmin Deficiency ○​ Ceruloplasmin, plays a role in transport of copper from the liver to other parts of the ●​ Produces lesions in the liver, brain, and eye ●​ Symptoms usually appear between 6 to 20 years old ●​ Neurologic symptoms, choreiform movements, psychosis, liver dysfunction (progressing to cirrhosis) mushrooms, nuts, shellfish body and in eliminating excess copper ●​ Kayser-Fleischer ring of the eye Hereditary alpha-1 antitrypsin deficiency ●​ An autosomal recessive disorder ●​ Codominant trait – milder S/S in carrier patients ●​ Presence of the PiZ allele of the gene that encodes for alpha -1 antitrypsin ●​ Accounts for 30% of cases of neonatal conjugated hyperbilirubinemia ●​ Alpha-1 antitrypsin is a protease inhibitor that inactivates neutrophil elastase Absence of a1-AT results in abnormal protein folds that accumulate in each organ ○​ lungs, liver ●​ May be latent until puberty or early adulthood ●​ Cirrhosis, emphysema – in early adulthood ○​ Late stage liver disease ●​ Initial signs may present as LRIs that do not respond to treatment Reye syndrome ●​ Rare acute disease of children characterized by microvascular steatosis, hepatic failure, and encephalopathy ●​ Early diagnosis and supportive therapy improve outcomes ●​ ASA is not recommended in children < 19 yo in the US when fever is present ●​ Possible link between aspirin use and viral illness in children ○​ Most likely influenza and varicella ●​ Results in organ damage especially the brain and liver ●​ Fatty liver, encephalopathy ●​ 5 stages moving from rash, lethargy and confusion ●​ (stage 1) to seizures, multiple organ failure and death (stage 5) ●​ Progressive disease-causing obstructive jaundice and biliary cirrhosis ●​ Increased risk of cholangiocellular carcinoma ●​ Cell-mediated (lymphocytes) destruction of intra and extra-hepatic bile ducts ○​ Fibrosis follows the immune reaction > 60% of patients have pre-existing IBD ○​ UC > Crohn’s Disease Primary Sclerosing Cholangitis Primary Biliary Cirrhosis (Cholangitis) Biliary Atresia ●​ Autoimmune basis of the disease ○​ Associated with increased frequency in Sjogren syndrome, scleroderma, RA, thyroiditis ○​ Aberrant HLA molecules are expressed in the biliary epithelium, which may be responsible for triggering an immune response ○​ Defective immunoregulation allows cytotoxic T cells to damage bile ducts ■​ Cytotoxic T Cell Activation ○​ High serum IgM levels ○​ Liver biopsy shows portal tract infiltrates composed of lymphocytes and plasma cells, granulomas, fibrosis of small bile duct ●​ Antimitochondrial antibodies can be seen in serum of affected patients ○​ M2 antibody specific ●​ Obstruction of the biliary system ●​ Rare obstructive cholangiopathy of intrahepatic and extrahepatic bile ducts ●​ ●​ ●​ ●​ ●​ Most commonly seen in middle-aged women S/S Pruritus (early symptom) Jaundice Elevated alkaline phosphatase AST/ALT may be normal in early disease, high serum cholesterol Unlike PSC, PBC does not share an association with IBD, colonic cancer or bile duct cancer ●​ Presents in neonates with jaundice, acholic stool, and hepatomegaly ●​ Unknown etiology ●​ Life expectancy (w/o liver transplant) 5-10 years ○​ Kasai procedure (hepatoportoenterostomy) diversion of bile from the liver to the intestine ●​ Accompanying abnormalities ○​ Intestinal malrotation, renal cysts Cholestasis ●​ Functionally – cholestasis represents decreased bile flow through the canaliculus and reduced secretion of water, bilirubin and bile acids ●​ Patients usually present with jaundice, pruritus, xanthomas and malabsorption Gallstones/Cholelithiasis ●​ Predisposition ○​ Obesity, DM, genetics, pregnancy, OC (Estrogen), fibrates, age (slower bile flow), malabsorption of bile from the large intestine ○​ 4 F’s – female, 40, fertile, fat Divided into intrahepatic vs extrahepatic disease ●​ Extrahepatic ○​ May be obstructed by gallstones lodged in the