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Ministry of Healthcare of Ukraine N.I. Pirogov National Medical University Department of Infectious Diseases Approved at the methodical meeting «___» _____________ 20 y. Head of the Department, prof. Moroz L.V. WORKBOOK for practical training on infectious diseases for V-year students of medical departments (1X - X term) Topic 11.1: Laboratory Diagnosis of Acute Viral Hepatitises. Specific and biochemical markers. Differential diagnosis of viral hepatitises. Therapeutic approach, medical aid for patients in prehospital phase. Prepared by : Candidate of Medical Sciences Popovich А.А. 2009 1 1. Relevance of the topic. Among human infectious diseases viral hepatitis takes up special place. In recent years, in addition to the well-known hepatitis viruses A, B, C, D, E , F and G, other viruses were added - TT and SEN(non-A, non-G) which can cause hepatitis and possibly many extrahepatic disease processes. Acute viral hepatitis is an acute viral disease affecting the liver, characterized by necrosis and inflammatory changes in the hepatic portal system and intralobular parenchyma. Among parenteral acute viral hepatitises the most dangerous and studied are viral hepatitis B and C. Every year 50 million people get infected by hepatitis B virus and 1.5 to 2 million people die from it. In Ukraine, the incidence rate of hepatitis B is about 14.5 per 100,000 of the population and those who carry the virus are about 1 million people. Hepatitis D as well as hepatitis B is practically widespread. The causative agent of hepatitis C was discovered and became the most common at the beginning of the XXI century. The number of people infected with hepatitis C virus has reached one billion people, almost 20% of the world's population. Hepatitis B and C have certain characteristics of the specific laboratory diagnosis and treatment. The common features of parenteral hepatitises are extremely dangerous consequences of the disease: cirrhosis and primary liver cancer. Therefore, early diagnosis is the main factor that allows to carry out the timely treatment of the patient and thus prevent death from these diseases. Laboratory diagnostic techniques used in the examination of patients with viral hepatitis provide a conduction and assessment of clinical, biochemical and specific researches. Among specific methods of diagnosis of viral hepatitises, the ones that deserve special attention are molecular biological methods including the polymerase chain reaction (PCR). Therapeutic approach for viral hepatitises consists of principles of etiotropic and pathogenetic therapy. In order to use etiotropic treatment, narrow and broad-spectrum antiviral chemotherapies are carried out. The most commonly used are anomalous nucleosides and interferons. Unfortunately, the current combination antiviral therapy has a number of adverse events which complicate and limit the use of appropriate medications, and also significantly worsen the life quality of patients. This factor applies most to the treatment of patients with chronic hepatitises. Pathogenetic principles of treatment that eliminate symptoms of intoxication, jaundice, diarrheal diseases and other syndromes are mainly used for patients with acute hepatitises. In cases of acute hepatitis A and E, the natural factors of the patient's own immune system act as the means of etiotropic therapy. 2 2. The aim of the course (with an indicating level of adoption of the program): 2.1. A Student must understand (learn): а-1 - have a general understanding of the place of acute viral hepatitis in the structure of infectious diseases, prevalence in different regions of the world and age groups, learn the statistical data on the sickness rate, lethality, complication rates, remote consequences of infections; - have a general understanding of the laboratory diagnostic methods of acute viral hepatitises - have a general understanding of the main methods of treatment of acute viral hepatitises - learn the history of the scientific study of