Liver Diseases PDF

‫بسم اهلل الرمحن الرحيم‬  Contents Chapter 1: Acute liver failure 1 Chapter 2: Cirrhosis and its complications 6 Cirrhosis Hepatic encephalopathy Ascites Spontaneous bacterial per...

‫بسم اهلل الرمحن الرحيم‬  Contents Chapter 1: Acute liver failure 1 Chapter 2: Cirrhosis and its complications 6 Cirrhosis Hepatic encephalopathy Ascites Spontaneous bacterial peritonitis Hepatorenal syndrome Hepatopulmonary syndrome Portal hypertension Varices and variceal bleeding Portal hypertensive gastropathy Chapter 3: Viral hepatitis 52 Hepatitis C virus Hepatitis B virus Hepatitis D virus Hepatitis A virus Hepatitis E virus Chapter 4: Autoimmune hepatitis 100 Chapter 5: Inherited liver disease 108 Hereditary haemochromatosis Wilson’s disease Alfa-1 antitrypsin deficiency Gilbert’s syndrome Chapter 6: Alcoholic liver disease 126 Chapter 7: Non-alcoholic fatty liver disease 131 Chapter 8: Intrahepatic biliary disease & Cholestasis 136 Primary biliary cirrhosis Secondary biliary cirrhosis Primary sclerosing cholangitis Chapter 9: Liver tumours 148 Hepatocellular carcinoma Secondary malignant tumours Hepatic haemangiomas Chapter 10: Liver abscess 160 Pyogenic liver abscess Amoebic liver abscess Hydatid liver cyst Chapter 11: Vascular liver disease 170 Portal vein thrombosis Budd-Chiari syndrome Veno-occlusive disease Chapter 12: Gallbladder disease 175 Gallstones Acute calcular cholecystitis Acute Acalcular cholecystitis Gallbladder carcinoma Post-Cholecystectomy Syndrome Chapter 13: Bile duct diseases 188 Choledocholithiasis Cholangiocarcinoma Chapter 14: Liver transplantation 192 Chapter 15: Drugs and liver 195 Drug induced liver injury Drug prescription in liver disease Chapter 16: Liver disease in pregnancy 205 Interpretation of LFT in normal pregnancy Hepatic disease unique to pregnancy Pregnancy in patient with chronic liver disease Viral hepatitis in pregnancy Chapter 17: Differential diagnosis in liver diseases 210 Jaundice Upper GIT bleeding Pruritis Hepatomegaly Ascites Elevated ALT CHAPTER 1: ACUTE LIVER FAILURE (ALF) Definition: Sudden severe impairment of hepatic function in absence of evidence of pre- existing liver disease. Classification: (O’Grady classification) Table 1.1: ALF classification Type Time: jaundice to Cerebral edema Common cause encephalopathy Hyperacute 3.5 2.8-3.5 12 is an indication for liver transplantation. - 12 -  Hepatic Encephalopathy (HE) Definition: It's complex neuropsychiatric disorder resulting from chronic parenchymal liver disease, often in conjugation with portal-systemic shunt. Classification: Hepatic Encephalopathy (HE) Type A Type B HE associated with acute liver failure HE with portosystemic bypass & no intrinsic hepatocellular disease Type C HE associated with cirrhosis or portal hypertension Episodic Resistant Spontaneous Mild stage (1-2) Precipitated Severe stage (3-4) Recurrent Covert/SubcIinical HE Only abnormal psychometric tests Figure 2.1: Classification of HE Pathogenesis: Failure of hepatic detoxification of neuroactive compounds arising from the gut with portosystemic shunting of these products cause HE. These compounds include: 1. Ammonia (NH3): Source: nitrogenous diet & bacterial products Effects: Block Cl channel, Modulate GABA receptors, ↑ brain glutamine & upregulates peripheral benzodiazepine (BZD) receptors. 2. Naturally occurring benzodiazepine. 3. Short-chain fatty acids (FA). - 13 - 4. Mercaptans 5. Aromatic amino acid 6. Manganese Predisposing factors: Table 2.3 : Predisposing factors of HE Factor Mechanism GIT bleeding N2 load, hepatic hypoperfusion Sepsis Protein catabolism, cytokines Azotaemia Ammonia generation (Ureases) Narcotics, BZD Antidepressant Activation of inhibitory neurotransmission High dietary protein N2 load Constipation NH3 generation by colonic bacteria Diuretics Hypokalaemia, Azotaemia, dehydration Hypokalaemia Renal NH3 generation, ↑ brain sensitivity to ammonia Surgery Anesthesia, hepatic hypoperfusion Acute hepatitis Liver injury, cytokines - 14 - Clinical Picture: 1. Mental Status Changes Table 2.4: Grades of HE Grade Manifestation Subclinical(0) Abnormal psychometric test but normal mental status & neurological examination 1 Trivial lack of awareness, reversed sleep cycle, short attention span 2 Lethargy, disorientation, personality changes, inappropriate behavior 3 Somnolence to semistupor, confusion, still responding to painful stimuli 4 Coma, no response to painful stimuli 2. Physical Signs: a) Foeter hepaticus: Purgent breath odor caused by breakdown products of sulfur-containing amino acids. b) Asterixis: Flapping tremors. c) Motor signs: 1) Slow monotonous speech pattern. 2) Extrapyramidal type movement disorder 3) Hyperreflexia, extensor plantar response, clonus. 4) Ataxia 5) Loss of fine motor skills (constructional apraxia) 6) Hyperventilation 7) Seizures, confusion, coma 8) Decerebrate/decorticate posturing d) Clinical picture of liver disease: see page before - 15 - Investigations: HE is mainly clinical diagnosis  Blood ammonia: Inaccurate  EEG: ↓ main cycle frequency  Critical Flicker/fusion frequency test (CFF)  MRI: Cortical atrophy, hyperintensity of basal ganglia on T1-image.  Proton MR spectroscopy: ↑ glutamine signals & ↓ myoinositol Diagnostic criteria: Useful diagnostic criteria of HE include: 1. Documented chronic parenchymatous liver disease. 2. Evidence of portal systemic shunting  Naturally occurring ( varices, venous collaterals)  TIPS  Surgical shunt 3. Mental status changes: (subclinical (0) → grade 1-4) 4. Clinical improvement with measures aimed at ↓ NH3 production/ N2 load. 5. Abnormal EEG: ↓ main cycle frequency (Not necessary in diagnosis) Differential Diagnosis (Other causes of coma in Liver disease):  Intracranial haemorrhage  Hypoglycemia  Drugs or alcohol intoxication  Alcohol withdrawal/delirium tremens  Wernicke's encephalopathy  Neurological Wilson disease  Post-ictal state  Primary psychiatric disorder - 16 - Treatment: 1. Treatment of any precipitating factor if present. 2. Gut cleansing: Repeated enemas 3. Lactulose (non-absorbable disaccharide) Composition: galactose fructose Mechanism: ↓ fecal PH, ↓ NH3 production by flora, ↑ fecal nitrogen excretion Dose: 30ml/6hours (aim: 2-3 bowel movement/day) Side effects: Overtreatment → dehydration & electrolytes imbalance. 4. Antibiotics: either a) Rifaximin: 550 mg twice daily b) Metronidazole: 250mg twice daily (oral) c) Neomycin: 500mg/6hours (potential nephrotoxicity) 5. Nutrition:  Low-protein (40-60 g) or zero-protein diet,  Calories: 25-35 Kcal/kg/day  Carbohydrate > 200g (to spare protein catabolism )  Vegetable-based diet ↑ elimination of nitrogenous product in stool.  Branched-chain amino acids are costly & data on efficacy are controversial. 6. Other treatments a) Flumazenil: may be effective but very short duration of action, b) Zinc: no large trials c) Sodium benzoate: 5g twice daily d) Ornithine aspartate: may be effective e) Vancomycin: 250mg/6hours orally Special issues in HE: 1. Type A HE (HE with acute liver failure) Treatment follows the same principle as in chronic HE with following exception:  Precipitating factor often is not obvious.  Poor response to empiric therapy.  Cerebral oedema & intracranial hypertension are common & often lethal. - 17 -   Other concurrent causes of encephalopathy are common (hypoglycemia, sepsis, and acidosis).  20% have agitated delirium or seizure phase. 2. Chronic HE (hepatocerebral degeneration); Gives rise to variable combinations of cerebellar dysfunction, Parkinsonian- syndromes, spastic paraplegia & dementia. 3. Intractable/Recurrent HE: options include  Liver transplantation.  Modifications of existing portosystemic shunt.  Liver support devices. - 18 -  Ascites Definition: Pathologic accumulation of fluid within peritoneal cavity Causes: 1. Portal hypertension:  Cirrhosis (the commonest cause 80%)  Congestive heart failure  Constrictive pericarditis  Budd-Chiari syndrome (BCS) & veno-occlusive disease  Fulminant hepatitis 2. Hypoalbuminaemia:  Nephrotic syndrome  Protein-losing enteropathy  Severe malnutrition 3. Peritoneal diseases:  Malignant ascites  Infectious peritonitis (T.B., fungal, etc.)  Ovarian disease (benign, carcinoma)  Eosinophilic gastroenteritis.  Starch granulomatous peritonitis  Rare in: sarcoidosis & Whipple disease. 4. Miscellaneous:  Myxoedema  Pancreatic ascites (pancreatitis, pseudocyst)  Nephrogenic ascites (in renal failure)  Chylous ascites (lymphoma, intestinal lymphangectasia, etc.)  Connective tissue diseases (SLE, RA) - 19 - Pathogenesis of ascites in cirrhosis: Causes of Ascites in cirrhosis: 1. Portal hypertension 2. Hypoalbuminaemia 3. ↑ salt & water retention secondary to ↑ aldosterone (due to ↓ effective circulatory volume & ↓ metabolism of aldosterone) Peripheral arterial vasodilatation theory (the most accepted): Cirrhosis & portal hypertension → splanchnic arterial vasodilatation → arterial underfilling & ↓ effective circulatory volume → stimulation of Renin-Angiotensin- Aldosterone System (RAAS) → salt & water retention → oedema & ascites. Clinical evaluation: 1. Features of Ascites: Inspection:  Generalized abdominal enlargement with fullness of the flanks.  Distortion or eversion of umbilicus.  Divercation of recti & obtuse costal angel (chronic cases) Percussion:  positive shifting dullness ( if peritoneal fluid 1500ml)  Fluid thrill ( if tense ascites)  10% have right sided pleural effusion. Grading of ascites:  Grade 1: detectable only by careful physical examination  Grade 2: easily detected but small amount  Grade 3: obvious  Grade 4: Tense - 21 - 2. Features of the cause:  Cirrhosis: stigmata of chronic liver disease.  