Clinical Aspects of Liver Diseases 22 Acute viral hepatitis

22 Acute viral hepatitis

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1 History of acute viral hepatitis 413 2 Morphology and aetiopathogenetic range 414

2.1 Histomorphological changes 415

2.2 Sonographic morphology 416

2.3 Specific courses of disease 416

2.3.1 Minimal hepatitis 416

2.3.2 Drug-induced hepatitis 416

2.3.3 Cholestatic course of disease 416 2.3.4 Anicteric course of disease 416 2.3.5 Fulminant course of disease 416

2.3.6 Giant-cell hepatitis 417

2.4 Aetiopathogenetic diversity 417

3 Acute viral hepatitis A 418

3.1 Definition 418

3.2 Pathogen 418

3.2.1 Inactivation 418

3.2.2 Detection 418

3.2.3 Replication 419

3.3 Transmission 419

3.4 Epidemiology 419

3.4.1 Frequency of disease 419

3.4.2 Obligation for notification 420

3.5 Pathogenesis 420

3.6 Serological diagnostics 420

3.7 Stages of disease 420

3.8 Extrahepatic manifestations 421

3.9 Clinical courses of disease 421

3.10 Formation of granulomas 422

3.11 Prophylactic measures 422

3.11.1 Passive immunization 422

3.11.2 Active vaccination 422

3.11.3 Simultaneous vaccination 422

3.12 Therapy 422

4 Acute viral hepatitis B 423

4.1 Definition 423

4.2 Pathogen 423

4.2.1 Inactivation 423

4.2.2 Pathogenesis 423

4.3 Antigens and antibodies 423

4.4 HBV variants 425

4.5 Specific serological courses of disease 425

4.6 Chronic HBsAg carriers 425

4.7 Epidemiology 426

4.7.1 Obligation for notification 426

4.8 Transmission 426

4.8.1 Parenteral infection 426

4.8.2 Sexual infection 427

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4.8.3 Perinatal infection and antenatal care 427

4.8.4 Close physical contact 428

4.9 Hepatitis B and medical personnel 428

4.9.1 Medical personnel 428

4.9.2 Hepatitis B and the dialysis unit 429

4.9.3 Hepatitis B and dentistry 429

4.9.4 Insurance questions 429

4.10 Stages of disease 430

4.11 Extrahepatic manifestations 431 4.12 Specific clinical courses of disease 431

4.12.1 Subclinical course 431

4.12.2 Anicteric course 431

4.12.3 Protracted course 432

4.12.4 Recurrent course 432

4.12.5 Cholestatic course 432

4.12.6 Fulminant course 432

4.12.7 Subacute course 433

4.12.8 Chronic course 433

4.13 Hepatitis B and pregnancy 433

4.14 Hepatitis B and hepatocellular carcinoma 433

4.15 Prophylaxis 433

4.15.1 General hygiene measures 434

4.15.2 Passive immunoprophylactic measures 434

4.15.3 Simultaneous vaccination 434

4.15.4 Active protective vaccination 434

4.16 Therapy 436

4.16.1 Aims of treatment 436

4.16.2 Methods of treatment 436

4.17 Healing of hepatitis B 437

4.17.1 Morphological healing process 437 4.17.2 Biochemical healing process 438

5 Acute viral hepatitis C 439

5.1 Definition 439

5.2 Pathogen 439

5.2.1 Genotypes 439

5.2.2 Inactivation 440

5.3 Serological diagnostics 440

5.3.1 Anti-HCV test 440

5.3.2 RT-PCR test 440

5.4 Epidemiology 440

5.5 Transmission 441

5.6 Histological findings 442

5.7 Stages of disease 442

5.8 Extrahepatic manifestations 443

5.9 Hepatitis C and hepatocellular carcinoma 444

5.10 Prophylaxis and therapy 444

6 Acute viral hepatitis D 445

6.2 Pathogen 445

6.2.1 Mutants 445

6.3 Transmission 445

6.4 Epidemiology 445

6.5 Serological diagnostics 446

6.5.1 Coinfection 446

6.5.2 Superinfection 446

6.6 Courses of disease 446

6.6.1 Coinfection 446

6.6.2 Superinfection 446

6.7 Special features of HDV infection 447

6.8 Prophylaxis 447

6.9 Therapy 447

7 Acute viral hepatitis E 447

7.1 Definition 447

7.3 Epidemiology 448

7.4 Transmission 448

7.5 Serological diagnostics 448

7.6 Clinical aspects and courses of disease 448

7.7 Prophylaxis and therapy 449

8 Acute viral hepatitis NA-NE 449

9 HF virus 449

10 HG virus 449

11 GB viruses 449

12 TT virus 450

13 SEN virus 451

14 Other viruses 451

앫 References (1⫺580) 451

(Figures 22.1 ⫺22.20; tables 22.1⫺22.8)

