Liver Dysfunction Biology 2291 PDF

**Biology 2291** **LIVER DYSFUNCTION** ***Topic Guidelines*** **(Review of liver structure and function -- see slides)** **Liver injury** **Sequelae of liver injury -** **Jaundice** **Hyperbilirubinemia** **Portal hypertension** **Fatty liver** **Fibrosis and cirrhosis of the liver** **He...

**Biology 2291** **LIVER DYSFUNCTION** ***Topic Guidelines*** **(Review of liver structure and function -- see slides)** **Liver injury** **Sequelae of liver injury -** **Jaundice** **Hyperbilirubinemia** **Portal hypertension** **Fatty liver** **Fibrosis and cirrhosis of the liver** **Hepatic failure** **Hepatotoxicity and hepatic biotransformation** **Reye's syndrome** **Tumours** **Viral hepatitis** **Gall Bladder dysfunction** ***\ *** **Liver Injury** **Classes of cause of liver injury** - **Metabolic** - **Toxic** - **Infectious** - **Circulatory** - **Neoplastic** - **because the liver has a large reserve capacity, manifestations of liver injury only appear when most of the liver is damaged** **Responses to injury:** **Depending on the nature, severity and chronicity of cause of liver injury, the liver will respond accordingly. There are several distinct patterns. Generally, the liver is renowned for possessing great regenerative capacity and hepatocytes will be prompted to undergo mitosis and thereby replace dead cells.** **Liver inflammation (hepatitis) is observed under many conditions and may be chronic with infection by hepatotropic viruses.** **There is a limit to the extent and the rate of regeneration, especially observed where there is severe toxicity (which will lead to fatty change followed by outright necrosis) or on-going toxic exposure (leading to fibrosis).** **Liver fibrosis (and the fibrotic pattern known as *cirrhosis),* along with several other factors, will impeded the large volume of blood flow through the liver parenchyma and cause back pressure on the portal and abdominal circulation --** **The loss of hepatocellular function and the impedance of blood flow in the liver lead to the principle sequelae of hepatic failure.** **Overview of Clinical Manifestations of Hepatic Failure** **1) jaundice - conjugated & unconjugated bilirubin (*mixed hyperbilirubinemia)*** **2) coagulopathy - reduced hepatic synthesis of blood clotting factors and malabsorption of vitamin K & B12** **3) hepatic encephalopathy / coma** **4) hypogonadism & gynecomastia in males - incr. peripheral adipose tissue) testosterone conversion to estradiol (E~2~) + reduced liver inactivation of estradiol imbalance of androgen/estrogen levels hyperestrogenism** **- a manifestation of this is** **5) palmar erythema - hyperestrogenism vasodilation of palms of the hands and soles of the feet** **6) 'spider angiomas' - focal red points with tiny radiating arms on skin (isolated, dilated arterioles)** **7) fetor hepaticus - high serum levels of ammonia / other aromatic residues normally metabolized by liver musty or "fruity" odors of breath** **8) ascites and edema - portal hypertension & hypoalbuminemia** **9) tissue wasting - muscular atrophy, weight loss, loss of plasma proteins** ***Most common etiology:*** **1) cirrhosis (very common)** **2) chronic active viral hepatitis (very common)** **3) chemicals & drugs ( acetaminophen, CCl4*, halothane, antidepressants, isoniazid*)** **\ ** **Hepatocytes** **Sequelae of liver injury and hepatic failure** **Jaundice (I[cterus])** **- yellowish-orange or yellowish-green coloration of body tissues & fluids due to accumulation of bilirubin in skin, sclerae (whites of eyes), mucous membranes *(clinical jaundice begins to appear at about 50 μmol/liter)*** **- jaundice indicates hyperbilirubinemia *(plasma bilirubin levels above 24 μmol/liter*)** **Portal Hypertension** **- sustained HTN in hepatic portal vein + tributaries** ***normal portal venous pressure is approx. 7 mm Hg.*** **- *causes, classified by site:*** **\ ** **Porto-Systemic Shunt** - **anastomotic channels connecting the portal vein with the systemic venous system (esophageal, umbilical, mesenteric, pancreatic, rectal shunts)** **- implications of porto-systemic shunts:** **1) *shunted portal blood bypasses liver* ** **a) large amounts of portal blood ammonia (NH~3~) are not detoxified by liver (*liver converts NH~3~ into urea)* - this may precipitate onset of hepatic encephalopathy, since NH~3~ is toxic to the CNS** **b) blood-borne bacteria from the intestines are not removed by liver possible *septicemia* *endocarditis, brain abscesses etc.*** **c) toxic substances by-pass liver without being detoxified accumulate injury to CNS, other vital organs** **d) nutrients from gut that are normally metabolized will be shunted directly into systemic circulation injury to tissues egs. *glucose, lipids*** **2) anastomotic vessels (porto-systemic shunts) dilated, distended varicosities veins become thin-walled rupture of vein** **- key vessels are: esophageal, umbilical, mesenteric, pancreatic & veins** **- major and most at risk are esophageal & rectal veins since they protrude into the GI lumen and subject to being traumatized by bolus or pressure** **NB1 - esophageal varices can become fragile and easily irritated by alcohol, gastric acidity, passage of food or vomiting walls of esophageal varices often rupture massive upper GI hemorrhage risk of sudden death** **- fatal outcome is due to blood clotting factor deficiencies** **NB2 - rectal hemorrhoids may rupture with passage of stool rectal hemorrhage** **NB3 blood loss into the GI tract (ie but others, such as bleeding ulcers, etc) RBC hemoglobin pigment digestion nitrogen-containing fragments from heme and globin ammonia + other neurotoxins