Cardiac ascites: orthopnea, TJVP, tender liver  Infection: fever, abdominal pain  Malignancy: weight loss, abdominal pain, source of malignancy  Budd-Chiari Syndrome: acute onset triad of ascites, abdominal pain & hepatomegaly.  Nephrotic syndrome: anasarca, frothy urine Investigations: 1. Abdominal US:  Detects as little as 100ml of ascitic fluid.  Detect presence of cirrhosis & portal hypertension (spleen size >12cm & ↑ portal vein size)  Can detect malignancy or ovarian mass 2. Ascitic fluid analysis (diagnostic paracentesis) a) Appearance  Clear, straw-colored → Cirrhosis  Bloody → Traumatic or malignancy  Cloudy, turbid → Infection  Bile staining → Bile communication  Milky-white → Chylous (lymphatic obstruction) b) Biochemical analysis 1. Ascitic fluid albumin  Serum Ascites Albumin Gradient (SAAG) = Serum Albumin(g/dl) - Ascites Albumin(g/dl)  Its value can help in determining the cause of the ascites Table 2.5: Causes of ascites according to SAAG level SAAG > g/dl SAAG < g/dl Cirrhosis Malignant Ascites Acute liver failure T.B Ascites Alcoholic hepatitis Pancreatic Ascites Cardiac Ascites Connective tissue disease Budd-Chiari syndrome Nephrotic syndrome Veno-occlusive disease Intestinal Obstruction/infarction Acute fatty liver of pregnancy Lymphatic leak Myxoedema - 21 -  2. Amylase Amylase > 1000U/L → Pancreatic ascites 3. Triglyceride (TG) TG > 200 mg/dl → Chylous ascites c) Cytological analysis:  PMNL ≥ 250/mm3 → Infection (or any inflammatory ascites)  Lymphocytosis → T.B  Malignant cells → Malignant ascites d) Microbiological analysis:  Gram stain  Ziehl-Neelsen stain  Culture - 22 - - 23 - Management of ascites in cirrhotic patients: A) Initial lines of treatment 1. Salt restriction:  Mainstay of treatment of ascites  Sodium intake of 2g/day (80 mmol/day)  Avoid hidden sources of sodium in diet or drugs (NSAIDS, antacids, effervescent preparations & parenteral antibiotics) 2. Bed rest: Facilitate dieresis because upright posture activate RAAS 3. Water restriction: If serum sodium < 125 mmol/L → restrict water intake to 0.5-1 liter/day. 4. Diuretics  Drugs: 1. Spironolactone (drug of choice): Mechanism: aldosterone antagonist Dose: start with 100mg/day → 400mg/day (as single dose) Side effects: gynecomastia, ↓ libido & hypogonadism (in male), hyperkalaemia 2. Loop diuretics: Mechanism: block Na-CI transport in thick ascending loop of Henle. Dose: Furosemide 40mg/day up to 160mg/day (split dose) Torsemide 20mg/day up t080mg/day (split dose) Side effects: hypokalaemia & hyponatraemia  Regimen: Combination of spironolactone 100mg & furosemide 40mg once daily &↑ while maintain same ratio between spironolactone & furosemide.  Limitations of use of diuretics: 1. Azotaemia 2. Electrolytes imbalance (Na & K) 3. Intravascular hypovolaemia 4. Hepatic encephalopathy - 24 -   Assessment of response to diuretics & diet: Clinical assessment: 1. Weight: loss of 0.5-1 kg/day is desirable 2. Ascitic fluid volume 3. Peripheral oedema 4. Encephalopathy Laboratory assessment: 1. 24-hour urinary Na: should be > 78mmol/day N.B. treatment failure when urinary NA > 78mmol/day indicate non-compliance as a cause 2. Serum Na, K & creatinine B) Management of refractory ascites: Definition: Ascites that cannot be mobilized nor satisfactory prevented by medical therapy. Criteria for diagnosis: 1. Failure to respond to 400mg spironolactone + 160 mg furosemide + salt restriction PLUS 2. Urinary Na excretion < 10mmol/24h Prevalence: 5% of cirrhotic patients Types: 1. Diuretic resistant: lack of response to maximum dose of diuretics & dietary Na restriction. 2. Diuretic intractable: development of diuretic-induced complications that preclude use of effective diuretic doses Management: 1. Large Volume Paracentesis (LVP): Definition: removal of 4-6 L of ascetic fluid /session Contraindications: sepsis, recent GIT bleeding, SBP, azotaemia & hypotension Precaution: a) IV volume expander must be given if paracentesis ≥ 5L of fluid (usually 8g albumin for every liter of ascetic fluid removed) - 25 -  b) LVP should not be performed more than every 2 weeks 2. Transjugular Intrahepatic portosystemic Shunt (TIPS): Principle: creating shunt between portal vein & hepatic vein Efficacy: effective in 90%of patients with refractory ascites Side effects: higher frequency of hepatic encephalopathy. 3. Peritoneovenous shunt (P VS) E.g. LeVeen shunt It's now abandoned procedure due to excessive complications & no survival advantages. Complications: Infection, SVC thrombosis, pulmonary oedema, bleeding varices, DIC & shunt closure 4. Liver transplantation It's the only lifesaving therapy in refractory ascites. Prognosis: 1-year survival in refractory ascites is 25% - 26 -  Spontaneous Bacterial Peritonitis (SBP) Definition: Primary bacterial infection 'of ascetic fluids by only one organism without gut perforation or other secondary cause. Epidemiology: Patient with cirrhosis & ascites have 10% annual risk of ascetic fluid infection. Classification of ascetic fluid infections: Table 2.6: Ascitic fluid infections Category Ascetic fluid analysis Comments PMNL (mm3) Culture Spontaneous Bacterial >250 Single Peritonitis (SBP) organism Culture-negative >250 Negative Causes: Neutrocytic Ascites a) Suboptimal culture (CNNA) technique. b) Resolution of transient bacterial contamination c) Malignancy d) T.B e) Pancreatitis f) Connective tissue disease Monomicrobial Non- 1g/dl Glucose < 50mg/dl,↑LDH - 27 - Pathogenesis of SBP: Bacterial seeding of ascetic fluid due to 1. Translocation of bacteria through intestinal wall (70%) 2. Haematogenous seeding of ascetic fluid (30%) Bacterial seeding → colonization of ascetic fluid (bacterascites) Microbiology of SBP: Ecoli, Pneumococci, Klebsiella (80% of SBP cases) Anaerobes (1%) Risk factors of SBP: 1. Prior SBP 2. GIT bleeding 3. Ascetic fluid total protein < 1g/dl Clinical pictures: Patient with cirrhosis & ascites: Asymptomatic Symptomatic:  Fever  Abdominal pain & abdominal tenderness  Hepatic encephalopathy  Sepsis & shock  Worsening renal function  Ileus Diagnosis: Ascetic fluid: PMNL >250/mm3 culture reveals single organism - 28 - Treatment: 1. Antibiotics:  Drug of choice: Cefotaxime 2g IV / 8hr over 5 days  Alternatives: Other 3rd generation cephalosporins: Ceftriaxone, Ceftazidime Fluroquinolone Amoxicillin-Clavulinic acid 2. IV volume expander: Dose: IV albumin I.5g/kg at time of diagnosis Then 1g/kg on day 3 of antibiotic treatment Value: ↓ risk of renal insufficiency & ↓ SBP related mortality. Follow-up: 1. Clinical response 2. Indications of follow-up paracentesis: a) Suspected 2ry bacterial peritonitis b) No clinical response to cefotaxime Prophylaxis of SBP:  Indications : Table 2.7: SBP prophylaxis Indication Duration of prophylaxis Recovery from an episode of SBP Indefinitely (best by norfloxacin) GIT bleeding in patient with cirrhosis 7 days (best by ceftriaxone) Ascetic fluid total protein < 1g/dl During hospitalization (best by norfloxacin) Ascetic fluid protein < 1.5 g/dl plus Continue until liver transplantation one of the following: performed 1. Child's score ≥ 9 & bilirubin > 3rng/dl 2- Creatinine ≥ 1-2mg/dl 3- BUN ≥ 25mg/dl 4- Na ≤ 130rnmol/L - 29 -  Antibiotic regimen: 1. Norfloxacin: Mechanism: poorly absorbed fluroquinolone → selective intestinal decontamination Dose: 400mg oral, once daily 2. Trimethoprim-sulfamethoxazole: Dose: Septrin DC once daily 3. Ciprofloxacin: Dose: 750 mg once weekly  Concerns of prophylaxis : 1. Fecal flora become resistant to norfloxacin 2. ↑ Rate of quinolone-resistant Gram-negative bacilli in SBP (50%) 3. ↑ Incidence of UTI by quinolone-resistant bacilli. - 31 -  Hepatorenal Syndrome (HRS) Definition: Functional renal failure (creatinine > 1.5mg/dl) in patients with end-stage liver disease Incidence: 8% per year in patients with cirrhosis and ascites. Pathogenesis: See figure 2.2 Types: 1. Type 1 HRS:  Severe rapidly progressive renal failure defined as doubling of initial serum creatinine > 2.5 mg/dL in less than 2 weeks.  Patient usually has severe liver failure (jaundice, encephalopathy & coagulopathy)  May occur following precipitating factors (SBP, GIT bleeding, therapeutic paracentesis without plasma exchange )  Median survival time is 2 weeks. Advanced cirrhosis & severe portal hypertension Splanchnic arterial vasodilatation ↓ Effective circulatory volume (arterial underfilling) Stimulate RAAS, sympathetic nervous system, ADH Sodium retention Ascites Water retention Hyponatraemia Renal vasoconstriction HRS Figure 2.2: Pathogenesis of HRS - 31 - 2. Type 2 HRS:  Moderate and stable impairment of renal function ( creatinine > 1.5 mg/dl ) that does not met the criteria for type 1 HRS  Associated with relatively preserved liver failure  Main clinical consequences is refractory ascites  Median survival 6 months Clinical picture: Patients with advanced liver failure + oliguria, progressive azotaemia, low blood pressure. Diagnostic criteria of HRS: According to International Ascites Club 2007 1. Cirrhosis with ascites 2. Serum creatinine > 1.5 mg/dl 3. No improvement of serum creatinine (to < 1.5mg/dl) after at least 2 days with diuretics withdrawal and volume expansion with albumin 1 g/kg/day up to a maximum 100g/day 4. Absence of shock 5. No current or recent treatment with nephrotoxic drugs 6. Absence of parenchymal kidney disease (i.e. no proteinuria > 500mg/day microhaematuria > 50 RBCs/HPF and/or abnormal renal ultrasonography) Differential Diagnosis (other causes of Acute Kidney Injury IAKII in cirrhosis): 1. Acute Tubular Necrosis (ATN):  Causes: Hypovolaemic shock, septic shock, nephrotoxic drugs.  