1 History of acute viral hepatitis

H ippocrates described a potentially dangerous disease widely witnessed in young people and accompanied by jaundice. • As early as 752, Pope Z acharias wrote in a letter to St. Boniface, Bishop of Mainz (Germany), about “jaundice of a contagious nature” where those affected would have to be segregated.

䉴 In 1629 ^H enry de Beer wrote about a jaundice epidemic in Spa (Belgium). In 1745 C leghorn described the clin- ical picture of jaundice witnessed during the course of an epidemic in Menorca (Spain). In 1761 I. F. H erlitz (14) observed many jaundice patients in Göttingen (Ger- many) and gave an impressive description of the clinical symptoms of this benign illness, which mainly occurred in winter; this was all the more interesting since he him- self was suffering from it. The term icterus epidemicus in fact stems from him (and was also proposed by A.

H ennig in 1890). • Descriptions of jaundice epidemics were to follow from Bremen (Germany) (1760), Essen (Germany) ( G. F. H. B ruening, 1772 ), Genova (Italy) (1792), Lüdenscheid (Germany) ( F. K ercksig, 1799 ), Greifswald (Germany) ( L. M ende, 1810 ), etc. In fact, more than 80 epidemics in Europe and 6 outside Europe were recorded by C. K öhnhorn (1877) (16) , C. F röhlich (1879) (11) and A. H ennig (1890) . Numerous publications focused on the frequency of epidemic jaundice in garri- sons and at theatres of war, so that the illness also became known as “soldier’s disease”. • Its causal origin was deemed to be poor hygiene, vermin, overcrowding, climatic factors, monotonous and nauseating nutrition, mental trauma, physical strain and polluted water. (quot.

in 4, 11, 16) H. E ppinger (1908) was of the opinion that this apparently epidemic jaundice was, in fact, an accidental accumulation of non-infectious diseases. Almost all epi- demics were accompanied by severe courses of disease and many deaths. As early as 1862, R. J. G raves drew attention to the fact that “the worst was to be feared if there were any signs of nervous symptoms during the course of jaundice” (hepatic encephalopathy?). He attributed the cause of jaundice to gastroenteritis and believed that it also affected the bile ducts. This opinion was so convincing for R. V irchow (1864) (29) that he later adopted the term icterus catarrhalis for catarrhal jaun- dice, a term that had been introduced by H. Q uincke (1903) : the bile was thick and sticky with subsequent obstruction of the small bile ducts and development of jaundice. At a later date, he also assumed the cause to be an intercurrent mucous plug in the duodenal papilla.

However, towards the end of the 19

^th

century, it was increasingly believed to be an infectious disease ( A. E. C h .

C hauffard, 1885 ; M. H eitler, 1887 ; S. P. B otkin, 1888 [it was also known as Botkin’s disease in Russia and the Baltic countries]; A. H ennig, 1890 ; O. M inkowski, 1904 , etc.). The

main localization of the disease was already considered to be in the liver parenchyma, but the source of the infection was unknown. Airborne transmission was also postulated. (6)

䉴 Reports that were drawn up by ^L ürman (20) and J ehn (15) on the epidemics in Bremen (Germany) and Merzig (Germany) following inoculation with smallpox vaccine are considered to be the first ever regarding the paren- teral route of infection (i.e. HBV and HCV infections).