encephalopathy** **Ascites** - **accumulation of fluid (a transudate, ultrafiltrate of plasma) in the peritoneal cavity** **abdominal swelling** **pressure on diaphragm dyspnea** ***Causes*** - **portal hypertension -** **↑ portal vein pressure ↑ hydrostatic pressure within the splanchnic capillaries** **fluid weeps into the peritoneal cavity** **plus** - **hypoalbuminemia** **reduced plasma osmotic pressure in the splanchnic capillaries** **Hypoalbuminemia occurs because of** **NB - the above may occur together in alcoholic liver disease severe ascites** ***Complications*** **ascites reduced central blood volume compensation incr HTN ascites** **(vicious cycle)** **Compensations include:** **1) aldosterone secretion from adrenal cortex salt retention at DCT of kidney water retention worse ascites** **2) ADH secretion (post. pit.) water retention worse ascites** **3) increased lymph flow in liver drips into peritoneal cavity worse ascites** **if there is no intervention severe generalized edema known as \"anasarca\" or "dropsy" (old terminology)** **NB - Anasarca is the morbid accumulation of water in tissues and all 3rd spaces as a result of hepatic cirrhosis, CHF and nephrotic syndrome** **Tx for Ascites** **1) IV albumin, prn** **2) fluid, salt restriction** **3) diuretics (e.g. spironolactone) to combat aldosterone & ADH compensatory mechanism** **4) paracentesis - peritoneal tapping of up to 5 liters over 2 hours however, fluid re-accumulates** **5) sx creation of peritoneo-venous shunt from peritoneum to internal jugular vein in neck -- risk of infection** **6) liver transplant** **[Px:] 5-year survival \< 20%** **Hyperbilirubinemia** **Abnormally high levels of plasma bilirubin can be analyzed according to whether or not it has undergone conjugation in the liver - It can be one of, or both of, the following, which provides important dx hints as to the cause:** ***Hyperbilirubinemia*** ***Unconjugated hyperbilirubinemia Conjugated hyperbilirubinemia*** **Causes may be:** **a) impairment of biliary liver function, specifically impairment of one or more of** - **bilirubin uptake by liver cells,** - **bilirubin conjugation in liver cell SER,** - **bilirubin secretion into bile canaliculi** **b) excessive hemolysis - destruction of RBCs** **c) obstruction of hepatobiliary tract** ***Unconjugated Hyperbilirubinemia*** **Causes:** 1. ***Hemolysis* - excessive rate of destruction of RBCs due to** - ***blood transfusion reactions* Ag-Ab rxs to donor RBCs** - ***result of cardiopulmonary bypass*** - ***sickle cell Hb (genetic HB defect) --* during hypoxemia RBCs fragment in tight vascular spaces fragments are hemolyzed at high rate in spleen** - ***thalassemia (*genetic Hb defect) -- hemolysis in bone marrow** - ***spherocytosis* (genetic Hb defect) -- hemolysis in spleen** - **drug- induced hemolysis esp. [oxidant drugs] such as primaquine (an anti- malarial drug), sulfonamides, etc.** **NOTE - bilirubin overproduction due to hemolysis is not usually the result of liver pathology -- liver conjugating capacity is saturated by the excessive conc. of unconj. plasma bilirubin** **2) [ ] *Decreased hepatocellular uptake of bilirubin*** **Causes due to** - **infection** - **toxicity** - **gene mutations that impairs bilirubin uptake (see insets)** **3) *Decreased conjugation:*** **i) [Neonatal Jaundice] ( physiological jaundice)** **- a transient deficiency of hepatocyte SER glucuronidation enzyme ( [glucuronyl transferase]) commonly seen in premature infants** **NOTE \~ 7% of term infants lack functional enzyme for the first 7-14 days of life** ***Tx*** **- glucuronyl transferase enzyme may be induced by phenobarbital treatment** **- [phototherapy] (uv): UV light converts unconjugated bilirubin to a photo-isomer which is water-soluble and is excreted via the urine without prior conjugation** **ii) Impaired [hepatocellular secretion of conjugated bilirubin into the bile:]** **[Dubin-Johnson syndrome] - deficiency of hepatocyte canalicular transport protein for conjugated bilirubin** - ***autosomal recessive trait that affects 1:1300 Iranian Jews*** - **grossly pigmented liver *(melanin-like pigment in hepatocyte cytoplasm*)** - **usually asymptomatic until age 10 - 30 yrs. → manifests as *abdominal pain, nausea/vomiting, hepatomegaly)* no Tx** **4) *Biliary Obstruction:*** - **obstruction in bile flow can result in spillover of conjugated or unconjugated hyperbilirubinemia [ ]** - **depends on location of obstruction** **a) [Intrahepatic obstruction] - cirrhosis and or edema in liver parenchyma, or necrosis due to toxicity** **b) E[xtrahepatic obstruction]** **i) gallstones** **ii) tumour** **iii) congenital atresia of biliary tree** ***(ie. congenital absence of the biliary tube or absence of its lumen)*** **iv) inflammatory stenosis** **v) surgical obstruction of the ampulla of Vater *(leading to the duodenum)*** ***Manifestations of extrahepatic obstruction*:** - **High serum levels of [conjugated] bilirubin** - **excretion of pigment in urine *(****∴ **urine turns brown)*** - ↓ **excretion in stool *(****∴ **feces turn pale)*** - **pruritis: *conjugated bilirubin deposited in skin*** → ***intense itching*** - **later S&S of extrahepatic obstruction:** **when liver becomes engorged with pigment incr *hepatocyte conjugation activity*** **mix of conjugated & unconjugated bilirubin in plasma** ***- the degree of jaundice correlates with severity of abnormality however, natural skin pigment of patients can make this difficult ie refer to sclera of eyes if patient has dark pigmented skin*** **\ ** **Fatty Liver** **- infiltration of hepatocytes with lipid** **- fat infiltration alone usually does not significantly disrupt liver cell function; however, it is a sign of chronic injury which may progress to fibrosis and sometimes cirrhosis** **- factors causing fat deposition in liver:** **1) high fat diet - "Non Alcoholic Fatty Liver Disease" in obese patient** **high lipid conc.