Differentiating features: a) ↑ urinary Na concentration b) Urine/serum osmolality < 1 c) Abnormal urinary sediments 2. Glomerular disease: Characterized by haematuria and proteinuria - 32 - 3. Drug-induced kidney injury: History of NSAIDs or Aminoglycoside 4. Pre-renal azotaemia: It occurs as a result of intravascular volume depletion (haemorrhage, vomiting, diarrhea, diuretics overdose) and usually improves after albumin expansion. Treatment: As a general role liver transplantation is the treatment of choice in patients with HRS 1. Treatment of type 1 HRS a) Terlipressin + IV albumin: Terlipressin (splanchnic vasoconstriction) 1-2 mg/4-6hours Albumin (plasma expander) 1 g/kg on 1st day followed by 20-40 g/day b) Catecholamines: Midodrine: 2.5-7.5 mg t.d.s. Noradrenalin: 0.5-3mg/hour c) TIPS: Improve renal function with HRS Indicated if the patients cannot receive vasoconstrictor drugs d) Haemodialysis: Done when the patients is waiting for liver transplantation e) Extracorporeal albumin dialysis: May improve renal function f) Liver transplantation 2. Treatment of type 2 HRS  Few data about the efficacy of vasoconstrictor  Management is mainly focused on treatment of refractory ascites  TIPS is effective in reversing refractory ascites.  Liver transplantation is curative - 33 - Prevention: Table 2.8: Prevention of HRS Condition Intervention Therapeutic paracentesis Albumin 8g/L of ascites removed SBP Albumin 1.5g/kg at diagnosis then 1g/kg after 2 days Primary prophylaxis of SBP Long term norfloxacin Severe acute alcoholic hepatitis Pentoxifylline 400mg t.d.s Prognosis: Type I HRS: median survival 2 weeks Type 2 HRS: median survival 6 months - 34 -  Hepato-Pulmonary Syndrome Definition: Triad of liver disease, increase alveolar-arterial gradient while breathing room air and intrapulmonary vascular dilatation Incidence: 5-50% of cirrhotic patients Pathophysiology: ↓ Metabolism of pulmonary vasoactive substances → formation of functional intrapulmonary vascular dilatation → hypoxaemia Types: Type 1: diffuse, respond well to oxygen Type 2: localized, poor response to oxygen Clinical picture: Stigmata of chronic liver disease Symptoms: dyspnea, platypnea (dyspnea in setting and decrease by lying down) Signs: cyanosis, clubbing Investigation: 1. Oxygen saturation: Orthodeoxia (hypoxemia that increase by upright posture) 2. Arterial blood gases: Hypoxaernia; Pa02 < 80 mmHg 3, Contrast-enhanced (bubble) echocardiography: Late appearing bubble in left atrium 4. 99Tc-macroaggrgated albumin scanning: > 5% extrapulmonary uptake of 99Tc- macroaggregates albumin 5. Pulmonary angiography: Rarely needed - 35 - Treatment: 1. Supplemental Oxygen (2-4 L/min) 2. Coil-spring embolization 3. Liver transplantation: can cause complete resolution of hepato-pulmonary syndrome. Differential diagnosis: Portopulmonary hypertension  6% of patients with cirrhosis.  Mean pulmonary arterial pressure > 25 mmHg in setting of normal pulmonary capillary wedge pressure  Clinical picture and treatment any pulmonary hypertension. - 36 -  Portal Hypertension Definition: Portal venous pressure > 12mmHg (normal 5-10 mmHg) Causes: Extrahepatic 1) Portal vein thrombosis 2) Malignant disease of pancreas / liver 3) Abdominal trauma (including surgery) Pre-sinusoidal Intrahepatic 1) Schistomiasis 2) Congenital hepatic fibrosis 3) Sarcoidosis 4) Azathioprine 5) Lymphoma, leukemia  Cirrhosis  Polycystic liver disease Sinusoidal  Nodular regerenative hyperplasia  Metastatic malignant disease Intrahepatic  Veno-occlusive disease Post-sinusoidal Extrahepatic 1) Budd-Chiari syndrome 2) High IVC obstruction 3) Pericardial effusion 4) Right sided heart failure Figure 2.3: Causes of portal hypertension - 37 - Pathophysiology: ↓ Portal vascular resistance → ↓ blood flow to liver & development of portosystemic collaterals at different sites (oesophagus, stomach, rectum, anterior abdominal wall, renal & lumbar vasculature) Clinical picture and complications: 1. Varices and variceal bleedings: Common sites: oesophagus, stomach Rare sites: duodenum, small intestine, rectum, stomach 2. Portal hypertensive gastropathy Dyspepsia, anorexia & may lead to GIT bleeding either acute or chronic causing anaemia. - 38 - 3. Caput medusa: Dilated veins around the umbilicus. It cause venous hum (Cruveilhier- Baumgarten sign). 4. Ascites: N.B. presinusoidal portal hypertension does not cause ascites as there's no distension of sinusoids 5. Splenomegaly: It's cardinal sign of portal hypertension It occurs as result of either: a) Congestive effect of portal hypertension b) Splenic vein thrombosis It may cause hypersplenism leading to mono-,bi- or pancytopenia 6. Hepatic encephalopathy Investigations: A) Investigation to hypertension & it’s complications 1. Laboratory investigation: CBC: may show anaemia, leucopenia and/or thrombocytopenia (hypersplenism) 2. Imaging: a) Abdominal US  Splenomegaly, collaterals  Ascites  Can diagnose cause as cirrhosis, fibrosis  Portal vein: dilated with reversal of portal vein flow on Doppler study. - 39 -  b) CT/MRI Help in assessment of portal vein patency 3. Upper GIT endoscopy: Indicated in all patients with cirrhosis Value:  Show varices and assessment of risk of bleeding  Show portal hypertensive gastropathy Types of varices: a) Oesophageal (japanese classification) F1: small straight varices F2: enlarged tortuous, < 1/3 of lumen F3: large, coil-shaped, > 1/3 of lumen b) Gastric IGV-1 IGV-2 c) Ectopic Duodenum 4. Measurement of portal pressure: a) Direct measurement; Invasive, expensive, complicated but accurate i. Operative portal vein measurement ii. Percutanous transhepatic measurement iii. Transjugular measurement b) lndirect measurement Less invasive, safer and less complicated  Wedge hepatic venous pressure (WHVP): accurately measure sinusoidal pressure B) Investigation of the cause E.g. HCV-Abs, liver biopsy, AMA, Echocardiography - 41 - Treatment: 1. Treatment of complications: a) Varices b) Ascites c) Hepatic encephalopathy d) Hypersplenism 2. TIPS 3. Surgical shunt 4. Liver transplantation - 41 -  Varices and Variceal Bleeding Management of varices Management of Prevention of recurrent Management of silent acute bleeding bleeding non-bleeding varices (Secondary prevention) (primary prevention( Figure 2.4: Management of varices A) Acute variceal bleeding Predisposing factors: 1. High portal pressure 2. Increase size of the varices 3. NSAIDs 4. Endoscopic features of high risk varices a) Large tortuous varices b) Red wale mark c) Cherry red spot on varices d) Haemocystic spot e) White nipple like projection (platelet or fibrin plug) Clinical presentation: 1. Haematemesis: either  Vomiting of fresh blood clots  Coffee ground : vomiting contain dark specks of old blood 2. Melena: Passage of dark black and tarry stool with distinctive smell 3. Haematochazia: Passage of fresh blood per rectum and if present in the context of upper GIT bleeding it indicate severe acute upper GIT bleeding. 4. Shock: In severe bleeding - 42 - 5. Hepatic encephalopathy: Upper GIT bleeding can precipitate HE in patients with cirrhosis Management: 1. Resuscitation: Done to all patients Over-resuscitation should be avoided as over vigorous volume repletion can precipitate further bleeding. For more detail see page after 2. Prophylactic antibiotic: Aim: decrease the rate of infection, SBP, bacteremia and death Drugs: IV cephalosporins or IV ciprofloxacin 3. Pharmacological therapy: a) IV vasopressin: Rarely used now Mechanism: vasoconstriction of splanchnic arteriole → ↓ portal blood flow → ↓ portal pressure. Dose: IV 0.4 U bolus followed by 0.4-1 U /hour (it must be given with glyceryltrinitrate GTN as it causes vasoconstriction and ischaemia) Side effects: angina, arrhythmia, MI, abdominal pain Contraindications: ischemic heart disease, pregnancy b) Terlipressin/Glypressin: Mechanism: analogue to vasopressin released in slow and sustained manner and has similar efficacy as vasopressin with no systemic side effects. Dose: 1-2mg/6 hours c) Octreotide (somatostatin analogue): Mechanism: vasoconstriction of splanchnic blood vessels leading to decrease portal pressure Dose: bolus of 25-50 mcg IV followed by continuous iv 25-50mcg/hour. 4. Endoscopic therapy: a) Sclerotherapy: Principle: injection of varices by sclerosing agents to obliterate it. Sclerosing material: - 43 -  - For oesophageal varices: ethanolamine or sodium morrhuate - For fundic varices: cyanoacrylate Site of injection: - Oesophageal varices: distal 5cm of the oesophagus - Fundic varices: into the varices. Advantage: stop bleeding in 80% of cases Side effects: 1) Transient chest/abdominal pain 2) Fever 3) Transient dysphagia 4) Oesophageal perforation 5) Oesophageal stricture b) Band ligation (Endoscopic Variceal Ligation-EVL): Principle: varices are sucked into an endoscope accessory then encircled by tight rubber band → occlude varices → sloughing with variceal obliteration. Advantages: 1. More effective to control bleeding (90%) 2. Less rebleeding 3. Fewer complications 4. Required fewer treatment session to obliterate the varices Disadvantage: can be difficult to perform if bleeding is active and severe. 