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Chronic Liver Disease Prof. Abla Abouzeid, MD Professor of Clinical and Chemical Pathology, AFM Causes of Chronic Liver Disease Toxins: alcohol, drugs Viruses: HBV, HCV Metabolic liver diseases: fatty liver disease, hemochromatosis, AAT deficiency, Wilso...

Chronic Liver Disease Prof. Abla Abouzeid, MD Professor of Clinical and Chemical Pathology, AFM Causes of Chronic Liver Disease Toxins: alcohol, drugs Viruses: HBV, HCV Metabolic liver diseases: fatty liver disease, hemochromatosis, AAT deficiency, Wilson disease Immune-mediated liver diseases: AIH, primary biliary cholangitis, primary sclerosing cholangitis Infiltration of the liver Tumors: benign and malignant (primary, secondary) Chronic Hepatitis Chronic hepatitis is defined as chronic inflammation of the liver that persists for at least 6 months, or signs and symptoms of chronic liver disease in the presence of increased cytosolic enzymes. It is characterized by ongoing inflammatory damage to hepatocytes, which are often accompanied by hepatocyte regeneration and scarring. Clinical features of chronic hepatitis are highly variable. Most patients are asymptomatic, but nonspecific features, such as fatigue, lack of concentration, and weakness may be present. Most patients are diagnosed because of an unexplained abnormality in aminotransferase activities or detection of positive results on a screening test for a cause of chronic hepatitis. Moderate increases in plasma aminotransferase activities (2 - ↑ AST, AST/ALT >1 suggests coexisting alcohol abuse or development of cirrhosis Chronic HBV Chronic hepatitis B results when the immune response is incomplete, and the virus is not eliminated from infected cells. This leads to a continuing cycle of viral replication, reinfection of regenerating hepatocytes.  Normally, hepatocytes express surface markers including HLA class 1 proteins. Primed lymphocytes then attack the infected hepatocytes. Many chronic hepatitis B patients are deficient in or have an inadequate response to INF and are therefore unable to express HLA antigens that would attract an appropriate lymphocyte response. In the chronic replicative form, viral DNA is found in the cytoplasm of infected hepatocytes, and complete viral particles are produced and released into the circulation. In the replicating form of infection, viral loads in plasma are usually high > 20,000 U/mL In the nonreplicating form, circulating viral load is low or undetectable, and evidence of hepatocyte injury is usually absent. This variant has been termed the HBV carrier state, current terminology: the immune control phase. Classification is based on HBV DNA concentrations with ALT activities and histology Patterns of chronic HBV infection Type AST/ALT HBsAg HBeAg Anti HBc HBV DNA Occult Normal Negative Negative Positive Negative Immune control Normal Positive Negative Positive Negative Immune tolerant Normal Positive Negative/ Positive Positive positive Immune active Increased Positive Positive Positive Positive HBeAg negative Increased Positive Negative Positive Positive Prognosis 20 to 30% of individuals with chronic hepatitis B will develop cirrhosis over a 20-year follow-up period; the risk is directly related to the amount of HBV DNA, with risk progressively increasing at viral loads of more than 2000 IU/mL Once cirrhosis has developed, annual risk of development of HCC is 1.5 to 5%.  Although the risk of HCC is lower in individuals with HBV infection who do not have cirrhosis, risk is directly related to viral load and rises at quantities above 2000 IU/mL. Even a person in the nonreplicating stage of infection has a 10-fold higher risk of HCC Efficacy of treatment is measured by response of ALT and/or AST and HBV DNA; Goals of treatment include normalization of ALT and suppression of HBV DNA below the limits of detection of assays, ideally with detection limits of approximately 20 to 50 IU/mL. Chronic Hepatitis C Chronicity develops in approx. 80% of patients with HCV infection 20 to 30% of patients with hepatitis C will progress to cirrhosis over 20 years. The frequency of progression appears to be increased by age older than 40 years at the time of infection, male sex, alcohol abuse, and immunosuppression, Cirrhosis risk is less than 5% after 20 years of infection in those infected during the first 20 to 30 years of life. In those who develop recurrent HCV after liver transplantation, the response rate is lower, and the rate of progression to cirrhosis is faster than in primary infection. The likelihood of progression to HCC is between 1.5 and 5% per year in those with cirrhosis. Infection with HCV is characterized by fluctuating ALT activities over time. Only about one-third of those with chronic HCV have continually increased ALT, and many of these