APPROACH TO LIVER DISEASES AND ETIOPATHOGENESIS

ETIOLOGY OF LIVER DISEASE

1. APPROACH TO ETIOLOGY AND PATHOGENSIS OF LIVER DISEASE

2. LIVER STRUCTURE AND FUNCTION LARGEST ORGAN LOCATION DUAL BLOOD SUPPLY - 20% OXYGEN RICH BLOOD FROM HEPATIC ARTERY, 80% - NUTRIENT RICH BLOOD FROM PORTAL VEIN.

3. LIVER The majority of cells : • hepatocytes (2/3 of the mass of the liver) The remaining cell are: • Kupffer cells (reticuloendothelial system) • S tellate (Ito or fat-storing) cells • E ndothelial cells and blood vessels • B ile ductular cells

4. LIVER MICROSCOPY In light microscopy: Lobuleswith portal areas at the periphery and central veins in the center of each lobule. Portal areas - Consist of : • S mall veins • Arteries • B ile ducts • L ymphatics organized in a loose stroma of matrix and collagen.

5. ACINI P hysiologic unit of the liver : • helps to explain the morphologic patterns and zonality of many vascular and biliary diseases not explained by the lobular arrangement. Acini F enestrae in sinusoids→ free flow of plasma but not cellular elements. P lasma is in direct contact with hepatocytes in the subendothelial space of Disse.

6. ZONES OF LIVER Blood flowing: • zone 1 → zone 3 of the acinus portal veins → hepatic (central ) veins Bile flowing: • zone 3 → zone 1 of the acinus

7. LIVER FUNCTIONS AND TEST 1- S ynthesis of most essential proteins 2- P roduction of bile and its carriers 3- R egulation of nutrients 4- M etabolism and conjugation of Lipophilic compounds for execretion in bile or urine S erum bilirubin • is a measure of hepatic conjugation and excretion Albumin and P rothrombin time These are measures of protein synthesis. H epatic dysfunction: Abnormalities of bilirubin, albumin, and prothrombin time

8. BILIRUBIN METABOLISM

9. CLASSIFICATION OF LIVER DISEASE Hepatocellular disease Features suggestive of liver injury , inflammation and necrosis predominate Eg- Viral Hepatitis , Alcoholic liver disease Cholestatic disease Features of inhibition of bile flow predominate Eg- Gallstone, Malignant obstruction,Primary biliary cholangitis Mixed pattern Features of both hepatocellular and cholestatic injury present Eg- Drug induced liver disease, Cholestatic form of Viral Hepatitis

10. Etiology of liver disease

11. MAJOR CAUSES OF LIVER DISEASE The most common cause of acute liver disease. Viral hepatitis Drug induced liver injury , Cholangitis Alcoholic liver disease The most common cause of chronic liver disease Chronic hepatitis c Alcoholic liver disease Non alcoholic steatohepatitis Cronic hepatitis b infection Autoimmune hepatitis Sclerosing cholangitis Primary bilary cholangitis Hemochromatosis and Wilson disease

12. CIRRHOSIS Key features: The parenchymal injury & consequent fibrosis are diffuse . The nodularity is part of the diagnosis  reflects balance between regeneration and scarring. Vascular architecture is re-organized by the parenchymal damage and scarring  formation of abnormal interconnections

13. ETIOLOGY OF CIRRHOSIS

14. PATHOGENSIS OF CIRRHOSIS Epithelial cell injury in combination with cytokine release by Kupffer cells and paracrine molecule release by sinusoidal endothelial cells leads to activation of hepatic stellate cells (or portal fibroblasts) into myofibroblasts. Reversal of fibrosis results from myofibroblast deactivation, apoptosis , senescence. Matrix proteases can also achieve fibrosis resolution

15. RISK FACTORS FOR LIVER DSORDER Personal habits ( Alcohol use , Injection drug use) • Medications ( herbal , OCP, and over-the-counter) • Sexual activity • Exposure to jaundiced or other high-risk persons • Recent surgery • Remote or recent blood products transfusion • Occupation • Accidental exposure to blood or needlestick • Familial history of liver disease.

16. CLINICAL SYMPTOMS Fatigue: The most common and most characteristic symptom of liver disease. • Typically after activity or exercise • Rarely present or severe in the morning after adequate rest • A fternoon versus morning Nausea Vomiting - Nausea occurs with more severe liver disease • May be provoked by odors of food or eating fatty foods. • Vomiting can occur but is rarely persistent or prominent. Poor appetite with weight loss • Poor appetite with weight loss occurs commonly in acute liver diseases It is rare in chronic disease • Except advanced cirrhosis Diarrhea - Diarrhea is uncommon in liver disease Except with severe jaundice • lack of bile acids can lead to steatorrhea