5. Balloon tamponade: Instrument: 1. Sengstaken-Blakemore tube: 3 lumen for gastric balloon, oesophageal balloon and gastric aspiration 2. Minnesota tube: 4 lumens (an additional lumen for oesophageal aspiration) Indications: 1. Variceal bleeding cannot be controlled by endoscopic therapy 2. Massive bleeding that prohibit endoscopic treatment Method: 1. Inflate gastric balloon firstly by 200-250cm air and apply traction till arrest cardia - 44 -  2. If bleeding don't stop, inflate oesophageal balloon to pressure of 30-40mmHg 3. Deflate oesophageal balloon for 10min every 3 hours to avoid mucosal damage. Advantages > 90% stop bleeding Disadvantages: 1. Oesophageal rupture 2. Oesophageal stricture 3. Rebleeding 6. Radiological therapy (TIPS): Principle: stent is placed between portal vein and hepatic vein (transjugular approach) → portosystemic shunt → ↓ portal pressure Side effects: 1. Encephalopathy 2. Shunt occlusion → rebleeding 3. Shunt migration Indication: persistent variceal bleeding despite endoscopic and medical attempts to control 7. Emergency surgery: These include: 1. Shunt operations: a) Non-selective portocaval shunt b) Selective distal splenorenal shunt 2. Oesophageal transection and reanastomosis 3. Liver transplantation - 45 - Algorithm for acute variceal bleeding: Upper GIT bleeding Massive bleeding ?? Variceal with haemodynamic unstability Upper GIT endoscopy available Balloon Tamponade YES NO Band ligation or Terlipressin or ScIerotherapy octreotide Is the bleeding controllable YES NO Arrange follow up Balloon tamponade Endoscopy and and/or give propranolol Repeat endoscopy and/or TIPS Figure 2.5: Management of acute variceal bleeding B) Secondary prevention of recurrent bleeding 1. Pharmacological therapy: Drugs: Non-selective P-blockers (propranolol, nadolol, timolol) +/- isosorbide mononitrate Carvidolol can be used as monotherapy Doses: Propranolol: start with 40mg bid → maximum 400mg/day Isosorbide mononitrate: start with 20mg daily →maximum 240mg/day - 46 -  2. Endoscopic therapy: Sclerotherapy or band ligation: repeated till the variceal obliteration and should be repeated regularly after complete variceal obliteration to detect any new varices. 3. TIPS: See before 4. Surgery: a) Total non-selective shunt: Portocaval shunt b) Selective shunt: Distal splenorenal shunt (Warren's shunt) Modified Warren's shunt c) Devascularization procedure: E.g. Sugiura: oesophageal transaction and reanastomosis + devascularization of lower oesophagus. 5. Liver transplantation C) Primary prevention of varices that not bleed Diagnosis of cirrhosis No Varices Medium/large Varices Small Varices Repeat endoscopy Endoscopic Non-selective at 2 years B-blocker Variceal B-blocker Ligation (EVL) Surveillance Tolerated Not tolerated endoscopy at 6 months interval Continue B-blocker Figure 2.6: Primary prevention of variceal bleeding - 47 - - 48 -  Portal Hypertensive Gastropathy (PHG) Definition: Endoscopic appearance of gastric erythema with whitish mosaic-like pattern due to portal hypertension. Epidemiology: 50-90% of portal hypertension. Pathogenesis: 1. Overproduction of nitric oxide leading to capillary dilatation. 2. ↑ vascular endothelial growth factor (VEGF) → ↑angiogenesis. Clinical picture: 1. Dyspepsia 2. Chronic anaemia and/or 3. Acute haematemesis. Endoscopy: Erythematous, oedematous, gastric mucosa (mosaic pattern or snakeskin appearance) Treatment: 1. Medical treatment: In acute bleeding: octreotide or terlipressin If there is no acute bleeding: non-selective B- blocker 2. TIPS 3. Surgical shunt 4. Liver transplantation N.B. Endoscopic therapy is of no proven value in PHG - 49 - - 51 - - 51 - CHAPTER 3: VIRAL HEPATITIS Hepatitis C Virus (HCV) Epidemiology:  Worldwide: chronic HCV affect 3% of population (170 million people)  Egypt: 5-7 million are chronically infected  Transmission: 1. Blood-borne transmission (main): risk categories include a) Recipient of blood/blood products b) Injecting drug users c) Haemodialysis d) Tattoos & body piercing e) Healthcare workers 2. Sexual Transmission: low efficiency, low frequency 3. Maternal-neonatal transmission: low efficiency, low frequency 4. Unknown (sporadic) risk factor: 10%  Incubation period: 2 weeks - 21 weeks The Virus:  Structure: Single stranded RNA virus Flaviviradea group, 40 nm  Genotypes: 6 major genotypes Genotype 1: main infection in USA Genotype 4: main infection in Egypt Genotype 2, 3: in Europe N.B genotype 1 and 4 are more resistant to treatment while genotype 2 and 3 more responsive to treatment  Subtypes: >50 subtypes Pathogenesis: 1. Immune-mediated hepatocyte destruction by sensitized T-cells: Main mechanism 2. Direct cytopathic damage Minor role Contribute to damage in immunosuppressive state 3. Virus-induced Autoimmunity - 52 - - 53 - Natural History of HCV: See figure 3.1 Acute HCV infection 15% 85% Clear virus Chronic within 6 weeks Hepatitis C 20% over 20 years develop cirrhosis HCC Decompensation (1- 4% per year) Figure 3.1: Natural history of HCV Risk factors of progression of chronic HCV to cirrhosis: 1. Age >40y 2. Alcohol > 50g/day 3. Male 4. Obesity 5. Insulin resistance 6. Elevated ALT 7. HIV co-infection 8. Significant necroinflammation & fibrosis on biopsy 9. Immunosuppression Clinical presentation : A) Acute HCV infection  Asymptomatic: in 85%  Symptomatic: in 15% Pre-icteric phase: Anorexia, nausea, malaise, vomiting, flu-like symptoms Icteric phase: Jaundice +/- right upper quadrant pain & mild tenderness Convalescent phase: Resolution of jaundice - 54 - B) Chronic HCV infection  Asymptomatic: most cases, discovered accidentally by ↑ ALT  Cirrhosis & its complications  HCC  Extrahepatic manifestations of HCV: see after Investigations : 1. ALT &AST: Increased. But in 30%, ALT is normal 2. Serology: HCV-Abs using 3rd generation EIA is 99% sensitive 3. HCV-RNA: Detected by PCR, HCV-RNA PCR become positive after 7-21 days following exposure. Qualitative PCR (i.e. result appear positive or negative): has sensitivity of 10IU/ml Quantitative PCR (i.e. detect level HCV in blood): high level of HCV if >800000IU/ml Indications of HCV-RNA PCR: 1. All patient with positive Anti- HCV Abs 2. Before treatment (Quantitative) 4. Genotyping: Help to plan dosing & duration of treatment & estimate likelihood of response 5. IL28B genotyping Predict response to Interferon (IFN) therapy:  C/C: Very high Sustained Virological Response (SVR)  T/C: Moderate SVR  T/T: Low SVR 6. Liver biopsy: Value: 1. Assessment of severity of liver damage (METAVIR & lshak score) which asses grade of inflammation & degree of fibrosis 2. Detect potential coexisting disease - 55 - Indications: 1. Genotype 1,4,5,6 2. Non-response or relapse after previous therapy Not-Indicated in: 1. Genotype 2,3 2. Presence of contraindications to therapy 3. High suspicion of cirrhosis Finding of biopsy: 1. Piecemeal necrosis 2. Hepatocellular necrosis 3. Portal inflammation 4. Fibrosis: F0: No fibrosis F1: Enlargement of portal area F2: Fibrosis extend out of portal area F3: Bridging fibrosis F4: Cirrhosis - 56 - Prevention : 1. Avoid risk factors 2. There's no effective vaccine 3. Post-exposure therapy: Not recommended until diagnosis of HCV is established Treatment : Goals of the therapy: Primary goals: 1. Eradicate infection early to prevent progression to end-stage liver disease 2. Sustained biochemical & virological response. 3. Histological improvement Additional goals: 1. Prevent viral transmission 2. ↓ Extrahepatic manifestations 3. Enhance quality of life - 57 - NCCVH Hepatitis C Therapy Protocol 2018 Inclusion criterion HCV RNA positivity. The test should be done within the past 6 months. If the patient has received HCV therapy during that period, a new test should be performed. Exclusion criteria Patients less than 18 years of age Child C cirrhosis Clinically manifest liver decompensation: ascites, encephalopathy, wasting, hepatorenal syndrome. Serum albumin less than 2.8 g/dL, total serum bilirubin more than 3 mg/dL, INR 1.7 or more Platelet count less than 50000/mm3 HCC, except 6 months after concluding intervention aiming at cure with no evidence of activity by dynamic CT or MRI. Extrahepatic malignancy except after two years of disease-free interval. In lymphomas and chronic lymphatic leukaemia, treatment can be initiated immediately after remission based on the treating oncologist’s report. Pregnancy or inability to use effective contraception. Inadequately controlled diabetes mellitus (HbA1c >9%). - 58 - Precautions before starting treatment Check HCV treatment history Patients older than 65 Y should have cardiac evaluation in the form of ECG and echocardiography. Ladies in child-bearing period should have a recent negative pregnancy test. A male receiving ribavirin should have two methods of contraception applied with his wife. Check medications received by the patient especially cardiovascular disease therapy, anti-psychotic therapy and statins. Family counseling. Patients are categorized Into easy to treat group or difficult to treat group, based on the preliminary tests performed, as such: Easy to treat group All of the following should be fulfilled: IFN and/or sofosbuvir (as sole agent) naive Total serum bilirubin 1.5 mg/dL or less Serum albumin 3.2 g/dL or more INR 1.5 or less Platelet count 100.000/mm3 or more. Easy to treat patients are treated by: - Paritaprevir-r/ombitasvir + ribavirin for 12 weeks, or - Sofosbuvir + daclatasvir for 12 weeks. Ribavirin dose is 1000 mg/day if the patient’s weight is less than 75 Kg, and 1200 mg/day if his weight is 75 Kg or more. - 59 - Difficult to treat group The presence of any of the following: IFN and/or sofosbuvir-experienced. Total serum bilirubin more than 1.5 mg/dL. Serum albumin less than 3.2 g/dL. INR more than 1.5. Platelet count less than 100.000/mm3. Recommended treatment options: Single criterion from the above: SOF + DCV + RBV (800 mg daily, fixed dose) for 12 weeks. Two or more criteria from the above: SOF + DCV + RBV (600 mg daily, fixed dose) for 12 weeks. Ribavirin cannot be given if