individuals show variation in ALT activity  Autoimmune Hepatitis AIH represents a rapidly progressive form of chronic hepatitis, with up to 40% 6-month mortality in untreated individuals It predominantly affects women of between 15 and 40 years of age but both genders of all ages are susceptible. Associated with other autoimmune disorders e.g T1DM, thyroiditis, ulcerative colitis It has been associated with specific HLA haplotypes, notably DR3 & DR4. Associated with the presence of liver and non-liver autoantibodies in plasma. These are helpful in diagnosis, but are not likely to be the cause of liver injury. Acute hepatitis component is present in up to 40% of cases. Pathogenesis: AIH is characterized by lack of immune tolerance (unresponsiveness of immune system to self-antigen). Combination of genetic predisposition and environmental stimuli as drugs or viruses lead to loss of tolerance leading to cytotoxic T cell mediated hepatocellular injury with participation of B cells: Environment, drugs, infection can induce susceptible genes (as HLA encoding genes) in carriers which can predispose them to AIH. The immune response to a pathogen can cause damage to self tissue, antigens released from damaged tissues may initiate a self-specific immune response. Also viral infection or environmental toxin could change hepatocyte epitopes, which could trigger immune response. Activation of CD4 T cells and release of cytokines stimulates B cells to produce antibodies. At the same time cytokine activation of CD8 T cells causes cell mediated cytotoxicity to kill hepatocytes. High serum levels of ALT, AST usually less than 500 U/mL, with normal ALP. Criteria for diagnosis: Exclusion of viral hepatitis. Increased IgG Positive autoantibodies. Compatible histological features NB: if AIH is a cause of acute hepatitis it differs clinically from other acute cause by having:  Decreased Albumin. Increased globulin (IgG) Prolonged increase in aminotransferase Classification: Type 1: presence of anti-smooth muscle antibody (ASMA) (replaced by anti-actin) and/or antinuclear antibody ( ANA ). Responds well to steroids Type 2: presence of anti-liver-kidney microsomal antibody (LKM-1), rare in adults. Disease can be severe Type 3: presence of anti-soluble liver antigen antibody/anti-hepatopancreatic antibody (SLA/LP) Type 4: No autoantibodies detected (20%) Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis NAFLD is caused by abnormal accumulation of lipids in hepatocytes and can progress from simple steatosis to necroinflammation and cirrhosis. Benign steatosis (NAFL) characterized by triglyceride accumulation inside hepatocytes Nonalcoholic steatohepatitis(NASH) : TG accumulation in addition to necroinflammation and fibrosis with risk for development of cirrhosis and HCC. Strongly associated with the metabolic syndrome and insulin resistance Metabolic syndrome: impaired glucose tolerance, abdominal obesity, hypertension, HDL< 40 mg/dL (50mg/dL in females), triglycerides > 150 mg/dL A clinical approach to the identification of patients with NASH typically involves a compatible clinical history and the presence of steatosis on imaging studies, exclusion of other causes of liver injury, and may include liver biopsy to confirm the diagnosis and determine the extent of injury (but not if patients improve clinically  with weight loss and exercise). NASH may be a major cause of cryptogenic cirrhosis, that is, cirrhosis for which no underlying cause can be determined NAFLD lab features: Persistent mild ALT elevation and in most cases higher than AST. Weight loss is associated with decreased ALT values. High ALT, AST, bilirubin and low albumin are often used to distinguish NASH from other forms of NAFLD, however, the degree of necroinflammatory damage is not related to increases in AST or ALT activity. In cirrhosis, AST may be higher thanALT but AST/ALT ratio is almost never greater than 2. Hyperglycemia and hypertriglyceridemia. Cytokeratin 18 and PIIINP may be used as potential serum markers of NASH. The NASH Fibrosis Score and ELF tests can predict long-term outcomes in NAFLD.