acute viral hepatitises, have an understanding of the scientific contribution of Russian scientists in the history of scientific research in this field. а-2 2.2. A student must know: 1. etiology of acute viral hepatitises 2. basic processes of pathogenesis that lead to changes in the general analysis of blood, urine, and feces of patients with acute viral hepatitises 3. basic processes of pathogenesis that lead to changes in biochemical analysis of blood of patients with acute viral hepatitises 4. clinical methods 5. biochemical methods 6. specific laboratory methods of research 7. principles of differential diagnosis of acute viral hepatitises among themselves and other diseases based on laboratory methods for diagnosis 8. treatment principles of acute viral hepatitises 9. characterization of the main antiviral drugs 10. the order for prescribing antiviral drugs to patients with acute viral hepatitises 11. characterization of pathogenic therapy for patients with acute viral hepatitises 12. the order for prescribing pathogenetic therapy drugs to patients with acute viral hepatitises 13. therapeutic approach for helping a patient in the events of emergency conditions 14. medical aid for patients in prehospital phase 2.3. A student must know how to: а–3 1. 2. 3. 4. 5. Make a plan for the laboratory examination of the patient. Interpret the results of clinical and biochemical researches. Evaluate the results of the specific diagnostic methods Carry out a differential diagnosis of acute viral hepatitises. Make an individual treatment plan considering the epidemiological data, stage of disease, complications, condition severity, allergic history, concomitant pathology and laboratory methods of examination. 6. Provide emergency care to patients with acute hepatic failure, hemorrhagic syndrome, cerebral edema. 7. Give an advise on the treatment and the diet. 3 2.4. Creative level (for most capable and trained students): а–4 Develop creative abilities of students in the process of conducting clinical researches and during analysis of scientific sources: get involved in a scientific study group of the faculty; suggest topics for essays about the most pressing issues, for example: « Prevention of viral hepatitises with different mechanisms of transmission», «Population consequences of conducting a mass vaccination against hepatitis B», «The possibility of using modern antiviral drugs for the treatment of acute viral hepatitises with different mechanisms of transmission», «Difficulties in the differential diagnosis of acute viral hepatitises with subclinical course» etc. 3. Educational aims (personality development): 1. Develop a deontological view. Know and be able to follow the principles of medical deontology. Master the ability to establish psychological contact with the patient and his family. 2. Develop understanding of the impact of antiepidemic measures on the prevalence of acute viral hepatitises. 3. Develop a sense of responsibility for the timeliness and accuracy of professional activities. 4. Intersubject integration: Discipline Microbiology Internal diseases propedeutics Epidemiology Immunology and allergology Physiology Know Properties of agents of acute viral hepatitis, serological response according to the period of disease, rules and terms of sample collection for specific diagnosis. Main stages and methods of clinical examination of the patient. An epidemic process (source, infecting mechanism,way of transmission) of acute viral hepatitises; prevalence of the disease in Ukraine and in the world. World Health Organization (WHO) strategy for eliminating these infections. The basic concepts of the subject, Role of the immune system in the infectious process, an effect on the period of elimination of the causative agent from the human body. Immunological aspects of the disease complications. The characteristics of physiological norms of human organs and systems; norms of the laboratory examination( blood sampling, urine, biochemistry of blood, characteristics of RIH, electrolytes, etc.). Know how to Collect specimens fot virological (feces and blood sample) and serological researches, interpret the results of the findings obtain the medical history, carry out a clinical examination of the patient's oragans, identify clinical signs of the disease. Analyze the results. Collect an epidemiologic evidence, conduct an antiepidemic and preventive measures in the nidus of infection Evaluate the results of the immunological research. Evaluate the results of the laboratory examination. 