the patient’s hemoglobin is less than 10 g/dL, in case of depression, or cardiac dysfunction. Ribavirin dose in cirrhotic patients starts by 600 mg/day and is raised gradually to 1000 mg/day according to tolerance. Precautions during treatment Patients on ribavirin need regular follow up. A drop of hemoglobin of 2 g, or less than 10 g/dL in case baseline hemoglobin necessitates intervention by the following: Dose reduction, Close monitoring Possible use of erythropoietin Possible discontinuation Precautions after the end of treatment SVR/relapse should be documented. Advanced fibrosis patients need lifelong follow up. HBV vaccination is initiated. Patients with chronic kidney disease If serum creatinine exceeds 1.2 mg/dL, calculate estimated glomerular filtration rate (eGFR). eGFR is an equation not a test. Automatic calculators are available online. The equation includes serum creatinine, sex, and age. It also includes the race; this is fixed for Egyptian patients (choose: “white or other”). - 61 - If eGFR is more than 30 mL/min, proceed in treatment as non-renal patients. However, ribavirin dose should be reduced if eGFR is 30-50 mL/min (300 mg/d; by alternating 200 and 400 mg ribavirin). If eGFR is 30 mL/min or less, the only treatment allowed is paritaprevir-r/Ombitasvir with ribavirin. This regimen necessities the following: Compensated liver; i.e. the patient is non-cirrhotic or has Child A cirrhosis. Hb 10 g/dL or more Control of any co-morbid disease prior to starting therapy. This includes diabetes, hypertension, cardiac disease or psychological illness. The patient’s treating nephrologist should approve, in a written report, the whole regimen and ribavirin dose. Ribavirin dose is 200 mg/day in those patients. Transplant patients Sofosbuvir + daclatasvir with weight-based ribavirin for 24 weeks. Management of treatment failure 1- Failed interferon-ribavirin, interferon-ribavirin-sofosbuvir, or sofosbuvir-ribavirin was already mentioned: they are managed as the “difficult to treat group”. 2- Failed simprevir-sofosbuvir: Sofosbuvir-daclatasvir with ribavirin for 12 weeks, or Sofosbuvir-daclatasvir with ribavirin 24 wk if the patient is ribavirin-ineligible 3- Failed paritaprevir-r/ombitasvir: Paritaprevir-r/ombitasvir + sofosbuvir + ribavirin for 24 weeks (provided the liver is compensated and eGFR > 30 mL/min). 4- Failed sofosbuvir-daclatasvir with or without ribavirin: a) Compensated liver Sofosbuvir + paritaprevir-r/ombitasvir with ribavirin for 12 weeks, or Sofosbuvir + simeprevir + daclatasvir + ribavirin for 12 weeks. Treatment is extended for 24 weeks if the patient is ribavirin-ineligible. - 61 -  b) Child B cirrhosis If the failed sofosbuvir-daclatasvir was given for 12 weeks without ribavirin, the following is used: Sofosbuvir-daclatasvir + ribavirin for 24 weeks. If the failed regimen included ribavirin or was given for 24 weeks, deferral of therapy is decided. Dual HBV and HCV infection HCV therapy is started immediately, following the same rules as HCV mono- infected. HBsAg positive patients are treated if the treatment requirements are present, as in the HBV mono-infected. In case these criteria are not met (like an inactive carrier state), one of 2 options are available: a) Initiate prophylactic Rx. Prophylaxis is continued until 12 wk after EOT, or, b) Monitor HBV DNA levels every 4 weeks, during and immediately after EOT for HCV. NUC initiated if HBV DNA rises by 10-fold (one log), or if HBV DNA exceeds 1000 IU/mL if it was previously undetectable. Combined HCV and HIV Infection Co-management by the hepatologist and the treating infectious disease physician is needed. Sofosbuvir should not be received in combination with tipranavir. - 62 - - 63 - - 64 - - 65 - - 66 - - 67 - - 68 -  Extrahepatic Manifestations of HCV Epidemiology: 40% of HCV-infected patients Include: Table 3.3: Extrahepatic manifestations of HCV Haematological Mixed cryoglobulinaemia B-cell non-Hodgkin lymphoma Aplastic anaemia Autoimmune haemolytic anaemia Thrombocytopenia Autoimmune Lymphocytic sialadenitis & sicca syndrome Autoantibodies Renal MPGN (Membranoproliferative Glomerulonephritis) Membranous nephropathy Fibrillary GN IgA nephropathy Dermatological Porphyria cutanea tarda Leukocytoclastic vasculitis Lichen planus Neurological Peripheral neuropathy Guillain-Barré syndrome Endocrine Insulin resistance & diabetes mellitus Hypothyroidism CVS Myocarditis & cardiomyopathy Musculoskeletal Arthralgia Inflammatory arthritis - 69 -  Hepatitis B virus (HBV) Epidemiology:  Worldwide: 5% are HBsAg-reactive 50% have had HBV exposure  Endemic areas: Asia, Sub-Saharan Africa  Transmission: 1. Blood-borne transmission (main): risk categories include a) Recipient of blood/blood products b) Injecting drug users c) Haemodialysis d) Healthcare workers 2. Sexual transmission: has a major role 3. Tissue penetration: a) Tattoos & body piercing b) Needle stick accident c) Reuse of contaminated medical equipment d) Shared razors blades & toothbrush 4. Maternal-neonatal, maternal-infant transmission 5. Unknown (sporadic) risk factor: 25%  Incubation period: 2 weeks-6months The Virus:  Structure: DNA virus, Hepadna group, 40 nm, composed of: a) Core:  dsDNA (double strand DNA)  DNA polymerase with reverse transcriptase activity  Core antigen: HBcAg  Envelop antigen: HBe Ag  HB x Protein b) Outer envelope:  Surface antigen: HBsAg - 71 -  Genotypes: 8 major genotypes (A-H) Genotype C: more severe disease  Mutations: a) Pre-core mutant (HBeAg negative mutant) Mainly in Mediterranean countries Associated with HBeAg negative & fluctuating levels of HBV-DNA b) S mutant: mutation in S gene c) P mutant: mutations in polymerase gene d) HBV vaccine-induced escape mutant e) Nucleos(t)ide-induced resistant mutant Pathogenesis: 1. Immune-mediated hepatocyte destruction by sensitized T-cells against HBcAg 2. T-cytotoxic mediated damage 3. Hyperreacive host response: may lead to fulminant hepatitis 4. HCC: occur due to viral integration into the host genome. Natural history of HBV: See figure 3.4  Risk of progression of chronic HBV to cirrhosis/HCC: 1. Old age 2. Alcohol 3. Obesity 4. Genotype C 5. High HBV-DNA 6. Diabetes mellitus 7. HIV, HCV, I-IDV coinfection 8. Aflatoxin - 71 -  Acute HBV infection Resolve Spontaneously in Chronic HBV infection 95% adults 5% adults Acute fulminant Hepatitis 10% infants 90% infants 15% in 5 y Cirrhosis HCC Acute Flare Liver decompensation Figure 3.4: Natural history of HBV Phases of chronic HBV: Table 3.4: Phases of Chronic HBV Phase HBs Anti- Anti HBe Anti ALT Liver biopsy HBV Ag HBS HBe Ag HBe DNA Immunotolerant + - + + - → Normal/ minimal ↑↑↑ phase inflammation Immune reactive + - + + - ↑ Active inflammation ↑↑ phase Inactive Carrier + - + - + → Normal/ minimal ULN Negative HBeAg ≥ 20,000 > ULN Positive HBeAg ≥ 2,000 Persistently normal Positive HBeAg and age > 30 years ULN  TE > 7 kPa, or ≥ 2,000 Normal  FIB4 > 1.45 Any Any  Family history of HCC.  cirrhosis (FIB4 >3.25, or TE > 12KPa), or  severe extra-hepatic manifestations (documented by specialty consultation) ULN, upper limit of normal. - 81 - 3. Treatment strategies a. Treatment-naive patients: o Tenofovir (TDF) 300 mg once daily, or entecavir (ETV) 0.5 mg once daily. o ETV is preferred in patients over 60 years or with bone disease (chronic steroid use or use of other medications that worsen bone density osteoporosis). b. Treatment-experienced patients o Patients on lamivudine (LAM): shift to TDF 300 mg once daily, o Patients on combined LAM and adefovir: shift to TDF 300 mg once daily c. Treatment failure: o Primary non-response: < 1 log10 decrease in HBV DNA after 3 months of therapy o Partial virological response: HBV DNA decreased by > 1 log10, but still detectable after 12 months of therapy. o Virological breakthrough: HBV DNA increase of > 1 log10 above on-therapy lowest level. o Compliance should be confirmed. o ETV should not be used in LAM experienced patients. Resistance/failure Recommended strategies LAM Switch to TDF ETV (very rare except in patients with Switch to TDF previous LAM failure) ADV If LAM-naïve: switch to ETV or TDF If LAM-failure: switch to TDF TDF (very rare if any) If LAM-naive: switch to ETV If LAM-failure: add ETV Multidrug Switch to ETV + TDF ADV, adefovir: ETV, entecavir, LAM. lamivudine: TDF, tenofovir. - 81 - 4. Follow-up of patients with chronic HBV a. Currently on treatment  Every month: to receive medication and monitor for compliance and side effects.  Every 3 months during the first year, and every 6-12 months there after  ALT  AST  Serum total bilirubin  Serum albumin  PT and INR  Quantitative serum HBV DNA level  AFP  Abdominal ultrasound  Serum phosphorus  Serum creatinine and eGFR  Closer renal monitoring is required in patients who develop eGFR < 60ml/min or serum phosphorus levels < 2 mg/dl  Long-term follow-up: HCC surveillance for all patients under effective long-term nucleos(t)ide analogue (NA) therapy (AFP, U/S every 4 months). b. Currently not on treatment  Every 6 months  ALT  Quantitative serum HBV DNA  AFP  Abdominal ultrasound  Every 2 years: TE or F18-4 to assess liver fibrosis. 