** **saturated metabolic capacity** **hepatocyte storage of triglycerides** **2) starvation or low-protein diet** - **starvation will cause the mobilization of adipose tissue to release fatty acids (FAs)** - **FAs infiltrate hepatocytes triglycerides are incorporated into VLDLs** ***- at the same time, the liver normally converts amino acids into glucose (via gluconeogenesis) to maintain plasma glucose conc.*** **3) alcoholism** **-*- if sectioned at autopsy, liver is soft, greasy & yellow*** **NB Ethyl alcohol is metabolized by the liver to acetaldehyde which is a hepatotoxin** **Mechanisms** **a) alcoholism often occurs along with starvation-like states fatty acids mobilized from adipose tissues fatty infiltration of liver** **b) diversion of hepatic enzymes and NAD^+^ co-enzyme away from fat catabolism in order to metabolize alcohol** **NB NAD^+^ is needed for Krebs cycle & for mitochondrial electron transport system, so less NAD reduced fatty acid catabolism** **\ ** ***Coagulopathy in hepatic failure*** - **60% of liver lobule function lost** **blood clotting factor declines** **coagulopathy** ***Pathophysiology*** **↓ liver lobular function ↓ bile salt production ↓ dietary fat emulsification decr GI vitamin K absorption ↓ hepatocyte vitamin K uptake defective synthesis of clotting factors in liver inactive clotting factors (proenzymes) may be synthesized but not activated ie. abnormal *post-translational modification of proteins*** **NB: the deficiency of blood clotting factors is an early sign of liver failure that occurs** **Usually before hypoalbuminemia** **- mechanisms leading to ↑↑ risk of hemorrhage:** **1) portal hypertension → splenic congestion → splenomegaly → hypersplenism** **excessive destruction of formed elements of blood by splenic macrophages →** **a) ↓ blood platelet levels ⇒ bleeding disturbances *(↓ ability to make platelet plug = 1st step of hemostasis*** **b) ↓ blood RBC levels ⇒ anemia** **c) ↓ blood WBC levels ⇒ immunodeficiency** **2) esophageal, umbilical, mesenteric, pancreatic & rectal varices - ie. common and dangerous sites of bleeding esp. in cirrhosis** ***Hepatorenal Syndrome (Hepatic Nephropathy)*** - **severe hepatic disease acute renal failure (ARF)** - **kidneys appear morphologically normal, but functionally impaired** - **may be gradual or sudden** **Manifestations of h*epatorenal syndrome*** **1) decr. urinary output (oliguria), with:** **a) Na^+^ & H~2~O retention fluid/electrolyte imbalance** **b) incr BUN, serum creatinine & ammonia N imbalance** **c) ascites, peripheral edema, 3rd spacing of vascular fluids** **2) worsening jaundice (kidneys cannot excrete conjugated bilirubin)** **Etiopathogenesis** **- accumulation of plasma vasoconstrictors decr renal blood flow renal shutdown** **Vasoconstricting substances could incl** **a) gut-derived bacterial endotoxins - '*false-neurotransmitters'* derived from digested Hb, food*)*** **b) *ascites/edema* compensatory renin-angiotensin-aldosterone reduced clearance by liver** ***Px of hepatorenal synd*[.:]** **- poor; *usually fatal*** ***NB - affected kidneys are basically normal; they have even been used in kidney transplant programs, after the death of the donor*** ***Hepatic Encephalopathy*** **- alteration in neurologic status in persons with significant liver disease** **- gradual or *(more often)* abrupt** **- precipitated by a major hemodynamic insult such as** **1) bleed from esophageal varices** **2) ingestion of narcotics or barbiturates** **3) administration of anesthetics** **4) excessive protein intake** **5) electrolyte imbalance** **6) hemodynamic alterations (e.g. hypovolemia or shock)** **- virtually anything that places metabolic demand on the marginally-functional liver cells may hepatic encephalopathy & coma** **- mechanisms of hepatic encephalopathy & coma:** **1) neurotoxins in blood not cleared by dysfunctioning liver** **action of GI bacteria nitrogenous products such as phenylethanolamine & octopamine absorbed into portal blood by-pass liver CNS act as \"false-neurotransmitters" to mimic endogenous neurotransmitters, such as epinephrine, dopamine, ACh, GABA,** **NOTE -- one tx is use of antibacterials to reduce production of neurotoxins improves brain function** **2) [ incr serum ammonia]** **- arises since deamination reactions continue to occur but liver cannot convert newly-synthesized NH~3~ to urea** **NH~3~ increases blood pH neurotransmitter receptor denaturation CNS function** ***3)* production of a circulating benzodiazepine - like GABA agonist** **- may be kyneuramine produced by interaction of melatonin with oxygen free radicals** **Clinical note on dx and monitoring of hepatic encephalopathy progression:** 1. **psychiatric & behavioral changes incl intellectual ability, confusion, delusions, violent abusive behavior** 2. **LOC - loss of alertness** **coma** **3) neurologic: a) hyper-reflexia ( overly exuberant reflexes)** **b) asterixis (\"flapping tremor\")** **4) EEG changes - Ie. depression of EEG wave forms** **NB - end-stage hepatic encephalopathy is associated with permanent changes in brain morphology obs on autopsy incl astrocyte proliferation (damage to blood-brain barrier), patchy cortical necrosis** **Px: with appropriate & timely Tx, early hepatic encephalopathy is reversible & shows no permanent brain pathology** ***Tx:*** **1) remove precipitating factors such as :** **2) correct the fluid/electrolyte abnormalities** **Pharmacological Liver Injury** **(see