In Bremen (Germany) 191 persons (out of 1,290 cases) and in Merzig (Germany) 144 persons (out of 510 cases) succumbed to the disease. Further reference to the parenteral transmissibility of infectious jaundice was made by A. F laum et al. (1926) , G. M. F indlay et al. (1937) ,

A. S. M cNalty et al. (1937) , S. A. P ropert (1938) , P. S elander (1942) , C. H. G rossman et al. (1946) , etc. After an inocula- tion campaign with a measles convalescent serum involving 109 children, A. S. M cNalty (1937) observed the occurrence of jaundice in 47% of cases with a mortality rate of 22%. • W. S iede (1949) reported that 19% of 125 children developed jaundice after an infusion of insulin and dextrose. • In 1943 in the USA, the term homolo- gous serum jaundice was introduced, but it was also known as serum hepatitis. Over the following years, the terms haematogenous hepatitis, inoculation hepatitis, transfusion hepatitis and homologous serum hepatitis were used as well. (21, 27)

䉴 In 1919 ^{F. L} indstedt introduced the term hepatitis epi- demica for epidemic jaundice. In 1930, however, ^{G. L} e- pehne proposed the term “hepatia” to avoid emphasizing its inflammatory character. The term icterus simplex can be attributed to G. v. B ergmann (1931) . Another term used was infectious hepatitis, proposed by ^{G. M. F} indlay et al.

(1939) . • Since the morphological studies carried out by

H. E ppinger et al. (1935) revealed “acute destructive hepa- titis” and the characteristics of “serous inflammation”

(R. R össle, 1929) , icterus catarrhalis has also been consid- ered morphologically as “hepatitis”, and the term

“acute interstitial serous hepatitis” is used. In 1937 H.

E ppinger distinguished the parenchymal from the peri- acinal or cholangiolitic form of hepatitis, an idea which is reflected by the present-day term of acute viral hepati- tis with cholestatic character. H. E ppinger was already familiar with the term anicteric hepatitis, which he called

“icterus sine ictero” (1937). • In 1940 F. C orelli claimed icterus catarrhalis to be an allergic inflammation which could possibly be improved by desensitization therapy.

He reports on a number of interesting observations of icteric patients under a variety of conditions. (7)

First World War: The tremendous jaundice epidemics

witnessed during the war in practically every army and

those in the thirties among the civilian population called

for a new definition. An excellent monograph was drawn up by F. v. B ormann (1940) , critically evaluating the entire material available (406 publications quoted!). (4)

The clinical picture was described in great detail, all the- ories and doctrines quoted and observations and experi- ments presented with the greatest of care. The viral nature of the pathogen was postulated on the basis of the findings. The publication brought out in the same year (1940) by F. L ainer from Eppinger’s hospital is an excellent supplement to the level of knowledge of that time ⫺ yet even in 1940, the opinion was still held that icterus catarrhalis occurred sporadically in the form of serous hepatitis, precipitated by endogenous or exoge- nous toxins and not by any specific icterogenic pathogen.

(18) • T. T h . A ndersen et al. (1938) were the first to trigger jaundice in young swine by feeding them the duodenal juice of jaundice patients. This in turn could be transmitted in a second passage to other swine by feed- ing them the raw liver of the first icteric group. The administration of the blood of jaundice patients to swine also led to the occurrence of jaundice with micro- scopic liver changes. No pathogen was found and so it was generally assumed to be an invisible virus (1) , as

M cDonald had already postulated in 1908.

䉴 Second World War: Large-scale epidemics, even pan- demics, of hepatitis were also rife during the Second World War. Entire military units were severely depleted by the illness. I was one of those affected in Russia in 1942. The number of cases of hepatitis in the Second World War has been estimated at approx. 16 million. • In this period, the first transmission of an infectious agent was effected in a self-experiment by ^{H. V} oegt (1941) , who was later to be my tutor in hepatology. Within 3 or 4 weeks, the oral intake of duodenal juice from a hepati- tis patient led to the contraction of hepatitis in both himself and in three medical student volunteers (who had not stayed in an epidemic area). Histological focus was on “capillaritis”. Six other test persons, who were orally administered haemolyzed blood or urine taken from a jaundice patient (2 cases) or received serum or blood by s.c. or i.m. injection (4 cases), showed symp- toms of hepatitis. The direct transmission path of an infectious virus was hence deemed proven (30) and the existence of “posthepatic residual damage” established

(12) . In 1952 H. V oegt told me personally at the univer- sity in Giessen (Germany) that he had changed the term icterus infectiosus ^{(K. G} utzeit, 1942) into hepatitis conta- giosa (1942) ⫺ also used by ^{A. D} ohmen in 1943. The term hepatitis infectiosa was proposed by ^{F. M} aythaler in 1942. • In 1943 F. O. M acCalum confirmed the transmissi- bility of an infectious agent. (22)

In 1947 M acCalum termed hepatitis epidemica as type A and inoculation hepatitis as type B. These results were validated by further studies. (13, 23, 24) S. K rugman et al.