5. NAs discontinuation rules Discontinuation strategy No cirrhosis Positive HBeAg HBeAg seroconversion and undetectable HBV DNA after: 12 months of consolidation therapy, 3 years of continuous treatment, and age > 40 years Negative HBeAg Indefinitely, or until HBsAg seroconversion and after 12 months of consolidation treatment Cirrhosis Do not stop anti-viral therapy - 82 - 6. Special groups: a. Acute Infection Antiviral treatment is indicated in patients with acute liver failure or who protracted a severe course denoted by the presence of 2 out of the following 3 criteria: o serum total bilirubin > 10 mg/dl o INR > 1.6 o encephalopathy Entecavir 0.5 mg daily for: o at least 6 months after seroconversion to anti-HBs, or o at least 12 months after seroconversion to anti-HBe without HBsAg loss. b. Liver Cirrhosis All patients with cirrhosis should receive oral antiviral therapy if HBV DNA is detectable. Compensated cirrhosis: ETV 0.5 mg or TDF 300 mg once daily. Decompensated cirrhosis: ETV 1 mg once daily The dose of antiviral therapy needs to be adjusted in patients with low creatinine clearance ( 2,000 IU/ml..  evidence of advanced liver disease. d. Pregnancy  All pregnant females should be screened for HBsAg in the first trimester and if negative to be vaccinated (test anti-HBc IgG and anti-HBs).  Criteria for NA use during pregnancy: o HBV DNA level ≥ 200,000 IU/ml at the end of the second trimester:  TDF (class B drug) 300 mg once daily should start at gestational week 24 28, and.  continue to 12 weeks after delivery, then re-evaluate. o Females who become pregnant while on treatment: continue or shift to TDF. o FIB-4 > 1.45 (if not already on treatment): start TDF 300 mg once daily  Pregnant women not fulfilling the criteria for NA use should be followed during pregnancy and after delivery for HBV reactivation.  Cesarean section does not decrease chances of MTC transmission compared to normal delivery and is not indicated to reduce this chance. - 84 -   Newborns for chronic HBV mothers should receive hepatitis B immunoglobulin (HBIG) and the first dose of HBV vaccine at birth (6-12 hours after delivery).  Breastfeeding is not contraindicated in mothers who are HBsAg-positive and untreated or on TDF. e. Renal Impairment, dialysis and renal transplantation All dialysis and renal transplant recipients should be screened for HBsAg. Seronegative patients should be vaccinated. ETV is preferred in naïve patients, dose should be adjusted according to eGFR. Patients who were already on TDF, should continue with the dose adjusted to eGFR. eGFR (ml/min)* Entecavir** Tenofovir ≥50 0.5 mg/day 300 mg/day 30 - 49 0.5 mg /2 days 300 mg /2 days 10 - 29 0.5 mg /3 days 300 mg /3 days < 10 0.5 mg / week 300 mg / week "In patients undergoing dialysis, all agents should be given once weekly after the dialysis session. **In patients with LAM failure or decompensated cirrhosis the dose of entecavir should be doubled. f. Immunosuppressed patients All candidates for chemotherapy and immunosuppressive therapy should be screened for HBsAg, anti-HBs and anti-HBc prior to initiation of treatment. Vaccination is mandatory for seronegative patients. Higher vaccine doses may be needed HBsAg Strategy Positive Irrespective of the viral load NA at the onset of chemotherapy and Negative Anti-HBc positive, and for 12 months after cessation of HBV DNA positive treatment. Anti-HBc positive, and Follow-up every 3 months. HBV DNA negative Start NA if DNA becomes positive. NA, nucleos(t)ide analogue. - 85 -  g. Liver Transplantation  Pre-transplant All patients with HBV who are candidates for liver transplantation should receive an NA to achieve undetectable HBV DNA and reduce the risk of graft infection.  Post-transplant: Combination of hepatitis B immunoglobulin (HBIG) and a potent, NA is recommended to prevent HBV recurrence.  Patients with a low risk of recurrence can discontinue HBIG but need continued monoprophylaxis with a potent NA.  HBsAg-negative patients receiving livers from donors with evidence of past HBV infection (anti-HBc positive) are at risk of HBV activation and should receive antiviral prophylaxis with NA. PEG-IFN Nucleoside analogues Nucleotide analogues Agent PEG-2a Lamivudine Telbivudine Entecavir Adefovir Tenofovir Dose 180 mg/wk 100 mg/d 600mg/d 0.5 mg/d 10mg/d 245mg/d Route SC Oral Oral Oral Oral Oral Defined course Yes 48 weeks Unclear Unclear Unclear Unclear Unclear Side effects Many Minimal Minimal Minimal Minimal Minimal Cost/year ++++ + ++ +++ ++ ++ Resistance No Yes Yes Minimal Yes No till now Anti HCV Yes No No No No No Viral suppression Moderate High High Very High Very Potent potent serologic Superior Inferior responses - 86 - - 87 - - 88 - - 89 - - 91 - - 91 -  Hepatitis D Virus (HDV) Epidemiology:  HDV occur only in individuals with HBV infection (coinfection or superinfection)  Worldwide: Endemic in Mediterranean basin, central Europe, part of Africa, Middle east, Amazon basin & Balkan. ↓ incidence with ↑ use of HBV vaccine  Transmission: 1- Blood-borne transmission (main) 2- Sexual transmission 3- Maternal-neonatal transmission  Incubation period: 4 weeks- 7weeks The Virus:  Structure :  Incomplete RNA virus  Require presence of HBV for complete viron assembly & secretion  35 nm  Genotypes: 8 genotypes Pathogenesis: 1. Simultaneous acute HBV & HDV coinfection: HDV infection is limited in duration by the duration of HBV infection. 2. Acute HDV superinfection: Occur in a person with chronic HBV. HDV infection invariably becomes chronic lasting as long as chronic HBV infection. - 92 - Natural History of HDV: HDV Acute HBV-HDV coinfection Acute HDV superinfection 95% 2% 2-5% 95% 2-5% Resolve Fulminant Chronic Fulminant spontaneously hepatitis infection hepatitis Cirrhosis (more rapid progression) Figure 3.6: Natural history of HDV Clinical Presentation: A) Acute HBV-HDV coinfection 1. Self-limited acute hepatitis 2. Fulminant hepatitis (5%): Acute liver failure B) Chronic HBV-HDV infection  Accelerate the natural history of chronic hepatitis of chronic hepatitis B → Cirrhosis.  N.B. there's negative association between HDV & I-ICC. Investigations:  Anti-HDV lgM or anti-HDV lgG > 1:1000 → ongoing viral replication.  In simultaneous coinfection: Anti-HBc IgM positive  In superinfection: Anti-HBc IgG positive  HDV-RNA by PCR - 93 - Prevention: By prevention of HBV (see page before) Treatment: 1. Drugs: The only approved treatment for chronic HDV is high dose IFN a (9mU 3times/week) or PEG- IFN a (for 1year or more). 2. Liver transplantation:  Patient with chronic HDV are at lower risk for HDV recurrence than are those with HBV infection alone.  HBIG + lamivudine may prevent post- transplant recurrence of HDV. - 94 -  Hepatitis A Virus (HAV) Epidemiology:  Worldwide distribution, highly endemic in developing countries (poor sanitation & poor hygiene)  Transmission: Fecal-oral transmission:  Person-to-person  Contaminated food, water, mollusks  Incubation period: 2 weeks-6weeks The Virus:  Structure:  RNA virus  Picornavirus (hepatovirus)  27 nm  Genotypes:  3 genotypes Pathogenesis: Cell-mediated immune cytotoxicity → hepatocyte degeneration & apoptosis Natural history: See figure 3.7 Acute HAV 1% 99% Fulminant hepatitis Acute self-limited hepatitis Acute Liver failure Figure 3.7: Natural history of HAV N.B. No chronic infection - 95 - Clinical presentation: 4 patterns: A) Self-limited disease 1. Anicteric coarse Recognized because of known contact with definite case or association by vague GIT complain. 2. Icteric coarse: 3 phases a) Prodroma (pre-icteric) Malaise, fatigue, nausea, anorexia, vomiting and flu-like symptoms Right upper quadrant pain Mild enlarged tender +/- lymphadenopathy +/- mild splenomegaly. b) Icteric phase Jaundice Dark urine c) Convalescent phase Disappearance of jaundice B) Acute liver failure Clinical picture of acute liver failure (see before) C) Cholestatic hepatitis Pruritis, deep jaundice Persistent anorexia & diarrhea May persist for months with excellent prognosis D) Relapsing hepatitis Returning of symptoms & signs of acute hepatitis during recovery HAV-IgM remain positive & HAV shed in stool Excellent prognosis Investigations: A) General investigations 1. Self-limited disease: ALT&AST: marked elevation Bilirubin: ↑ hepatocellular pattern CBC: normal or mild leucopenia +/- relative lymphocytosis - 96 -  2. Cholestatic disease: Bilirubin: ↑ ↑ ( direct hyperbilirubinaemia ) ALT & AST: normal/mild ↑ ALP & GGT: ↑ PT: prolonged ( respond to I.V vitamin K) 3. Acute liver failure: ↑↑ INR/PT, ↓ albumin ↓ glucose ↑ bilirubin, ↑ ALT 4. Relapsing hepatitis: ↑ ALT, bilirubin after normalization. B) Serology 1. IgM anti-HAV: detected in acute phase & for 3-6months thereafter. 2. IgG anti-HAV without IgM anti-HAV: past infection. Prevention: 1. General measures: Safe water supply & proper environment hygiene. 2. Pre-exposure immunoprophylaxis: Inactivated HAV vaccine (HAVRIX 720U, 1440U)  Indications: a) All children at age 1 year b) Food handler c) Travelers to high-risk area d) Homosexual e) Injecting drug users f) Chronic liver disease g) Lab workers h) Stuffin day-care center i) Household contact in adopters from endemic region  Dose:  Children > 1year HARVEX 720U at 0 & 6 months  Adults > 19year HARVEX 1440U at 0 & 6 months - 97 - 3. Post-exposure immunoprophylaxis: Immunoglobulin (0.02ml/kg) + HAV vaccine within 2 weeks of onset of exposure. Treatment: 1. Self-limited infection: Mainly supportive care: a) Rest b) Avoid hepatotoxic drugs & avoid alcohol c) Avoid prolonged/vigorous physical activity d) Maintain adequate caloric & fluid intake 2. Acute liver failure: a) Supportive care & treatment of complications. b) IV N-acetylcysteine. c) Liver transplantation. 3. Cholestatic hepatitis: a) Short-term prednisone or UDCA (no trials of efficacy) b) Cholestyramine for pruritis. 4. Relapsing hepatitis: Treatment is similar to self-limited disease. - 98 -  Hepatitis E Virus (HEV) Epidemiology: Widely distributed  Transmission: a) Fecal-oral transmission: water-borne b) Maternal-neonatal transmission  Incubation period: 2 weeks-6weeks The Virus: RNA virus, Hepeviridae, 27 nm Pathogenesis: Immune-mediated destruction of hepatocytes. Clinical presentation: As hepatitis A virus. 