slides for APAP section)** **many drugs cause hepatotoxic effects** ***e.g. tetracyclines, salicylates, ethanol, acetaminophen, halothane, methotrexate, phenytoin, sulfonamides, etc*** **Most commonly acetaminophen in Canada** ***Hepatotoxicity* may result from** - **direct toxicity of the agent (e.g. acetaminophen)** - **biotransformation by liver toxic metabolites (e.g. EtOH** → **acetaldehyde)** - **conversion of a drug (or its metabolite) into immunogenic species by it being covalently bound to liver proteins** **e.g. chlorpromazine, isoniazid, halothane, etc** **- drug-protein complex is recognized by the pt.'s immune system as foreign/NOT-SELF** **hypersensitivity rxs which may be manifested wks or months after Tx** **Reye\'s Syndrome** **- acute illness precipitated by acute liver failure** **- characterized by acute encephalopathy with cerebral edema, as well as effects on other vital organs - occurs most frequently in children 6mos to 15 yrs 3-5 days after a viral illness (e.g. varicella = chickenpox, influenza B, upper respiratory infection, or gastroenteritis) - associated with Tx of viral fever with ASA (aspirin)** ***Manifestations*** 1. 2. 3. 4. **Results in** **1) massive fatty infiltration (\"[steatosis]\") of liver & other organs (e.g. CNS, kidney, heart)** **2) characteristic ultrastructural signs of cellular necrosis seen in liver & brain (e.g. mitochondria swelling)** **3) cerebral edema** - **4) liver failure** ***Prognosis*** **fatality rates: 10-40% depending upon age of pt. *(severity is inversely related to age)*** **- importance of [prevention] *by* substituting acetaminophen for ASA for kids** **- *incidence of Reye's synd. is sharply declining however parents must be reminded not to treat febrile illness in children with ASA*** ***Treatment*** **supportive measures (*since a specific Tx not available)*** **1) lactulose (*to ↓ NH~3~ in GI tract*)** **2) admin. of fresh-frozen plasma (to replace defic. blood clotting factors)** **3) mechanical ventilation, prn** **4) corticosteroids (*e.g. dexamethasone*) to ↓ intracranial pressure** **Cirrhosis of the Liver** **- \"cirrhosis\" is a general term for irreversible degenerative change in the normal 3-dimensional structure of an organ (in this case, the liver), causing loss of function** **- structural features of hepatic cirrhosis:** **1) destruction of liver parenchyma** **2) separation of lobules by fibrous tissue** ***fibrous scar tissue surrounds fatty liver cells → destruction of 3-D lobular architecture*** **3) formation of nodules** ***- hepatocytes respond to fibrotic destruction of the lobules by undergoing mitosis in* attempt to regenerate fully functional liver lobules, however, the outcome of hepatocyte proliferation is isolated pockets of dividing cells ("nodules") surrounded by fibrous tissue** **3 different histologic patterns of cirrhosis:** **1. [micronodular cirrhosis] = liver appears granular with 1 mm nodules (only visible with a microscope)** **2. [macronodular cirrhosis] = liver shows 1 cm nodules (∴ grossly visible)** **3. [mixed micro- & macro-nodular cirrhosis]** **NOTE: these are histopathologic descriptive terms only & they do not bear on the clinical presentation or course of the disease** **4) abnormal vascular architecture** **Classes of Cirrhosis by Cause: 4 classes according to cause or resulting pathology** **A) biliary cirrhosis -- primary - autoimmune** **- secondary -- biliary obstruction** **B) post-necrotic cirrhosis -- due to hepatitis** **C) alcoholic cirrhosis** **D) cryptogenic cirrhosis (mechanism unknown/ no identifiable cause -** A. **Biliary Cirrhosis:** - **begins in bile ducts, unlike post-necrotic or alcoholic cirrhosis, where damage begins in hepatocytes** **- 2 sub-types of biliary cirrhosis:** 1. **Primary (Intrahepatic) Biliary Cirrhosis:** **- etiology: unknown - however, this is the most common type of cirrhosis women \> 40** **(possible endocrine-related mechanism)** **- slow insidious course results from autoimmune destruction of interlobular bile ducts** **- common in autoimmune collagen diseases (such as SLE) chronic inflammation & periportal fibrosis scar tissue surrounds hepatocytes & separates lobules** **Px - death occurs 5-10 yrs after onset of clinical manifestations, usually due to complications** **a) portal hypertension** **b) encephalopathy** **Tx - glucocorticoids or immunosuppressants (due to autoimmunity) + tx by symptom ie. anti-pruritic drugs (e.g. cholestyramine to bind bile salts) +** **I.M. vit. D & K Tx (defic. due to ↓ bile salts)** 2. **Secondary (Obstructive) Biliary Cirrhosis:** **Px: Poor - liver failure or infection** **Tx - surgery to relieve biliary stasis (obstruction)** B. **Post necrotic Cirrhosis:** **- most common cause of hepatic cirrhosis globally (ie. Canada, most common is alcoholic cirrhosis)** **- the result of massive liver necrosis due to:** **1) viral hepatitis (B or C)** **NB \> 25% of pts. with hepatitis C develop this type of cirrhosis** **2) hepatotoxin exposure** **- carbon tetrachloride, drugs (such as isoniazid, methyldopa (antihypertensive)** **3) inherited metabolic diseases** **- hereditary α~1~-antitrypsin defic.,Wilson's disease (copper storage disease)** **- hepatocytes are the first cell type to be affected, unlike biliary cirrhosis** **Infection or toxicity massive necrosis inflammation stroma irreversibly fibrotic bands large proliferative nodules loss of lobular structure of parenchyma** **Manifestations** **1) early : enlarged, tender liver (hepatomegaly with RUQ pain)** **2) late: liver is shrunken & nodular and evident hyperbilirubinemia, jaundice** **b) elevated BUN (due to oliguria if hepatorenal syndrome develops)** **c) elevated