(1967) introduced the terms MS1 and MS2 for these two types of virus, which at a later date were to correspond to HAV and HBV. (17) In 1970 virus B was detected by

D. S. D ane et al. (8) ⫺ following the identification of the Australian antigen by B. S. B lumberg et al. (1965) (3) and

A. M. P rince (1968) . (25) In 1973 the hepatitis A virus was discovered by S. M. F einstone et al. (9) In 1977 the delta virus was detected by M. R izzetto et al. (28) A pathogen termed hepatitis E virus was identified in 1983 in the stool of an infected volunteer (M. S. B alayan et al.) . (2) It was assumed that another virus existed (10, 26) , which was termed the hepatitis C virus after being identified by Q. L. C hoo et al. in 1989. (5) Detection of the hepatitis G virus (HGV) followed in 1996 (J. L innen et al.) . (19)

Infectious jaundice presents the most imposing clin- ical picture in hepatology and has occupied phys- icians for more than 2,500 years, caused epidemics and pandemics all over the world (thus significantly influencing the outcome of wars), led to innumerable experiments as well as controversial theories and cul- minated in absurd speculations including treatment by the oral administration of live sheep lice (a prac- tice still occasionally found nowadays). • Today, hep- atitis viruses have been (almost) fully explained down to the last molecular, biological and serological detail.

2 Morphology and

aetiopathogenetic range

䉴 Histologically, the suffix “itis” denotes inflammation, thus “hepatitis” can be defined as “inflammation of the liver”. This term was coined by J. B. B ianchi as early as 1725 in order to summarize various diffuse inflamma- tions of the parenchyma.

The classical criteria of inflammation (1.) exudation, (2.) cellulation and (3.) proliferation can only partly be applied to the liver, since this organ is predominantly characterized by sinusoids rather than capillaries. An essential problem thus arises in the morphological context of the term “hepatitis”. Due to this specific vas- cular feature, the otherwise valid association between the terms “inflammation” and “infection” is only marginally true in the case of the liver. In fact, this association is only given with infectious changes within the vascular- ized fibrous tissue of the portal fields. • The problem concerning the definition of “hepatitis” has already been outlined in detail in the last chapter. (s. p. 404)

Macroscopically, acute viral hepatitis presents as a

large red liver ^{(H. K} alk, 1947) . The enlargement is prob-

ably due to hyperaemia and to the oedematization of

the portal area. The reddening is brought about by

hyperaemia and the accumulation of large quantities

of stagnating erythrocytes in the empty lattice fibre

network.

2.1 Histomorphological changes

Histologically, the parenchyma, the mesenchyma and the connective tissue are affected in an almost identical manner. The combination of all lesions together with the onset of hepatocellular regeneration gives the typic- ally unsettled variegated picture of acute viral hepatitis, which is more characteristic than any single finding on its own (H.-W. A ltmann, 1971) . The liver lobules are affected as a whole and in all their components, whereby particularly the hepatocytes at the centre of the lobule are most severely damaged. For this reason, acute viral hepatitis is deemed to be lobular hepatitis. These changes are shown as constant or inconstant lesions. (31, 34, 36) (s. tab. 22.1)

Lobular Portal and periportal

Con- Liver cell degenerations Infiltration by small stant (hydropic swelling, eosin- lymphocytes, plasma

ophilic degeneration, pin cells and other mono- cells, hyaline bodies) and nuclear cells ( ⫽ lym- cell polymorphy, single phohistiocytic).

cell necrosis in the form of (acidophilic) Councilman bodies, infiltration of lympho- cytes, macrophages and activated stellate cells (yet only few plasma cells and neutrophilic granulocytes), prolifer- ation of sinusoidal cells.

Incon- Confluent liver cell necro- Flow of infiltrates into stant sis, possibly developing adjacent lobular areas,

into bridging necroses fibroblast activity, (32) or multilobular damage to and prolif- (< 3% of cases) or even eration of bile ducts, massive necroses in B, accumulation of ceroid B/D and C hepatitis, as and siderin in macro- well as in E hepatitis dur- phages.

ing pregnancy; collapse of the lattice fibre net- work. Formation of pas- sive septa, cholestasis, ac- cumulation of ceroid and siderin in macrophages and stellate cells.