(ELF score uses HA, PIIINP and TIMP-1) Alcoholic liver disease C h ro n i c an d e x ce s s i v e a l co h o l c o n s u mp t i o n p ro d u c e s a w i d e s p e c t ru m o f h ep at i c l e s i o n s w h i ch a r e s t e at o s i s , h e p at i t i s , f ib r o s i s / ci r rh o s i s , H C C. P a t h o ph y s i o l o g y : S e v e re s t e at o s i s m ay i n d u c e s t e at o h e p at i t i s w h i ch r e s u l t s i n h e p at o cy t e s w el l i n g , a n d n e c ro s i s. T h e i n f l a m m at o ry r es p o n s e i n d u c es fi b ro s i s R i s k fa c to r s : a - d u r at i o n a n d m ag n i t u d e o f a l c o h o l ab u s e ( > 4 0 g / d a y i n m e n an d 10 g / d a y i n w o m en ) , b -w o me n ar e m o r e l i k e l y t o d ev e l o p c i rr h o s i s , c - p r es en c e o f co - i n f ec t i o n w i t h H BV a n d H CV. L a b fi n d i ng s : AST higher than ALT. AST is rarely > 300 U/L and ALT is often normal ( due to alcohol induced Inherited Liver deficiency Diseases of pyridoxal phosphate Presenting as Chronic (B6). Hepatitis Wilson Disease Hemochromatosis Wilson Disease Autosomal recessive disorder of copper metabolism characterized by decreased  biliary excretion of copper and decreased incorporation of copper into ceruloplasmin It is caused by mutations in the ATP7B gene that codes for an ATPase responsible for the transport of copper across intracellular membranes, particularly in hepatocytes. Defect of ATP7B leads to release of unbound copper into the circulation where it is deposited in the liver, basal ganglia of the brain and in the cornea. Dietary copper is absorbed from the duodenum via the ATP7A transporter. Following absorption, copper is transported to the liver via the portal vein. In hepatocytes, the ATP7B transporter (this is defective in WD) either resides in the trans-Golgi network or at the apical membrane depending on the intracellular copper concentration. When intracellular copper is low, the ATP7B resides in the trans-Golgi network and incorporates copper into apoceruloplasmin to form ceruloplasmin which moves into the plasma. When intracellular copper is high, the ATP7B moves to the apical membrane to excrete copper via the bile duct. Clinical presentation: Most commonly in childhood in the form of acute liver disease, accompanied by hemolysis and a kidney tubular defect (because of the toxicity of the free copper released from hepatocytes), or in young adulthood with cirrhosis or manifestations of disease of the basal ganglia (e.g. dysarthria, tremor and choreiform movements. There may also be psychiatric manifestations. Hepatosplenomegaly and Kayser-Fleischer rings on cornea. Lab features of Wilson disease : Reduced plasma ceruloplasmin 0.75 μmol/24 h) Measurement of urine copper excretion is the most specific noninvasive test for Wilson disease. Unfortunately, the clinical sensitivity of copper excretion is only 75 to 85% Definitive diagnostic test: high copper content in liver tissue obtained by biopsy; (also seen in primary biliary cirrhosis and in neonatal biliary atresia) Genetic diagnosis Analytical procedures for determination of ceruloplasmin include: Immunoturbidimetry and nephelometry, in which Cp is reacted with anti-Cp antibodies to give insoluble aggregates whose absorbance is proportional to the concentration of Cp in the sample. Bichromatic method: kinetic enzymatic assays based on the oxidase activity of Cp on the substrate of p-phenylenediamine (PPD) to yield a purple colored product measured by spectrophotometric method. ELISA based on Cp antigen to antibody complex and colorimetric detection method. Hemochromatosis Hereditary hemochromatosis (HH) is an autosomal recessive disorder of iron metabolism that results in excessive intestinal iron absorption and accumulation in tissues, specifically in the parenchymal cells of the liver, heart, pancreas, and other organs Haemochromatosis is a result of mutations in genes involved in iron metabolism.  The most frequent mutations affecting adults are in the hereditary haemochromatosis (HFE) gene (haemochromatosis type 1, classic haemochromatosis). HH is caused by mutations that affect any of the proteins that control the entry of iron into the circulation. These proteins include hepcidin, HFE, transferrin receptor 2 (Tfr2), hemojuvelin (HJV) and ferroportin (FPN). Hepcidin is the major regulator of dietary iron absorption and cellular iron release. Secondary hemochromatosis due to erythropoiesis disorders or iron overload as in thalesthemia and sickle cell anemia. Clinically: Iron deposited in the tissue mainly liver, heart and endocrine glands. Causing cardiomyopathy, liver failure and infertility and growth retardation There is a classic group of four manifestations resulting from hemochromatosis. The "tetrad" consists of (1) cirrhosis (2) diabetes mellitus (3) hyperpigmentation of the skin (bronze colouring), and (4) cardiac failure. Lab findings: Increased iron > 150mcg/dl, ferritin > 300 ng/ml in males and >200 ng/ml in females, transferrin saturation > 45% (AST) is increased late. Genetic testing : HFE Mutation detection Cause Diagnosis Hepatitis B History, HBsAg, anti-HBs, anti-HBc, HBV DNA Hepatitis C Anti-HCV, HCV RNA by PCR Autoimmune type 1 ANA, anti–smooth muscle antibody Autoimmune type 2 SLA, anti-LKM1 Wilson disease Ceruloplasmin  Drugs History AAT deficiency AAT phenotype NAFLD Metabolic syndrome, liver ultrasound, liver biopsy Idiopathic Liver biopsy, absence of markers Liver cirrhosis Cirrhosis, diffuse fibrosis with nodular regeneration, represents the end stage of scar formation and regeneration in chronic liver injury. Compensated cirrhosis: the early stages of transition from chronic hepatitis to cirrhosis: Laboratory abnormalities usually appear before clinical findings Clinically: (1) ascites, (2) gynecomastia, (3) palmar erythema, and (4) portal hypertension. Lab findings: (1)Fall in platelet count, (2) increase in PT , (3) decrease in the albumin to globulin concentration ratio to 1. Survival in compensated cirrhosis is good; 10-year survival rate is approx. 