serum liver enzymes due to hepatocyte necrosis** **d) hypoalbuminemia** **e) bleeding diathesis ( predisposition to bleeds, due to ↓ in blood clotting factors)** **f) endocrine disturbances** **g) hypoglycemia** **h) portal hypertension splenomegaly, ascites, varicosities, risk of hemorrhage, encephalopathy)** **Px - death usually due to a fatal bleed or hepatic encephalopathy** **C) Alcoholic (Laennec\'s) Cirrhosis:** **- most prevalent cirrhosis Canada -- highest prev. in men \> 40 years** **Etiopathology - chronic alcohol abuse** **What qualifies as alcohol abuse? -various studies show a range of doses, however:** **- males of alcohol tolerant ethnogenetic groups: roughly 10-15 years ingestion of \> 80 g/day ethanol (8 beers, 1 L wine, 350 ml spirits)** **- females: roughly 1/3 to 1/2 male dose** **- close association between alcohol abuse and poor diet - liver toxicity is compounded by poor diet -- however, even where alcohol abuse is accompanied by nutritionally-sufficient diet, cirrhosis can still result ie. nutritional deficiency is not a sufficient cause** **Typically, chronic alcohol abuse cause liver changes that follow 3 phases:** **Phase 1. *Alcoholic steatosis*:** **- this is usually reversible with cessation of drinking. It occurs due to** **a) improper metabolism of fatty acids ( beta-oxidation) due to ↓ NAD^+^** **b) incr synthesis of triglycerides due to ↑ NADH** **c) decr. release of lipoproteins due to ↓ hepatic apoprotein synthesis accumulation of fat within the hepatocytes cytoplasm** **Manifestations - steatosis may be asymptomatic, or may manifest as:** **a) malaise d) hepatomegaly** **b) anorexia & nausea e) jaundice** **c) liver tenderness f) occasionally, sudden death (due to portal hypertension)** **Phase 2. *Alcoholic hepatitis:*** **- acute liver cell necrosis inflammation of liver (PMNs, lymphocytes infiltration)** **necrotic areas surrounded by WBC's & fibroblasts + Mallory Bodies ( hyalinized intermediate filament protein- SEE HISTOLOGY SLIDES) (NB, on biopsy, these are a histological marker of liver cell death from alcoholic liver disease) pericellular & perivenular fibrosis & liver enlargement infiltrating fibroblasts, collagen deposition** **Phase 3. *Alcoholic cirrhosis:*** **- 25% of alcoholics display morphologic evidence of cirrhosis** **- 10% of alcoholics display clinical evidence of cirrhosis** **- scarring occurs between the lobules centrilobular sclerosis fibrosis spreads between hepatic central veins destruction of hepatic central veins** **- isolated hepatocytes proliferate formation of hyperplastic nodules** **Manifestations:** **Portal HTN, hepatic failure** a. **abnormal liver function tests i) biliary obstruction** b. **ascites i) GI bleeding** c. **jaundice** d. **esophageal varices k) muscle wasting** e. **coagulopathy L) polyneuritis (periph. nervous system)** f. **hypoproteinemia m) CNS -- mental changes** g. **testicular atrophy + loss of libido and sexual function (due to incr. estradiol E~2~)** h. **splenomegaly hypersplenism anemia + immunodeficiency + coagulopathy** **dx: a) liver biopsy (confirms cirrhosis)** **b) liver function tests ( show  serum hepatic enzymes ⇒ liver cell necrosis)** **tx: a)rest** b. **nutrition** c. **abstinence from alcohol** d. **Tx of complications** **Px:** **- - \> 50% of persons with significant liver cirrhosis die within 5 years** **- 40% 5-yr. survival, if continued alcohol abuse** **- 60-70% 5-yr. survival, if abstain ⇒ most pts. cannot abstain** **- depending on how far along in the process, abstinence may result in return of liver function to normal and reversal of fat accumulation** **- fibrosis/cirrhosis is irreversible** **- continued alcohol abuse recurrent bouts of alcoholic hepatitis decompensation hepatic failure** **- final causes of death incl:** **a) complications of hepatic failure** **b) infection** **c) GI bleed (incl. esophageal)** **d) hepatocellular carcinoma (3-6% of cases)** **\ ** **Tumours of the Liver** **Primary Liver Tumours** **- liver tumours causing loss of function are almost always malignant** **- primary & secondary malignancies of the liver are responsible for approx. 2% of all cancer death in Canada** **Benign Hepatic Tumours** **1) Hepatic Cell Adenomas:** **- usually in post-menopausal women - related to use of oral contraceptives** **- well-circumscribed masses (5-20 cm diameter)** **- microscopically like normal liver cells, but no lobular structure** **- may cause abdominal pain** **- may rupture & bleed intra-abdominally** **- usually do not recur following surgical excision** **2) Hemangiomas:** **3 ) Bile Duct Adenomas** **- common small white nodules, and often mistaken for metastatic tumours** **Primary Malignancies of Liver** **- relatively rare compared to secondary ( metastatic) tumours** **- approx. 2 - 19 new cases/ 100,000 population each year** **- may arise within bile duct, hepatocyte or vascular epithelium and incl:** **1. Cholangiocellular carcinoma (CCC)** **- bile duct cancers that are approx. 