4 Neurology Clinical and laboratory signs of hepatic encephalopathy Carry out the clinical examination of the patient with affection of CNS. Clinical pharmacology Pharmacokinetics and pharmacodynamics , side effects of etiotropic and pathogenetic therapy. Prescribe the treatment based on age, individual characteristics of the patient, select a dose regimen, write a prescription. Reanimation and intensive care Emergency: Hepatic encephalopathy Brain edema Diagnose and provide first aid in case of emergecy: Hepatic encephalopathy Brain edema 5. The content of the course and its structure. LABORATORY DIAGNOSIS OF ACUTE VIRAL HEPATITISES Biochemical markers 1. Cytolytic syndrome: Elevated levels of ALT, AST (starting from the end of the incubation period), high iron levels in blood, reduced PI and other coagulation factors, reduced albumin, cholesteryl ester. 2. Mesenchymal-inflammatory syndrome: Increased levels of α2 - β - γ - globulins, all classes of immunoglobulins, modified colloidal probes (reduced sublimate titer and increased thymol test) 3. Cholestatic syndrome: Increased levels of conjugated bilirubin, bile acids, cholesterol, copper, ALP, 5'-nucleotidase, GGT, bilirubinuria. Specific markers VIRAL HEPATITIS A 1. 2. 3. 4. Virological research (immunoelectron microscopy of fecal filtrate) Detection of HAVAg by ELISA Serological methods: detection of anti-НАV IgM by RIA, ELISA (four weeks after exposure) Positive PCR on RNA in blood and feces 5 ACUTE VIRAL HEPATITIS В 1. Serological methods: detection of НВsAg, HBeAg, anti-HBcorIgМ, negative antiHBcorIgМ by ELISA, Counterimmunoelectrophoresis, RIA (eight weeks after exposure) 2. Positive PCR НВV DNA in blood ACUTE VIRAL HEPATITIS D (Acute co-infection) Detection of acute hepatitis B markers Serological methods: detection of HDVAg by ELISA, anti-HDVIgМ (sixteen weeks after exposure) by ELISA Positive PCR НDV RNA in blood ACUTE VIRAL HEPATITIS С 1. Serological methods: detection of anti-HCVcorIgМ, negative - anti-HCVcorIgG, antiHCVNS4IgG by ELISA (twelve weeks after exposure) 2. Positive PCR НCV RNA in blood VIRAL HEPATITIS Е 1. Virological research (immune electron microscopy of fecal filtrate) 2. Serological methods: detection of anti-HЕV IgM 3. Positive PCR HEV RNA in blood Differential diagnosis of viral hepatitises Characteristics: HAV - Seasonality (summer- fall) The possibility of group outbreaks Acute onset (Pseudo-influenza, mixed type) Short fever (1-3 days) Improvement of health on the onset of jaundice Mainly mild course The presence of specific markers НВV - An indication of the different parenteral manipulations 3-6 months before the development of symptoms More common in older people, drug addicts, homosexuals Sporadic cases Gradual onset Preicteric period: arthralgis, dyspepsia, mixed type (fever is not typical) The condition does not improve since the appearance of jaundice Mainly moderate course The presence of specific markers 6 НDV - Risk group - people with Australia antigen Preicteric period fever - 60% of the patients Constant pain in right upper quadrant Mainly fluctuating course GC worsen the corse of the disease The presence of specific markers - Risk group - people who received blood transfusions Gradual onset Mainly mild course Chronization in most cases The presence of specific markers - Prevalence mainly in Asia, Africa, South America An explosive epidemic, mainly water transferred Age of patients: 15-18 years, 28-40 years Acute onset The condition does not improve since the appearance of jaundice Preicteric