Tab. 22.1: Morphological changes with acute viral hepatitis Mitoses: The consumption of liver cells by necroses is considerable, as is the concurrent regeneration process, particularly at the onset of acute hepatitis and during the retrogressive phase. • This also explains the remarkable observation that patients with the Dubin- Johnson syndrome are found to have far fewer pigment-charged liver cells subsequent to acute viral hepatitis. (s. pp 222, 421)

Stellate cell activation: At the climax of acute viral hepatitis, the stellate cells are diffuse and highly activated. Stellate cell nodules (s. fig. 22.3) are formed. The diffuse spread of the swelling and the proliferation of sinusoidal cells may recede during the retrogressive phase into more localized proliferations. These somewhat indis- tinctly contoured stellate cell nodules can often be detected in the necrotic area already at an early stage. In this event, they generally contain the liver disintegration pigment ceroid (s. fig. 21.6), later also lipofuscin (s. fig. 21.3) and siderin. Such so-called residual

Fig. 22.1: Acute viral hepatitis A: Periportal inflammation and periportal cell loss

Fig. 22.2: Subsiding acute viral hepatitis A with lytic loss of hepa- tocytes and round-cell infiltrates

Fig. 22.3: Kupffer cell nodules (arrow) in subsiding acute viral hepatitis B; hydropic hepatocytes, often binuclear

nodules (H. K alk et al., 1947) or late-phase nodules (W. W epler et al., 1968) are frequently still found 1 to 2 months after the acute hepati- tis is deemed to be clinically healed. The nodules remain diffusely distributed in the parenchyma until they gradually diminish, lose their pigment and ultimately disappear completely.

Regeneration: Regenerative processes overlap with the slowly dwindling inflammation. They are characterized by a proliferation of the liver cell columns, an uneven pattern of cell nuclei, an increase in mitoses and the formation of liver cell rosettes. (s. p.

229) Acute viral hepatitis usually heals completely within a period

of 4 ⫺8 weeks.

Formation of collagen: The empty lattice fibre structure in a de- epithelialized area (with possible collapse of the lattice fibres) becomes increasingly collagenized, so that sclerosis occurs at the centre of the lobules in place of lost liver cells. This process may be completely reversible if the regenerated liver cells succeed in respreading the fibres. Otherwise, central fibre scars persist for a long period of time. This fibre production occurs far earlier and to a more pronounced extent at the periphery of the lobules. In delayed epithelial regeneration, the fibre layers or cicatrized changes remain as portal fibrosis. (s. p. 404)

2.2 Sonographic morphology

With the help of sonography, it is possible in acute viral hepatitis to obtain the following findings: (1.) hepato- megaly, (2.) slight increase in brightness, (3.) truncated lower liver margin, (4.) thickening of the gall-bladder wall (35) , and (5.) increased blood flow (using duplex sonography).

2.3 Specific courses of disease

Various endogenous or exogenous factors can alter the histomorphological picture of acute viral hepatitis, so that specific courses of disease may become apparent.

2.3.1 Minimal hepatitis

The course of minimal hepatitis (O. K linge, 1976) is generally found in anicteric or subicteric patients and only shows minor histological lesions. It is even possible over a period of several years to detect the hyaline bodies, the activation of the sinusoidal cells and the moder- ate round-cell infiltration of the portal fields as well as single cell necrosis. These changes show no progression, so that histology largely corresponds to that of chronic persistent hepatitis.

2.3.2 Drug-induced hepatitis

Irrespective of the type of drug, acute hepatitis (so-called “hippie hepatitis”) prevails in drug addicts. It is characterized by portal infiltration, generally with a large number of eosinophilic leuco- cytes. Cholestasis is common. The lobular borders are often diffi- cult to define. In most cases, phagocytized exogenous pigments or waste substances are found in the macrophages. • However, the extent to which primary or secondary hepatotropic viruses are involved must always be clarified. (s. tab. 5.16) • Histology, the course of disease and the prognosis are determined by the duration and intensity of drug intake, polytoxicomania or additional viral infections.

2.3.3 Cholestatic course of disease

䉴 The “cholestatic course of disease” ^{(W. S} iede, 1942) is largely identical to the “periacinal form of icterus catarrhalis” (H.