10% of all primary liver cancers (far less common than hepatocyte cancers)** **Causes incl** **a) liver fluke infestations (most common in S.E. China)** **b) cholangitis (bile duct inflammation) - presents with pain, anorexia, wt. loss, gradual jaundice - poor Px (survival \< 6 months after Dx)** 2. **Hepatocellular carcinoma (HCC)** **- 90% of all primary liver cancers - *rare before 40 yrs*** **etiopathogenesis** **a) consumption of dietary carcinogens (e.g. aflatoxin -- these are mycotoxins produced by Aspergillus spp. on moldy nuts & grain** **b) any number of other liver diseases (viral hepatitis/chronic carrier state, liver cirrhosis, parasitic liver infections)** **- may secrete bile products, grow rapidly and metastasize early, invading *hepatic & portal veins, heart, lungs, brain, kidney, spleen*** ***some HCC tumours rupture spontaneous hemorrhage* but death is usually due to GI hemorrhage or liver failure** ***Manifestations*** **- often these tumours do not cause any functional disturbance until [advanced stages] - changes in liver function tests reflect the degree to which liver function has been disrupted** **- slow [or] abrupt onset of anorexia, nausea, vomiting, fullness, pressure, dull ache in rt. hypochondrium** **- jaundice (due to cirrhosis)** **- portal hypertension & ascites** **- metabolic disturbances related to functional impairment of liver cells (hypoalbuminemia, hypoglycemia, coagulopathy** **- as tumour enlarges pain , wt. loss & [cachexia] (wasting)** ***Dx*** **clinical + non-specific lab tests *(e.g. liver function tests: serum AST & ALT levels)*** **CT or ultrasound** **exploratory laparotomy** **liver biopsy -** ***Tx*** **surgical resection of liver tumours is not usually possible [unless:] tumour is localized to a removable lobe, pt. does not have cirrhosis, tumour removal does not compromise necessary hepatic vascular supply** **chemo** **radio-Tx -- not used as much since lethal high dose radiation required for Tx of tumour cells also kills too many normal hepatocytes** ***Px*** **- median survival rates in symptomatic pts of 3 - 4 months** **- occasional long-term survival** **- after surgical resection, many pts. develop metastases** **3) [Angiosarcomas:]** **multiple hemorrhagic cancers arising from vascular endothelium** **- caused by various environmental hazards, including:** **\ ** **Metastatic (Secondary) Carcinoma of the Liver** **- much more common than primary liver cancer ie. liver is a frequent site of metastases from cancers arising from GI tract, pulmonary, breast** **- liver is especially vulnerable to mets because** **1) it receives a large blood volume - metastatic liver tumours usually arrive via portal vein & systemic circulation** **2) liver has a large reserve lymphatic drainage, which is a factor in intra-hepatic spread** **- metastases are usually diffusely distributed throughout the liver, seriously disrupting its function ⇒ abnormal liver function tests, etc** **- serum carcinoembryonic antigen (CEA) level correlates with tumour size & degree of metastases** **clinical course depends on:** **- rapidity of growth of metastases &** **- cell type of the primary malignancy** **Manifestations:** **- rapid decline of nutritional status** **- marked cachexia** **- muscle wasting** **- splenomegaly** **- possible biliary obstruction compression of intrahepatic bile ducts due to extensive deposition of metastatic tumours** **- jaundice & other liver dysfunctions** **Px** **- poor - almost always non-resectable** **- 5-yr survival: \< 5%** **\ Viral Hepatitis** **- inflammation of the liver may be caused by:** **- viruses / microorganisms** **- toxins** **- drugs** **- alcohol** **- acute viral hepatitis is inflammation caused by infection by different strains of viruses** **1) hepatotropic viruses:** **- hepatitis A (HAV)** **- hepatitis B (HBV)** **- hepatitis C (HCV)** **- delta hepatitis (HDV)** **- hepatitis E (HEV)** **- hepatitis non A-E** **NB: most of these viruses are unrelated viral types** **- HAV, HBV, HCV, HDV, HEV particles are distinguishable by their antigenic properties** **- Non A-E hepatitis particles have not yet been precisely identified** **2) non-hepatotrophic viruses can (less commonly) cause hepatitis:** **Clinical Manifestations** **- initially similar in all forms of acute viral hepatitis** **- nausea, anorexia, low-grade fever, general malaise, hepatomegaly, RUQ abdominal tenderness, jaundice** **\ ** **Hepatitis A** **- produced by HAV = a 27 nm-diameter RNA enterovirus of the picorna group** **- originally this disease was called \"infectious hepatitis\"** **- HAV → a benign, self-limited disease** **- incubation period: 1-6 weeks before definitive clinical S&S are evident (e.g. jaundice)** **⇒ infected individuals have plenty of time to spread their disease, before they know they have it** **- frequently occurs in crowded unsanitary living conditions** **- \"dormitory disease\" due to outbreaks infecting students living close together** **45% of adults in urban areas show anti-HAV antibodies in their blood** **- accounts for 25% of acute hepatitis cases in developing countries** **transmission: - fecal-oral spread** **- by sewage-contaminated water** **- sewage-contaminated undercooked shellfish** **NB- on occasion, HAV is directly transmitted via blood/body fluids** **NB: HAV does not lead to chronic hepatitis nor a carrier state** **Manifestations** **Children :** **- diarrhea, nausea, & malaise (∴ non-specific)** **- usually anicteric (i.e. without jaundice)** **Adults:** **- more severe than in children** **- initial flu-like symptoms, followed by jaundice** **3 phases of Hep A in adults:** **1) prodromal phase: (usually 1-3 wks)** **a) malaise** **b) anorexia** **c) nausea & vomiting** **d) low-grade fever** **e) right upper quadrant pain** **2) icteric (jaundice) phase: (usually 1-4 weeks, but may be up to 8 wks)** **- mixed unconjugated/conjugated hyperbilirubinemia- total plasma bilirubin \> 2.5 mg/dL - if cholestasis occurs, stools become lighter (clay-colored), urine dark** **- elevated serum IgM & IgG levels - serum IgG may remain ↑ for years which confers ongoing immunity to HAVc)** **- serum liver enzymes** **i) alanine aminotransferase (ALT) &** **ii) aspartate aminotransferase (AST)** **- hepatic necrosis** **3) recovery:** **- parenchyma regenerates** **- weakness & mildly abnormal liver function