10-20% of pregnant women with HEV → acute liver failure → high maternal & fetal mortality. Investigations: 1. General investigations: as HAV 2. Serology: lgM anti-HEV HEV -RNA by PCR Prevention: 1. IgG anti-HEV Ig (uncertain efficacy) 2. HEY vaccine (phase Il clinical trials) Treatment; as HAV - 99 - CHAPTER 4: AUTOIMMUNE HEPATITIS (AIH) Definition: It's chronic inflammatory hepatic disorder characterized by interface hepatitis, increase serum ɣ-globulin and autoantibodies. Epidemiology:  All races  Female: male → 4:1 Aetiology:  Unknown  Genetic predisposition and environmental triggers (toxins and infection) Pathogenesis: 2 main hypothesis: 1. Autoantigen-driven cell-mediated hypothesis 2. Antibody-dependent cell-mediated cytotoxicity hypothesis - 111 - Types; 1. Type 1 AIH:  Positive antinuclear antibody (ANA) or anti- smooth muscle antibody (ASMA)  Occur at all age and more in female (female: male → 4:1)  Associated with HLA-DR3 and HLA-DR4 2. Type 2 AIH:  Positive anti-liver kidney microsomal antibody (ALKM)  More in children and younger women (2nd and 3rd decades)  More in female than male  Associated with HLA-DRB10701 3. Type 3 AIH:  Associated with anti-soluble liver antigen(ASLA)  This has been abandoned because ASLA is also present in some patients with type 1 and type 2 AIH. Associated autoimmune diseases in AIH:  Autoimmune thyroiditis and Graves' disease  Rheumatoid arthritis  Ulcerative colitis  Other less common: type 1 diabetes, celiac sprue, vitiligo, myasthenia gravis, pernicious anaemia, and fibrosing alveolitis. - 111 - Clinical picture:  Onset: 75%: insidious onset with fatigue, anorexia, jaundice 25%: acute onset resembling viral hepatitis  Symptoms: 1. Easy fatigability (85%) 2. Jaundice (80%) 3. Right upper quadrant pain (50%) 4. Anorexia (30%) 5. Amenorrhea  Signs: 1. Hepatomegaly (80%) 2. Spider nevi (60%) 3. Splenomegaly (40%) 4. Ascites and encephalopathy (20%) Investigations: 1. Liver function tests:  ↑ ALT and AST  ↑ bilirubin  ↓ albumin and ↑ INR are an indication of defect in synthetic function and indicate more severe liver damage 2. ɣ -globulin: ↑↑ (mainly IgG) 3. Serological tests:  ANA and ASMA are positive in type 1 AIH  ALKM in type 2 AIH 4. Liver biopsy: interface hepatitis with lymphoplasmacytosis infiltrate in portal area. - 112 - Diagnostic criteria: Table 4.1: Simplified international scoring system for diagnosis of AIH: Clinical feature Points ANA or ASMA ≥1:40 +1 ANA or ASMA ≥1:80 or ALKM1 ≥1:40 or ASLA-positive +2 Serum IgG > upper limit of normal +1 > 1.1 times upper limit of normal +2 Histologic findings Compatible with AIH +1 Typical of AIH +2 Hepatitis viral markers Negative +2 Aggregate score without treatment Definite AIH ≥7 Probable AIH ≥6 ANA= antinuclear antibody; ASMA= smooth muscle antibody ALKM1= liver kidney microsomal antibody; ASLA= soluble liver antigen antibody; Ig = immunoglobulin Differential diagnosis: 1. Toxin-induced hepatitis 2. Viral hepatitis 3. Wilson's disease 4. Non-alcoholic steatohepatitis 5. Hereditary haemochromatosis 6. α1-Antitrypsin deficiency - 113 - Treatment:  Indications: Table 4.2: When treat AIH Treatment indicated Treatment NOT Urgent indication Non-urgent indication indicated 1. Incapacitating symptoms 1. Mild or no symptoms 1. No symptoms or acute fulminant onset. 2. ALT or AST 67% and/or worsen histological activity. Occur in: 9% Action: prednisone 60 mg daily OR (prednisone 30 mg + azathioprine 150 mg/day) 3. Incomplete response: Definition: improved but insufficient to satisfy remission criteria after 3 years. Occur in: 13% Action: long-term treatment (low-dose prednisone) 4. Drug toxicity: Definition: intolerable side effects Occur in: 13% Action: a) Dose reduction or elimination of the offending agents b) Continue therapy with tolerated agents c) Consider Mycophenolate mofetil (MME) - 115 -  Treatment algorithm: Autoimmune Hepatitis Treatment Incomplete Remission failure response Drug toxicity Drug High dose steroid Azathioprine Dose reduction withdrawal +/-Azathioprine maintenance or withdrawal over 6 weeks If fail Single therapy Relapse Inactive MMF or with tolerated Cyclosporine or agent. Liver transplantation Azathioprine Monitor maintenance Consider 2mg/kg/day MMF Figure 4.1: Treatment of AIH  Promising immunosuppressive drugs: 1. Cyclosporine 2. MMF 3. Tacrolimus 4. Budesonide Liver transplantation in AIH:  Indication: Decompensated patients + failure of corticosteroid  Recurrence: 10-40 % 2 years after transplantation and respond to adjustment in immunosuppressive regimen or reintroduction of corticosteroid Prognosis:  10-year survival of treated patients is 94%  Risk of hepatocellular carcinoma is 0.5 % and occurs only in patients with cirrhosis. - 116 - Variants of AIH: 1. Autoimmune hepatitis (AIH) - Primary biliary cirrhosis (PBC) overlap: 2 patterns: a) Positive Antimitochondrial (AMA) and histology of AIH (majority): treated as AIH b) Negative AMA, positive ANA or ASMA and histology of PBC: treated by prednisone and ursodeoxycholic acid (UDCA) 2. Autoimmune hepatitis (AIH) - Primary sclerosing cholangitis (PSC) overlap: Definition: features of AIH and cholestasis in addition to histology of bile duct injury and abnormal bile duct by MRCP Clues to diagnosis:  Presence of inflammatory bowel disease (IBD)  Suboptimal response to corticosteroids and/or  Increase alkaline phosphatase (ALP) Treatment: prednisone and UDCA 3. Autoimmune hepatitis (AIH) - chronic viral hepatitis (HCV) overlap: Table 4.3: AIH-HCV overlap Autoimmune predominant disease Viral predominant disease AIH scoring system Definite or probable AIH by scoring Non-diagnostic scoring system system of AIH Liver biopsy Moderate portal plasma cell Portal lymphoid aggregate, infiltrate, acinar inflammation, steatosis, bile duct damage interface hepatitis Treatment Corticosteroid DAA + Ribavirin - 117 - CHAPTER 5: INHERITED LIVER DISEASES Hereditary Haemochromatosis (HH) Definition: Inherited disorder characterized by iron- mediated tissue injury due to increase total body iron as a result of impaired regulation of intestinal iron absorption. Epidemiology:  Male > female  Present in men at earlier age than women (menstruation delay presentation)  Peak age: in male: 30-50y, in female: 40-60y Aetiology: Autosomal recessive due to defect in HFE gene on short arm of chromosome 6. Mutations in HFE gene are either: a) C282Y mutation (95%) b) H63D mutation (5%) c) Heterozygous C282Y/H63D - 118 - Pathogenesis: Normally:  Only 10% of dietary iron is absorbed  Iron absorption is down regulated when serum transferrin saturation is high. In HH:  ↑↑ Iron absorption and is not down regulated →↑ total body iron which may reach 20-40 g (normal 4g) → iron deposition in multiple organs (liver, pancreas, joints, skin,..) Clinical picture: 1. General: Insidious onset, lethargy, fatigue, tiredness, arthralgia 2. Liver: one or more of the following a) Elevated liver enzymes b) Hepatomegaly c) Cirrhosis and its complications d) HCC (200 times more than general population) 3. Heart: a) Dilated cardiomyopathy b) Mixed dilated-restrictive cardiomyopathy c) Arrhythmias 4. Endocrine: a) Diabetes mellitus: due to iron deposition in the pancreas and insulin resistance (↑ iron → insulin resistance) b) Hypogonadism: secondary hypogonadism due to iron deposition in pituitary - 119 - 5. Arthropathy: Occur in: 70% and is a major cause of morbidity Main sites: 2nd and 3rd metacarpophalangeal joint (MCPJ) and wrist Features: joint space narrowing, chondrocalcinosis, subchondral cysts, pseudogout. 6. Skin: a) Bronzing of the skin (hence the name of HH; bronzed diabetes): it's metallic or slate- gray hue b) Cutaneous atrophy and flattening of the nail 7. Infections: Increase risk of bacterial, viral, and fungal infections due to iron-mediated impairment of Immune response Investigations: 1. Fasting iron studies: a) Fasting Transferring saturation: Calculation: (serum iron/TIBC) * 100 Diagnostic value: value >45% in female or >50% in male is suggestive of HH b) Serum ferritin: Value >200 mcg/L in female or >300mcg/L in male is suggestive of HH. N.B. ferritin is an acute phase reactant and can be elevated in inflammatory conditions and other chronic liver diseases. 