common bile duct, cancer of the duct or surrounding tissue or biliary atresia ●​ Intrahepatic ○​ Inability to excrete bile acids into canaliculi may be due to several mechanisms, including alterations in Na+/K+ ATPase, altered contractile properties of the canaliculus, or canalicular membrane permeability ●​ Cholesterol stones ○​ Hypersecretion of bile that is supersaturated with cholesterol (75% cholesterol composition) ●​ Pigmentary stones ○​ Cholesterol and calcium salts ●​ The gallbladder maybe inflamed ○​ Infection is common - entry of enteric bacteria, most likely E. coli ***** ○​ Inflamed serosa can form adhesions and fistulas with the intestines ●​ Cholesterol stones ⇒ Yellow in color ●​ Pigmentary stones ⇒ Black, yellow or brown in color ●​ More common in women than men ●​ Neutrophilia with a left shift - inflammation ●​ Asymptomatic to severe symptoms ●​ Biliary colic ○​ Smooth muscle contraction ○​ Bouts of pain associated with obstruction ●​ Obstruction of bile flow ○​ Jaundice ●​ Murphy’s sign ○​ Tests for cholecystitis ○​ May be positive or negative in cholelithiasis depending on the degree of inflammation present Malignancies Condition Pathophysiology Signs/Symptoms Carcinoma of the Gallbladder ●​ Originates from surface epithelia ●​ The tumor may progress to invade the hepatic duct and duodenum ●​ Delayed diagnosis b/c the symptoms are vague ●​ N/V, abdominal pain ●​ 5-year survival rate 10% Cholangiocarcinoma ●​ Malignant tumor of the bile duct ○​ Rare in the US ●​ Closely associated with infestation of the Chinese River Fluke ○​ endemic to Japan, China, Taiwan, and Southeast Asia ●​ Other risk factors ○​ Chronic liver disease (hepatitis B & C), PSC, smoking, DM, CF ●​ ●​ ●​ ●​ Hepatocellular Adenoma ●​ Benign, usually solitary, sharply demarcated masses ●​ May be related to the use of oral contraceptives ○​ May disappear with d/c of OC Jaundice Pruritus Acholic stools, fatigue Weight loss, fever, night sweats ○​ Related to estrogen use ●​ When the adenoma is subcapsular in location, it may rupture, resulting in severe intraperitoneal hemorrhage Hemangioma Hepatocellular Carcinoma Metastasis to the Liver ●​ ●​ ●​ ●​ ●​ Most common benign tumor of the liver Are usually small and asymptomatic May grow to cause pain Estrogen surges in pregnancy estrogens may cause hemangiomas to grow in size ●​ Primary tumor of the liver ○​ Most tumors develop in cirrhotic livers ○​ Increased risk with HBV & HCV infections ●​ Highly malignant ●​ Male-to-female ratio 4:1 ○​ Incidence in the US has increased over threefold in the past few decades ●​ Hepatoblastoma ○​ Rare liver cancer affecting children ●​ Pathology ○​ 3 forms – diffuse infiltrate; solitary mass; multiple nodules ○​ Tumor cells may synthesize alpha-fetoprotein (AFP) – found in 50% of patients ●​ Early non-specific signs of malignant disease ○​ weight loss, N, enlarged tender liver ●​ Portal HTN, bloody ascites, splenomegaly ●​ Paraneoplastic syndrome – ****** ○​ Hypoglycemia (secondary to the production of insulin-like hormones) ○​ Polycythemia (secondary to the production of EPO-like hormones) ○​ Hypercholesterolemia (hyperproduction) ○​ Hypercalcemia (PTH-like hormone production) ●​ Poor prognosis 5-year survival rate - < 20% ●​ Secondary liver tumors are more common in the US than primary liver tumors ●​ Most likely seen with tumors of the GI tract, lungs, and breast ●​ Mets typically appear as multiple round nodules with a central necrotic area ●​ ●​ ●​ ●​ Jaundice Hepatomegaly Ascites Splenomegaly Budd-Chiari Syndrome ●​ Assoc. with massive liver enlargement with venous congestion with thrombus formation and webbing of vessels ●​ Known causes ○​ Polycythemia vera ○​ Sickle cell disease ○​ IBD ○​ Pregnancy ○​ OC use ○​ Trauma ●​ Progression to cirrhosis, hepatocellular carcinoma ●​ ●​ ●​ ●​ Ascites, pain Jaundice, peripheral edema Liver failure Hepatic encephalopathy, splenomegaly,