tests may persist for months** **- HAV infection → long-term (probably life-time) immunity** **Prognosis** **most pts. fully recover** **- chronic or fulminant (ie. occurring with great rapidity) hepatitis is rare** **- fatality rate: \< 0.3% (death due to development of fulminant hepatitis)** **Therapy:** **1) supportive management, rest to avoid fatigue** **2) consume a high carb/high pro nutritious diet** **3) multi-vitamin supplementation** **4) abstain from alcohol or drugs or toxins** **Prevention and prophylaxis:** **1) HAV vaccine** **2) immune serum globulin (ISG, -globulin) for exposed individuals** **NB - passive immunization as tx is prepared from pooled sera of many human donors** **Ie. contamination of product with HBV, HCV** **\ Hepatitis B** **-infection by HBV , a 47 nm-diameter double stranded DNA virus (Hepadna virus)** **- Hep B was originally called \"serum hepatitis\"** **5 clinical states in infected individuals:** **1) *asymptomatic carrier state*:** **- individuals appear "healthy\" and show no overt evidence of disease** **- risk of later development of chronic hepatitis B and hepatocellular carcinoma (HCC)** **- 200 X risk of HCC compared to non-carriers; occurs 20-30 yrs. post-infection** **- can transmit Hep B to others** **probable carriers include:** **- immunodeficient** **- children who receive virus during childbirth** **2) *subclinical/asymptomatic*** **- approx. 65% of infected individuals** **- some of these will progress to chronic Hep B or become asymptomatic carriers** **3) *acute self-limiting Hepatitis B infection:*** **- approx. 25% of infected individuals** **- most recover with life-long immunity to subsequent Hep B infections** **- approx. 1% die due to development of fulminant hepatitis** **4) *chronic infection:*** **- approx. 5-10% of infected individuals** **Possible outcomes include:** **- ongoing indolent infection** **- death from liver failure in 2-3 weeks** **HBV transmission** **- parenteral routes: transfusion, dialysis, blood products, needle-stick accidents, shared needles among drug abusers, tattooing, acupuncture during parturition, perinatal, transplacental** **- HBV may be transmitted by oral or sexual routes** **- present in saliva, semen, vaginal fluid & breast milk (postnatal transmission)** **- relatively few HBV particles are required to infect individuals especially if pts. are immunosuppressed, e.g. HIV infected persons, pts. on immunosuppressant drugs or corticosteroids, patients with diabetes mellitus, family members, caregivers & others in close contact with the Hep B pt. are at risk due to possible contact with body secretions** **NB HBV virions can withstand dehydration for approx. 1 week before becoming denatured** **Manifestations** **Incubation is typically 6-8 wks (but may be up to 6 months)** **Phases of infection:** **a) pre-icteric (prodromal) phase:** **b) icteric phase: (jaundice phase):** **in 50% of acute Hep B cases, similar to HAV icteric phase, only more severe** **- liver tenderness & dysfunction** **- serum liver enzymes elevated, prolonged prothrombin time, etc** **- some complications incl aplastic anemia, pancreatitis, cardiomyopathy, neuropathy, skeletal myopathy** **c) recovery phase:** **resolution of jaundice etc. - may take 1-6 months (or more) after exposure** **- 5-10% of HBV infections become chronic:** **- 1/3 are indolent infection that may not disrupt liver function too much in the short run, but can become progressive** **- 2/3 of cases show chronic active hepatitis progressive liver damage** **- in absence of tx** **a) cirrhosis,** **b) hepatic failure** **Pathogenesis:** **HBV stimulates immune-mediated hepatocyte injury and necrosis** **- HBV is not directly cytopathic, as evident by HBV carrier state** **- complete HBV particles may be present within hepatocytes for many years without liver injury however, genetic uptake of HBV sequences HCC** **Tx** **a) Interferon α & β (IFN α/β)** **- IFN's = naturally-occurring glycoprotein cytokines that inhibit viral replication however many toxic reaction to this peptide when given as a drug (pancytopenia, neurotoxicity, cardiotoxicity...)** **b) immunosuppressants (e.g. azathioprine or prednisone), - rationale for immunosuppressant Tx:** **- this is done for the purpose of suppressing over-exuberant immune attack on infected liver** **Prophylaxis:** **- HBV vaccinations are highly effective** **Hepatitis C** **- caused by HCV (=30-60 nm diameter RNA virus)** **- HCV is endemic in large areas of the world** **Transmission:** **- similar to HBV - parenteral, sexual, transplacental, & via breast milk** **- HCV causes most cases of post-transfusion hepatitis** **Manifestations** **- onset: insidious with incubation of 8 wks to many years** **- 10-35% of cases are asymptomatic or sub-acute - may progress to HCV carrier state** **- 65-90% of HCV infected develop acute Hepatitis C** **- 50-75% of HCV infected persons chronic Hepatitis C with the disease following a remitting/relapsing course, and spanning decades** **- in one study, the time to outcomes was as follows:** **1) chronic Hep C - 10 yrs** **2) cirrhosis of the liver = 21 yrs** **3) HCC = 29 yrs** **- there is rarely progression to fulminant hepatitis** **Tx** **1) similar to HBV hepatitis:** **- rest, hi-carb/hi-pro diet, vitamin supplementation, no alcohol** **2) use of INFα** **3) antivirals (such as velpatasir and others) with or without ribavirin (which has some distinct toxic effects such as some dose-dependent mild GI & CNS effects** **Prophylaxis** **- none available yet but several in the pipeline as of 2020** **Hepatitis D** **- caused by small defective 35 nm-diameter RNA virus that can replicate & cause infection only when encapsulated by HBsAg** **- HDV infection only occurs with HBV co-infection** **Transmission** **- parenteral & sexual transmission & probably fecal/oral** **- usually transmitted from mother to child during delivery, through contact with blood or other body fluids** **- sex with an infected partner** **- injection-drug use that involves sharing needles, syringes, or drug-preparation equipment and needle sticks or exposures to sharp instruments.