period - acute epigastric pain Phase 2 enzyme activity increase Severe course with pregnant patients, high mortality rate GC worsen the corse of the disease The presence of specific markers НCV HEV Hepatocellular jaundice: Causes: - Transfusion of incompatible blood Effect of parasites on red blood cells (malaria) Toxic effect on red blood cells: alcohol, chemicals, medicaments Toxic effect of pathogenicity factors of different microorganism Symptoms: - Yellow discoloration of the skin - Different degrees of severity of Anemia (high reticulocyte count) - Dark urine colour - Pale stool - Unconjugated hyperbilirubinemia due to increased bilirubin production - Normal levels of ALT, AST - Normal levels of ALP 7 Post-hepatic Jaundice Causes: - Bile duct obstruction Liver abscess of the caudate lobule Severe sepsis Peptic ulcer, duodenal ulcer, common bile duct tumor Pancreatic head lesion Enlarged lymph nodes during hematologic diseases Symptoms: - Clinical patterns of the disease - Yellow discoloration of the skin - Pale stool - Dark urine colour - Conjugated hyperbilirubinemia - Normal levels of ALT, AST / insignificantlyelevated levels - Elevated levels of ALP Pre-hepatic Jaundice Causes: - Crigler-Najjar syndrome Gilbert's syndrome Toxic hepatitis Cholestasis of pregnancy Hepatic steatosis Infectious diseases (brucellosis, tularemia, legionellosis, Q fever, leptospirosis, herpesviridae, yellow fever, etc.) Viral Hepatitises Symptoms: - Crigler-Najjar syndrome: appears in the first days of life , apparent jaundice, affection of CNS, autosomal recessive inheritance - Gilbert's syndrome: unconjugated hyperbilirubinemia due to insignificantly increased bilirubin production, normal activity of transaminases and other hematologic signs, the dominant-recessive pattern of inheritance, efficacy of phenobarbital - Toxic hepatitis: anamnesis of aspirin dosage, sulfanilamides, tuberculostatic drugs and others, mushroom poisoning, increased levels of bilirubin and transaminases - Cholestasis of pregnancy: mostly during third trimester pregnancy, itch (sometimes unbearable), jaundice, dark urine, fatigue, nausea, liver is not increased, slightly increased transaminases , symptoms disappear after pregnancy in a few days. - Hepatic steatosis (acute fatty liver of pregnancy): mostly during third trimester pregnancy (late gestosis), acute onset (much like fulminant hepatitis) with rapid development of kidney and liver failure, possibility of massive bleeding, liver is not increased, increased levels of conjugated bilirubin, insignificantlyelevated /normal levels of ALT, AST , high ammonia levels in blood, uric acid, at the beginning of the first/second week patients usually die. 8 Therapeutic approach for acute viral hepatitises (HAV) Regimen – bed rest in any severity of the disease up to dehydration Diet - №5, 5а (protein – 1,5-2 g/kg, fat – 0,8-1,8 g/kg, carbohydrates – 4-5 g/kg) Etiotropic therapy: - treatment of acute viral hepatitis С Schemes: 1. Interferon 3-6 m IU х 3 times a week or daily, for 3-6 months 2. Interferon 3-6 m IU х 3 times a week or daily + Ribavirin 1000-1200 mg/day (15mg/kg) daily, for 3-6 months 3. Peginterferon 180 mcg subcutaneously once a week for 3-6 months - treatment of acute viral hepatitis B with lingering course 1. Peginterferon 180 mcg subcutaneously once a week for 6 months Pathogenetic therapy (detoxification therapy, metabolic therapy, decongestant therapy for improving microcirculation and reducing the itching). MILD CLINICAL COURSE – diet (with drinking enough water) + bed rest + Ascorutin х 3 times a day (for 7 days) + Lactulose 15-20 mL х 3 times a day (for 7 days). MODERATE CLINICAL COURSE - diet + bed rest (with drinking enough water) microclysters with 2-3% solution of sodium bicarbonate rectal infusion of 2-4% sodium bicarbonate solution 150-200 mL per day glucose-insulin-potassium mixture 50-70 mL of potassium chloride + 300-500 mL 5% of glucose + insulin «Acesol», «Trisolum» i.v. drip-feed 200-400 mL daily for 5-7 days (especially if the vomiting