90%. As cirrhosis progresses, decompensation (loss of functionality) occurs with clinical evidence of portal hypertension. 10-year survival is only about 20%. Prognosis in cirrhosis is usually based on the Model for End-Stage Liver Disease (MELD) score: MELD score = 3.8 + ln bilirubin (mg/dL) + 11.2 Ln INR + 9.6 Ln creatinine (mg/dL) + 6.4 × etiology score (O if alcohol or obstruction, 1for all other causes) Risk of death over 3 months is low in those with MELD scores below 10, intermediate in those with scores 10 to 20, and high in those with scores above 20.7 MELD scores are the primary means used to assign priority for liver transplantation.  Persistence of elevation of ALT and AST is a risk factor for development of HCC. Increases in alpha fetoprotein (AFP) are common in cirrhotic patients, even in the absence of HCC. Hepatic Encephalopathy Hepatic encephalopathy is a metabolic disorder characterized by a wide spectrum of neuropsychiatric dysfunction. It may occur as an acute syndrome in patients with acute hepatic failure, or as a chronic, relapsing syndrome associated with cirrhosis. Clinically: Disturbed consciousness followed by apathy, and coma. Personality changes: Irritability and confusion. Neurologic abnormalities: slurred speech, tremors, increased muscle tone, and abnormal reflexes. In chronic encephalopathy, these changes typically fluctuate over time. Acute encephalopathy progresses rapidly, often within hours, and is characterized by cerebral edema, which may result in brainstem herniation and death. Ammonia concentrations are typically increased with acute encephalopathy but may fluctuate in chronic encephalopathy. A reduction in plasma ammonia concentration is often associated with symptomatic improvement. However, plasma ammonia concentrations do not correlate with the severity of the encephalopathy. The main acquired causes of hyperammonemia are advanced liver disease and renal failure. Reye syndrome, a primarily CNS disorder with minor hepatic dysfunction, is also associated with hyperammonemia. Hepatic encephalopathy in the cirrhotic patient is often precipitated by GI bleeding, which enhances ammonia production through bacterial metabolism of protein found in blood. Other precipitating causes include excess dietary protein, constipation, infection, drugs (particularly central nervous system depressants and diuretics), and electrolyte and acid-base imbalance (alkalosis). Because cirrhosis is accompanied by portosystemic shunting, ammonia clearance is impaired, leading to increased concentrations of blood ammonia. Impaired renal function also causes hyperammonemia. As blood urea concentration increases, more diffuses into the GI tract, where it is converted to ammonia. Hepatorenal syndrome (HRS) It is a severe complication of end-stage cirrhosis characterized by increased  splanchnic blood flow, a state of decreased central volume, and extreme kidney vasoconstriction leading to decreased GFR. Portal hypertension is a common factor in all cases of HRS that develop in chronic liver disease, but HRS may also occur in ALF. Type 2 HRS is more common: slowly progressive or stable decline in renal function Type 1, or classic HRS, represents rapidly declining renal function, usually in a person with preexisting type 2 HRS. Type 1 HRS usually develops in the setting of an acute decrease in SBP or variceal bleeding. There is activation of the renin–angiotensin–aldosterone axis, which is caused by intravascular volume depletion. As with other forms of prerenal azotemia, HRS in the untreated patient is generally associated with increased antidiuretic hormone. This leads to the development of hyponatremia, hypokalemia, metabolic alkalosis, low urine sodium, high urine potassium excretion, and high urine osmolality. Plasma urea and creatinine concentrations, and creatinine clearance are not reliable indicators of renal function in HRS: Urea production by the liver is often decreased in advanced liver disease; it is also increased after upper GI bleeding, which is a common cause of worsening renal function in HRS. Creatinine production by muscle is reduced in cirrhosis, causing a misleadingly low plasma creatinine concentration and creatinine clearance. Diagnosis depends on presence of severe liver disease, a rise in creatinine to more than 1.5 mg/dL, no evidence of other renal disease by urinalysis and clinical history, and lack of improvement in renal function with treatments that increase intravascular volume (such as stopping diuretics, or administration of fluids). Fulminant Hepatic Failure. In acute fulminant hepatic failure, an uncommon but highly fatal condition, massive destruction of liver tissue results in complete liver failure. Causes: Reye syndrome: a child has an acute viral infection with fever and is treated with aspirin. Within 1 to 2 weeks after the infection and fever have dissipated, the child suddenly becomes encephalopathic secondary to hyperammonemia caused by acute hepatic failure.  