** **- duration of infection dependent upon duration of HBV infection i.e. up to 6 mos** **- dx is often overlooked** **Manifestations** **- HDV has direct cytopathic effects + additional damage caused by immune reaction to HBV acceleration of hepatic failure** **- HDV is a common cause of serious fulminant hepatitis** **Hepatitis D virus (HDV) is a virus that requires hepatitis B virus (HBV) for its replication. HDV infection occurs only simultaneously or as super-infection with HBV.** **WHO Notes** **- globally affects globally nearly 5% of people who have a chronic infection with HBV.** **- geographical hotspots - Mongolia, Republic of Moldova, Western and Middle Africa.** **- at risk pops incl injecting drug users, indigenous populations and recipients of hemodialysis.** **- overall number of HDV infection has decreased since 1980s due to successful global HBV vaccination** ***HDV-HBV co-infection is considered the most severe form of chronic viral hepatitis due to rapid progression towards liver-related death and hepatocellular carcinoma.*** **Tx** **success rates are generally low.** **- prevented by hepatitis B immunization.** **Hepatitis E** **- caused by HEV = 32 nm-diameter RNA virus** **- usually affects children & young adults** **- incubation 15-60 days** **- fecal-oral transmission ie hygiene, water purity important** **- acute onset, no carrier state, usually mild disease (except in pregnant females), no chronic hepatitis - similarities to HAV infections** ***NOTE: there are other hepatitis viruses -- the list goes on, however, the ones above are most prevalent globally*** **\ ** **Gall Bladder Disease** **- most common disorders are cholecystitis and cholelithiasis** **Cholecystitis:** **- inflammation of the gallbladder** **- second most frequent cause of abdominal pain requiring abdominal surgery** **(most common is appendicitis)** **- cholecystitis presents with:** **- acute RUQ pain** **- leukocytosis & fever (38-39^o^)** **2 types of cholecystitis** **1) acute calculous cholecystitis** **- 90% of cases are caused by gallstone obstruction of neck of gallbladder or cystic duct distended, inflamed & painful gallbladder** **Complications (in absence of tx)** **- ischemic necrosis of the gallbladder** **- perforation of the gallbladder** **Manifestations** **- intolerance to fatty food - S&S: nausea, vomiting & pain after eating fatty foods** **Ie. fat in duodenum → CCK-PZ release from intestinal cells → contraction of the gallbladder** **2) acalculous cholecystitis** **- 10% of cases, this is precipitated by various other factors:** **- previous surgery** **- prolonged labour** **- severe trauma** **- bacteremia** **Tx:** **1) laparoscopic or open cholecystectomy (removal of gallbladder)** **2) various Tx's to remove stones such as** **- extracorporeal biliary lithotripsy:** **(breaking up stones within the biliary tract, using shock waves)** - **Note some fragments may often be too large to pass (\> 5 mm)** **- use of chemicals to dissolve stones ie tert-butyl ether via a catheter** **- supportive Tx's:** **1) antibiotics, prn (e.g. ampicillin or tobramycin)** **2) analgesics for pain management such as meperidine (IM @ 2-4 hrs )** **Cholelithiasis:** **- bile stones (gallstones)** **- most form in gallbladder** **3 kinds of gallstones:** **1) cholesterol stones: 75% of gallstone cases in Western countries** **2) pigment stones ( bilirubin stones): common in Asia (diet differences?)** **3) mixed stones** **Manifestations** **1) pain (\"biliary colic\") - epigastric or RUQ that can mimic an MI** **2) cholestasis ( blockage of bile excretion) jaundice esp. if blockage occurs in common bile duct or lower** **3) nausea, vomiting, sweating, bloating, fat intolerance, flatus --** **- complications incl** **Patho** **stone formation over years - obstruction of bile duct by gallstone(s) stasis of bile flow chemical irritation of gallbladder (prolonged exposure to concentrated bile) acute cholecystitis pressure, distension & ischemia in gallbladder pancreatic reflux may occur irritation of bile duct mucosa by contact with pancreatic enzymes possible pancreatitis** **- obstruction may lead to jaundice & cirrhosis (extrahepatic biliary cirrhosis)** **Risk factors:** **- middle age** **- obesity** **- rapid wt. loss** **- female gender, pregnancy, multiparity** **- estrogen (oral contraceptive use or HRT)** **mechanisms of formation:** **NOTE pigment stones** **- biliary infection bacterial enzymes digest conjug bilirubin unconjug bilirubin low solubility precipitation in biliary ducts** **Dx:** **- oral cholecystogram to visualize stones** **- Ca^2+^-pigment stones may show on X-ray** **Tx** **see cholecystitis section (Tx of stones)** **Biliary Atresia:** - **congenital malformation in which intra- or extra-hepatic bile ducts are either absent or stenosed/obstructed** **- onset of clinical S&S: in first weeks or months of life characterized by inflammation, jaundice, fibrosis & destruction of hepatic or common bile ducts → biliary cirrhosis** **Px:** **- cirrhosis & liver failure ⇒ death within 2 years, if not Tx** **Tx: liver transplantation** **- "split liver" procedures using partial donor livers from relatives \-- effective in approx. 40% of Tx children**