2. Genetic testing: For C282Y and H63D mutations in HFE gene - 111 - 3. Liver biopsy: Done for diagnosis and staging a) Diagnosis of HH: 1. Hepatic iron index >1.9 in HH. 2. Staining of hepatic iron by Perls' Prussian blue stain b) Staging: For presence or absence of cirrhosis 4. Quantitative phlebotomy: Removal of 4-5g of iron through documented successive phlebotomy (16-20 times) without development of anaemia is indicative of iron overload. N.B. removal of 500ml blood = removal of 0.25g iron 5. Hepatic MRI: For quantitative assessment of hepatic iron 6. Investigations Of systems damaged by HH: FSH, LH, testosterone, oestradiol for e.g. hypogonadism, fasting blood glucose for diabetes, echocardiography for cardiomyopathy. - 111 - Differential diagnosis: (=other causes of secondary iron overload) 1. Repeated blood transfusion 2. Iron loading anaemia: a) Thalassemia b) Sideroblastic anaemia c) Chronic haemolytic anaemia 3. Iron overload with chronic liver diseases: a) Alcoholic liver disease b) Chronic hepatitis B and C. 4. Miscellaneous: a) Porphyria cutanea tarda b) African iron overload c) Neonatal haemochromatosis d) Juvenile haemochromatosis e) Aceruloplasminemia f) Atransferrinemia Treatment: 1. Serial phlebotomy:  Weekly 500ml-phlebotomy until ferritin become 50-100 mcg/L  Maintaining phlebotomy 2-4 times /year 2. Iron chelators:  Include: deferoxamine, deferiprone and deferasirox  They are less effective and more expensive than phlebotomy  They are used if the patient cannot tolerate phlebotomy - 112 - Monitoring:  Serum ferritin every 4 months  Haematocrit  Screening of HCC by abdominal US and α- fetoprotein Family screening: All 1st degree relatives of patients with HH should be screened by: a) HFE gene mutation analysis OR b) Fasting transferrin saturation Prognosis:  Liver failure or HCC account for 60% of mortality  Some manifestations improve with iron depletion (as malaise, fatigue, skin pigmentation, diabetes mellitus, abdominal pain)  Other manifestations don't improve with iron depletion (arthropathy, hypogonadism, cirrhosis) - 113 -  Wilson's Disease (WD) Definition: A rare disease of impaired biliary excretion of copper leading to copper deposition in many organs Epidemiology: Occur in 1:30,000 Age: 250 mcg/g dry liver 5. Genetic diagnosis: For ATP7B mutations - 117 - Diagnostic approach: Suspected WD Serum ceruloplasmin Normal 21 unit/week in female, >28 unit/week in male) Table 6.1: Type of Alcohol Alcohol type % alcohol by volume Amount Units Beer 3.5 440 ml (pint) 2 9 440 ml (pint) 4 Wine 10 125 ml 1 Vodka 37.5 25 ml 1 Whisky 40 700 ml 28 Epidemiology: One of the most common cause of liver disease in developed world e.g. in USA 44% of deaths from cirrhosis were the result of alcoholic liver disease. Risk factors of alcoholic liver disease: 1. Amount of alcohol: Alcoholic liver disease is associated with high amount of alcohol consumption. 2. Drinking pattern: Liver damage is more likely to occur in continuous rather than binge drinkers 3. Gender: Women experience more toxicity per dose men 4. Genetic variability in alcohol-metabolizing enzymes 5. Nutrition: Choline-deficient diet is more likely to develop alcoholic liver disease. 6. Concurrent exposure to drugs and toxins: e.g. chronic alcoholics are more susceptible to hepatotoxicity from low dose paracetamol. Pathogenesis: - 126 - Alcohol is metabolised almost exclusively by the liver via one of 2 main pathways:  80% of alcohol: Alcohol → acetaldehyde → form adduct with cellular proteins in hepatocytes which activate the immune system → liver injury.  20% of alcohol: Metabolized by cytochrome CYP2E1 to acetate releasing oxygen free radicals → lipid peroxidation → mitochondrial damage → liver damage. - 127 - - 128 - Clinical presentations: 1. Alcoholic fatty liver disease:  Asymptomatic elevated transaminases +/- hepatomegaly  Good prognosis. 2. Alcoholic hepatitis:  Jaundice, hepatomegaly, malnutrition with feature of portal hypertension as ascites and encephalopathy.  About 30% of patients die in acute episode. 3. Alcoholic cirrhosis:  Stigmata of chronic liver disease with complications of cirrhosis as varices, ascites, encephalopathy and hepatocellular carcinoma.  5-year survival rate is 50%. Investigations: 1. Establishment of alcohol consumption:  Clinical history is the most important  Macrocytosis in absence of anaemia  Raised ɣ-GT (non-specific) 2. Exclude alternative causes of liver disease As HCV and haemochromatosis - 129 - 3. Liver function tests: AST/ALT ratio > 2 4. Liver biopsy: Not essential in diagnosis but is helpful in staging of fibrosis and ascertain whether other chronic liver disease is contributing 5. Maddrey score (also known as discriminant function):  This score allow clinician to assess prognosis in alcoholic hepatitis  Maddrey score= (4.6 x increase in PT (sec)) + bilirubin (mg/dL)  A value over 32 indicate severe liver disease and poor prognosis Treatment: 1. Cessation of alcohol consumption (the key) 2. Treatment of complications of cirrhosis 3. Treatment of other alcohol related problems including alcohol withdrawal and Wernicke's encephalopathy 4. Good nutrition is very important 5. Corticosteroids in severe alcoholic hepatitis (Maddrey's score > 32) 6. Pentoxifylline in severe alcoholic hepatitis 7. Liver transplantation: require a 6-month period of abstinence from alcohol before a patient is considered for a transplantation. - 131 - CHAPTER 7: NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) Definition: Excessive hepatocellular triglyceride accumulation when alcohol consumption is minimal (< 2-4 drinks daily) Types: 1. Simple steatosis (non-alcoholic fatty liver (NAFL)): Fat accumulation in absence of inflammation in the liver 2. Non-alcoholic steatohepatitis (NASH): Presence of steatosis and inflammation and fibrosis in the liver Epidemiology:  Simple steatosis: affect 20% of general population  NASH: affects 2-3% of general population Risk factors and aetiology: 1. Insulin resistance 2. Obesity especially central obesity 3. Type 2 diabetes 4. Hyperlipidemia especially hypertriglyceridemia 5. Medications: tamoxifen, corticosteroids 6. Sedentary lifestyle 7. Others: total parental nutrition, rapid weight loss, abetalipoproteinemia and jejunoileal bypass. - 131 - Pathogenesis: The two-hit hypothesis: Normal Liver First hit ? FA influx ? FA synthesis in liver ? FA oxidation ? VLDL assembly Insulin resistance Fatty Liver (Simple steatosis) Second hit TNF Oxidative stress Lipotoxic FA metabolite Endotoxins NASH 85-90% 10-15% No fibrosis Progressive No cirrhosis fibrosis Figure 7.1: Pathogenesis of NAFLD. FA: fatty acid, VLDL: very low density lipoprotein, TNF: tumour necrosis factor Cirrhosis - 132 - Clinical picture: 1. Asymptomatic: In most cases and discovered accidentally by elevated AST and ALT or during abdominal ultrasonography. 2. Right upper quadrant pain and hepatomegaly 3. Cirrhosis and its complications: Only in 10-15% of NASH 4. Clinical picture of aetiology: e.g. central obesity - 133 - Investigation: 1. Liver function tests:  ↑ ALT and AST  AST/ALT ratio 500 ng/rnl) in virtually diagnostic of HCC b) AFP-L3 (Lectin-bound fraction of AFP): More specific than AFP for HCC 2. Imaging: a) Abdominal Ultrasound:  It can detects HCC as small as 0.5-1 cm  Appear as hypoechoic focal lesion  Doppler US may show portal vein hrombosis b) Triphasic CT abdomen:  Arterial enhancement and venous washout are characteristics of HCC.  CT also detects metastasis and portal vein thrombosis c) MRI abdomen: Confirm diagnosis 3. Liver biopsy: Usually not necessary if imaging has characteristics of HCC - 151 - Treatment: HCC  Treatment algorithm: see Fig 9.1 Very early Stage 0 Early Stage A Intermediate Stage B Advanced Stage C Terminal Stage D  Single ≤ 2cm  Single or upto 3  Multinodular  Portal invasion  End-stage liver  Preserved liver nodules ≤ 3cm  Preserved liver  Extrahepatic spread function, Stage 0 function,  Preserved liver function,  Preserved liver  PS 3-4  PS 0 function,  PS 0 function, PST O, Child pugh A  PS 0  PS1-2 Solitary Upto 3 nodules ≤ 3cm Optimal surgical candidate Transplant Yes No candidate Yes No Ablation Resection Transplantation Ablation Chemoembolization Systemic therapy Best supportive care >5 years >2.5 years ≥ 10 months 3 months Figure 9.1: Modified BCLC guideline in treatment of HCC. PS, performance status; Preserved liver function refer to child A with out any ascites - 152 -  Treatment lines: 1. Surgical resection: Indication: only if tumour single + confined to one lobe + < 2-5 cm + no cirrhosis (or only Child A) Recurrence rate: 70% 2. Liver transplantation: Selection criteria: Milan criteria  Solitary nodule < 5 cm + no evidence of metastasis OR  3 nodules each ≤ 3 cm + no evidence of metastasis 3. Ablation therapy: a) Radiofrequency ablation (RFA): It's a percutaneous technique using thermal modality to destruct tumour b) Percutaneous ethanol injection: It causes tumour necrosis and its use should be confined only to those < 4cm 4. Transarterial chemoembolization (TACE): Principle: chemotherapeutic agents (cisplatin and doxorubicin) are injected into the hepatic artery which is subsequently occluded → shrinkage of tumour and improve survival Side effects: a) Post-embolization syndrome: abdominal pain and fever b) Liver failure 5. Targeted molecular therapies: Sorafenib (Nexavar) Mechanism: it's a multikinase inhibitor used in advanced HCC Dose: 400mg twice daily Side effects: diarrhea, weight loss, hand-foot skin reaction and hyperphosphataemia. N.B. systemic chemotherapy and radiotherapy have NO role in HCC. Prognosis : Poor prognosis (generally median survival is 6 months) Prevention of HCC: HBV vaccination - 153 - Screening of HCC:  Indications: 1. All cirrhotic patients (ONLY who would be suitable for curative therapy if diagnosed with HCC) 2. Chronic hepatitis B  Method and intervals: Combined ultrasound and AFP every 6 months  How to approach a liver nodule discovered during screening: See figure 9.2  Potential newer screening tools of HCC: Include:  AFP-L3  des-ɣ-carboxy prothrombin  glycosylated AFP ratio  glypican 3  α-fucosidase. - 154 -  Liver nodule < 1cm > 1cm Repeat ultrasound at 3 months Triphasic CT/ dynamic contrast enhanced MRI Stable Growing or Arterial enhancement changing character AND venous or delayed phase washout YES NO Continue CT/MRI follow up US Liver biopsy HCC Other contrast enhanced 5 study (CT/MRI) HCC Arterial enhancement AND venous or delayed phase washout YES NO Figure 9.2: Screening of HCC - 155 -  Secondary Malignant Tumours Definition: These are malignant liver tumours secondary to distant spread from carcinomas in the lung, breast, abdomen or pelvis Clinical picture: 1. Clinical picture of primary neoplasm: Asymptomatic in 50% of patients 2. Clinical picture of liver metastasis: Hard hepatomegaly, weight loss, Jaundice Investigations: 1.