An adult form of Reye syndrome has also been described. Acute hepatitis B with hepatitis D superinfection, Budd-Chiari syndrome and other hepatic vein thrombotic conditions, vascular hypoperfusion of the liver, Ileojejunal bypass for obesity, acetaminophen intoxication, alcoholism, and cirrhosis. fatty liver of pregnancy Diagnostic laboratory findings for fulminant hepatic failure include Rapid increases in serum levels of the aminotransferases to markedly elevated AST may be higher than 20,000 IU/L, and at least 1.5 times ALT because of acute release of mitochondrial AST, Total protein and albumin are markedly decreased. This pattern resembles hepatitis and end-stage cirrhosis combined, except that usually in acute hepatitis, except alcoholic hepatitis, AST and ALT rise in a ratio of about 1:1 or in a ratio that favors ALT. Shortly after these patterns occur, serum ammonia increases rapidly, leading to encephalopathy. LD, ALP, and bilirubin all increase markedly. All of these changes occur over a period of about 1 week. After another week, the serum AST and ALT return to low, sometimes undetectable, levels. This finding signifies complete destruction of all viable liver tissue Other lab findings include: Severe coagulopathy, particularly disseminated intravascular coagulopathy, Anemia Renal failure as a result of the hepatorenal syndrome and acute tubular necrosis. Many patients become hypoglycemic, possibly because of the absence of enzymes involved in glycogenolysis. Lactic acidosis due to poor tissue perfusion. Acute Non-Viral Hepatitis Toxic hepatitis inflammation of liver caused by alcohol, chemicals, drugs or nutritional supplements. Symptoms Mild forms of toxic hepatitis may not cause any symptoms If present : jaundice Itching Abdominal pain in the upper right portion of the abdomen Fatigue Loss of appetite, nausea and vomiting Rash Fever Weight loss Dark or tea-colored urine Lab findings in toxic hepatitis First lab abnormality is an increase in PT (4sec above control value), Followed by cytosolic enzymes i.e LDH>AST>ALT in this order with peak activities (>X100 URL) by 24 to 48 hrs followed by rapid clearance at rate ~ half-lives of the enzymes. (about 47 hrs for ALT, 17 hrs for total AST and, on average, 87 hrs for mitochondrial AST). Prognosis is related closely to the prolonged increase in PT: prolonged up to 4 days post ingestion = poor prognosis. Or development of acute renal failure and presence of lactic acidosis (w/t pH < 7.30) Reye's syndrome Acute encephalopathy in combination with fatty degeneration of the liver following febrile viral illness (usually influenza B or varicella) Linked with use of aspirin For children younger than age 2 Diarrhea Rapid breathing For older children and teenagers, Persistent or continuous vomiting Unusual sleepiness or lethargy Additional signs and symptoms Irritable,Confusion, disorientation or hallucinations Seizures , Decreased level of consciousness Lab Findings:  AST , ALT and PT increase, the concentration of ammonia increases. mild increase in bilirubin level hypoglycemia and hyperuricemia. Ischemic hepatitis It is characterized by a massive, rapid , transient rise in serum aminotransferases resulting from reduced oxygen delivery to the liver. The most common predisposing condition is cardiac failure. May also occur due to sepsis, vasculitis or during transplantation surgery One of the most common cause of elevated cytosolic enzymes (>10 URL). In hospitalized patients it is the most common cause of acute hepatitis. Lab Investigations There is marked elevation of AST, ALT and LDH Slight increase : bilirubin, ALP , GGT and PT Liver function returns normal in 5–10 days with correction of underlying cause. Acute renal failure is a common complicating factor. Prognosis: related to underlying cause of hypotension. Poor prognosis = prolonged elevation of bilirubin. If the cause is not corrected or if the liver has been previously damaged, acute ischemic/hypoxic insult may lead to picture of fulminant hepatic failure. Mortality is high and depends on the underlying cause and not the liver injury