occurs) Reamberin, Reosorbilact 200-400 mL i.v. drip-feed daily for 7-10 days Enterosgel 1 tbsp. 3 times a day, orally, daily for 5-7 days Lactulose 15-30 mL х 3 times a day, daily Vitamin С 1000 mg i.v. with saline solution or 5% glucose solution Hepasol A 500 mL, Aminosteril N-Hера 8% - 500 mL, Hepa-Merz 40 mL with saline solution, Aminosol 500 mL i.v. drip-feed Citrarginine 10 mL х 3 times a day, orally for 5-7 days Trental 200 mg х 3 times a day after meals for 7-10 days Osetron 8-mg per day for 5-7 days SEVERE CLINICAL COURSE - diet + bed rest (with drinking enough water) microclysters with Lactulose rectal infusion of 2-4% sodium bicarbonate solution 150-200 mL per day glucose-insulin-potassium mixture 50-70 mL of potassium chloride + 300-500 mL 5% of glucose + insulin «Acesol», «Trisolum» i.v. drip-feed 200-400 mL daily for 5-7 days (especially if the vomiting occurs) Reamberin, Reosorbilact 200-400 mL i.v. drip-feed daily for 7-10 days Furosemide 1%-1-2 mL, Mannitol 30% - 200 mL per day Vitamin С 1000 mg i.v. with saline solution or 5% glucose solution 9 Amino acids with high levels of branched-chain amino acids and low levels of aromatic amino acids: Hepasol A 500 mL, Aminosteril N-Hера 8% - 500 mL, Hepa-Merz 40 mL with saline solution, Aminosol 500 mL i.v. drip-feed Citrarginine 10 mL х 3 times a day, orally for 5-7 days Lactulose 30-50 mL х 3 times a day, orally for 7-10 days Bifiform 2 capsules х 2-3 times a day , orally for 5-7 days Enterosgel 1 tbsp. 3 times a day, orally, daily for 5-7 days Trental 200 mg х 3 times a day after meals for 7-10 days TREATMENT OF HEPATIC ENCEPHALOPATHY Diet (protein deprivation up to 50mg per day) + strict bed rest For reduction of ammonia formation in the intestine: - Lactulose 30-120 mL per day orally or rectally 1-3 mL 20% solution. The use of oral non-absorbable antibiotics: - Ciprofloxacin 500 mg х 2 times per day – for 7 days - Metronidazole 800-1000 mg per day — for 7 days - Neomycin (in severe cases) 4-6g per day for7 days Increase of neutralization of ammonia in the liver: - L-ornithine - L-Aspartate (Hepa-Merz ) 9-18 g per day, orally or 20-40 g/daily i.v. drip-feed - Ornicetil - 3-6 g х 3 times a day Ammonia neutralization in blood: - Glutamic acid 1% - 150 mL i.v. drip-feed - L-Arginine -L- glutamate (Glutargin) 40% - 5mL with saline solution Drugs that reduce inhibitory processes in the CNS: - Flumazenil - Levodopa - Bromocriptine Combined action drugs: - Hepasol A 500 mL х 2 times a day, i.v. drip-feed Siphonage bowel ATC: Mannitol 30% - 400mL per day, Sorbitol 15% - 400mL в сутки, Furosemide 1% 4-8mL per day Medical aid for patient in prehospital phase provides oral detoxification (drinking plenty of fluids, lactulose, sorbents (enterosgel, white coal)), in case of nausea and vomiting use prokinetics (motilium, ondansetron). 6. Organizational structure and planning of the course: Main stages of the course, functions and content 1 Learning Methods of objectives control and in levels of training adoption 2 3 Methodology resources (control, instructions) 4 Time (min.) 5 1 0 1. Preparatory stage: 1. Planning a course 2. Goal-setting and motivation 3. Control of the initial knowledge II Interview. Individual survey. Test control. См. п.1 ”Relevance”; См. п.2 ”Learning Objectives”; Personal interview questions. 2nd level tests. 15 min. Table of contents - see P.2.1; P.2.2 ”Learning Objectives” 2. Main stage: Shaping a system of III professional skills Table of contents - see P.2.2; P.2.3 ”Learning Objectives” 3. Final stage: 1. Control and improvement of professional skills 2. Summarizing the course 3. Homework with the academic book list (basic, complementary) III Practical professional training in dealing with different (typical and atypical) clinical tasks. Patient care supervision. Anamnesis. Discharge abstract. 2nd - 3rd level situational problems. Individual control of practical skills and professional activities of the students. Analysis of common mistakes. Test control. 3rd level tests. 3rd level situational problems. 60 min. 15 min. 1 1