E ppinger, 1937) , “cholangiolitic hepatitis” (C. J. W atson et al., 1946) , “hepatitis with intrahepatic obstruction” (I. M agyar, 1953) and “hepatitis with a cholestatic element” (H. K alk, 1957) .

Those forms of acute viral hepatitis that have a normal clinical course also present discrete quantities of bile to be found as intra- epithelial drops and intercellular cylinders or deposits in the stel- late cells. These findings cannot be confirmed biochemically. • A cholestatic course of disease is occasionally witnessed with a marked increase in alkaline phosphatase, particularly in older patients and in women. It is mostly accompanied by jaundice. The

patient’s general well-being is significantly compromised, and pruritus is pronounced in most cases.

Histologically, changes linked to the respective stage of hepatitis can be observed together with an abundance of bile drops in the liver cells, above all in the centre of the lobule; in addition, there are bilirubin cylinders inside the canaliculi that are often dilated and tubular in shape. Sometimes, tubular reshaping of the liver cell plates is noticeable, with a bile canal in the centre. • Cholestatic liver cell rosettes develop in isolated surviving hepatocytes or small groups of hepatocytes within areas of collapse. These parenchymal islands of hepatocytes are arranged in a tubular pattern resembling that of the cholestatic liver cell rosettes. Evidence of bile retention is not always obvious, but copper and copper-associated protein are often demonstrable. Bile duct proliferation is usually inconspic- uous. (s. p. 229) Bilirubin cylinders can also be detected in the ductuli. In the portal fields, the picture of cholangiolitis is wit- nessed: small, round-cell infiltration with embedded leucocytes and degenerative changes of the portal bile ducts. (s. fig. 22.4)

Fig. 22.4: Feathery degeneration (arrows) of ballooned hepato- cytes, massive liver cell oedema and bilirubinostasis in the cana- liculi. Clinically: cholestatic course of acute viral hepatitis B

2.3.4 Anicteric course of disease

As early as 1904, O. M inkowski observed the anicteric form, and later, in 1937, H. E ppinger described it using the term “icterus sine ictero”, i. e. the bilirubin values in the serum are not in excess of 1.5 ⫺1.8 mg/dl, with the result that no jaundice of the sclerae can develop. This is a clinical phenomenon and not a morphological one. There are even reports of fatal acute liver necrosis without jaundice. Generally, the clinical findings are less pronounced than with the icteric course of disease. Bilirubinuria is only observed in isolated cases, whereas urobilinogenuria is usually detectable. (s.

pp 421, 432)

2.3.5 Fulminant course of disease

Hepatitis fulminans (B. L ucke´ et al., 1946) is the most severe course

of viral hepatitis, and in 80 ⫺90% of cases, it is fatal. The term is

used if signs of liver insufficiency emerge within 8 weeks following

the onset of disease. (If this occurs later, preference is given to

the term “subacute necrotizing hepatitis”.) • The clinical findings

suddenly and swiftly multiply in intensity and acuity. In addition,

fever, nausea, vomiting and hepatic foetor are witnessed, and the

sensorium becomes dulled. Cutaneous and mucosal bleeding

occurs, and there may be evidence of oliguria and oedemas. Labo-

ratory parameters show a considerable decrease in enzyme activity,

serum iron (after an initial increase), Quick’s value, albumin and

cholinesterase. Leucocytosis is frequently observed. The morpho-

logical picture is characterized by extensive, confluent parenchy-

mal necrosis (liver dystrophy). There is virtually no sign of a mes-

enchymal reaction. Postdystrophic scarred liver is usually found in those surviving the disease. (s. figs. 21.13; 22.16; 35.14)