17. RUQ pain - RUQ pain occurs in many liver diseases and is usually marked tenderness The pain arises from stretching or irritation of Glisson's capsule, which is rich in nerve endings. Severe RUQ pain Is most typical of: • Gallbladder disease • Liver abscess • Severe venoocclusive disease • Occasional accompaniment of acute hepatitis. Itching acute liver disease • early in obstructive jaundice • L ater in hepatocellular disease (acute hepatitis). chronic liver diseases • C holestatic disease (PSC and PBC) occur before the onset of jaundice • Itching can occur in any liver disease, particularly cirrhosis Jaundice hallmark symptom of liver disease and perhaps the most reliable marker of severity. Patients usually report darkening of the urine before scleral icterus. Jaundice is rarely detectable in bilirubinlevel <2.5 mg/dL. S evere Jaundice With S evere C holestasis : • lightening of the color of the stools • S teatorrhea

18. FAMILY HISTORY Familial causes of liver disease include: • Wilson's disease - Severe Liver Disease in childhood with neuropsychiatric disturbance • Hemochromatosis - diabetes , endocrine failure , liver disease in adulthood - IRON STATUS • Al ph a 1 antitrypsin deficiency - History of emphysema • Familial intrahepatic cholestasis less common • Benign recurrent intrahepaticcholestasis inherited disease • Alagille syndrome - bile builds up in liver because few bile ducts to drain the bile.

19. PHYSICAL SIGNS Typical physical findings in liver disease are: Icterus Hepatomegaly Hepatic tenderness Splenomegaly Spider angiomata Palmar erythema Excoriations

20. SIGNS OF ADVANCED LIVER DISEASE Muscle wasting Ascites and edema Dilated abdominal veins Hepatic fetor Asterixis Mental confusion Stupor and coma Gynecomastia, Testicular atrophy Loss of male pattern hair distribution THESE ARE SIGNS OF HYPERESTROGENEMIA MALE WITH CIRRHOSIS -ALCOHOL USE

21. ICTERUS Sclera under natural light. F air-skinned individuals : yellow skin may be obvious D ark-skinned individuals, the mucous membranes below the tongue demonstrate jaundice. Jaundice is rarely detectable if the serum bilirubin level is < (2.5 mg/dL) but may remain detectable below this level during recovery from jaundice

22. SPIDER ANGIOMATA Superficial, tortuous arterioles Unlike simple telangiectases - typically fill from the center outward. O nly on the arms, face, upper torso Etiology : occur in both Acute liver disease and Chronic liver disease Especially prominent in cirrhosis Occur in normal individuals F requently during pregnancy

23. SPIDER ANGIOMA PALMAR ERYTHEMA

24. Hepatomegaly Marked Hepatomegaly is typical of Cirrhosis Sinusoidal obstruction syndrome Infiltrative disorder amyloidosis Metastatic or primary cancer of liver Alcoholic hepatitis The most reliable physical finding in liver examination is hepatic tenderness

25. Hepatic Failure First sign of hepatic encephalopathy Subtle and nonspecific change in sleep pattern Change in personality, Mental dullness, Irritability Thereafter, Confusion,Disorientation,Stupor Eventually Coma supervenes IN ACUTE LIVER FAILURE EXCITABILITY AND MANIA MAY BE PRESENT

26. HEPATIC FAILURE Physical signs Asterixis and flappng tremor of body and tongue FETOR HEPATICUS - slightly sweet ammonical odour In a chronic liver disease Encephalopathy is usually Trigerred by a medical complication Gastointestinal bleeding Over diuresis Uremia Dehydration Electrolyte imbalance Infection Constipation Use of narcotc analgesics

27. A Helpful Measure for Hepatic Encephalopathy Trial - making test - Consists of a series of 25 numbered circles ,to be connected as rapidly as possible using a pencil . Normal range 15-30 secs Considerably longer in patient with early hepatic encephalopathy Drawing of abstract object Comparison of signature to previous examples Electroencephalography and Visual Evoked Potential - More sophisticated testing .Detects mild forms , Rarely used clincally

28. Other Signs of Advanced liver disease Umblical hernia from ascites , hydrothorax Prominent veins over abdomen and caput medusa Widened pulse pressure and signs of hyperdynamic circulation

29. SPECIFIC SIGNS OF LIVER DISEASE Kayser-Fleischer ring - in Wilson's disease • golden-brown copper in Descemet's membrane at periphery of the cornea • best seen by slit-lamp examination. Dupuytren contracture P arotid enlargement suggestive of alcholic liver disease Signs of cachexia and wasting and hepatic bruit- hepatocellular carcinoma

30. SKIN MANIFESTATION IN LIVER DISEASE Hyperpigmentation - chronic cholestatic diseases (PBCand PSC) Xanthelasma and tendon xanthomata as result of retention of lipids and cholesterol. Slate - Gray pigmentation occurs with hemochromatosis Mucocutaneous vasculitis with palpable purpura :typical of cryoglobulinemia of HCV but also occur in HBV.

31. PATHOLOGICAL CLASSIFICATION OF JAUNDICE A. Hemolytic jaundice, conditioned by the surplus formation of unconjugated bilirubin B.    Hepatocellular jaundice, conditioned by hepatocytes pathology. C.   Obstructive jaundice, which takes place on the basis of the insufficient bile outflow.

32. COMPLICATION OF CIRRHOSIS

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