2.3.6 Giant-cell hepatitis

Giant cell hepatitis in children: During infancy, acute viral hepatitis can occur with the formation of syncytial, polynuclear balloon-like giant cells. Recessive autoso- mal hereditary factors are said to contribute to this form of hepatocyte reaction. In recurrent intrahepatic chole- stasis of the Aagenaes type, giant-cell hepatitis usually develops. The pathogens include CMV, the herpes, vari- cella, Coxsackie, ECHO, HBV and rubella viruses, as well as listeriosis, toxoplasmosis and syphilis. The pattern of epithelial damage largely corresponds to clas- sic acute viral hepatitis ⫺ however, the histological pic- ture is dominated by giant cells. (s. fig. 22.5) (s. p. 467!) Differentiation is made between two types: (1.) giant cells in a regular arrangement (with evenly placed giant cells around the former canaliculi) and (2.) giant cells in an irregular arrangement. Both types may appear simul- taneously. • Their development is probably due to the confluence of liver cells following disintegration of the membrane ⫺ so-called confluent giant cells ^{(O. K} linge, 1970) . This process is facilitated by the fact that in chil- dren up to the age of five, liver cells are usually still in a double epithelial plate-like arrangement. Following their cytolysis, the giant cells are replaced by regular epithelium. The prognosis is often good, but reports have also been received of severe courses of disease.

Fig. 22.5: Numerous multinuclear giant cells (centre of picture) as well as bile duct proliferation (arrow) in so-called giant-cell hepatitis (HE)

Postinfantile giant-cell hepatitis: This term was intro- duced by H. T haler in 1982. The form itself is rare; only about 70 cases have been reported so far. (33) Generally, it develops in a similar way to progressive cholestasis of unknown aetiology. It mainly affects zone 3. The giant cells make up > 10% of the hepatocytes. They contain large numbers of nuclei (up to 40 per cell). Numerous luminae can be detected in the cytoplasm. Pathogenet- ically, this is a syncytial formation (and not amitotic cell regeneration as in the infantile form). The morpho-

logical spectrum extends from acute to chronic hepatitis and ultimately to cirrhosis. The giant cells are often pre- sent to such a minimal extent that they are undetectable in a biopsy specimen. The frequency of disease is possi- bly greater than has been assumed up to now. It may be caused not only by infections, but also by medication or the Epstein-Barr virus and paramyxoviruses. The fre- quent evidence of autoantibodies (e. g. ANA) and signif- icant increases in γ-globulin levels point to a close corre- lation between giant-cell hepatitis and autoimmune processes such as PSC.

2.4 Aetiopathogenetic diversity

The problem of working in line with morphological classification is rendered more complicated by the aetio- pathogenetic diversity of acute hepatitis. The tissue changes in acute hepatitis arise not only from primary hepatotropic viruses and secondary hepatotropic or exotic types of viruses, but also from bacterial or para- sitic agents. • Changes identical to these can, however, also be caused by alcohol, chemical substances, toxins or allergic and immunological reactions as well as by reactions to radiation (so-called radiogenic hepatitis), for example from cobalt ⫺ and even by the early forms of Wilson’s disease or primary biliary cholangitis.

A recently discovered form of acute hepatitis was attrib- uted to a deficiency of lipoamide dehydrogenase ( ⫽ catalytic subunit E3 of the pyruvate dehydrogenase complex). This LAD deficiency was allocated to chro- mosome 7 (q31-q32). So far, about ten well-documented cases have been reported. The patients all died during early childhood. (32) • Recently, there were reports of episodes of acute hepatitis each with significantly increased transaminases, slight jaundice and uncharac- teristic symptomatology. Between the episodes, all the liver values were normal. Histological analyses only revealed minor findings in the form of non-specific reactive hepatitis. The aetiology could not be deter- mined even though the entire range of clinical examina- tions was applied. This entity is considered to be iden- tical to benign recurrent intrahepatic cholestasis. (37)

The respective lesions in the area of the lobules and portal fields and at the hepatocytes, the mesenchyma and connective tissue differ in intensity from case to case (also depending on the respective stage of the dis- ease) ⫺ yet the picture of “acute hepatitis” predomi- nates. • In each case of liver disease which remains unre- solved in terms of differential diagnosis, thought must be given to the possibility of acute hepatitis with its wide range of aetiological causes. (s. fig. 22.6)

Acute hepatitis is not an entity in itself, either clin-

ically, aetiologically or morphologically ⫺ but must be

seen as a syndrome.

Fig. 22.6: Syndrome of acute hepatitis (s. tab. 5.16)

3 Acute viral hepatitis A

3.1 Definition

Acute viral hepatitis A is caused by an enterally transmitted RNA virus of 27 ( ⫺32) nm in diameter. It is self-limiting and usually self-healing, contracted by people lacking virus A antibodies ⫺ hence its prefer- ence for children. With good hygienic living standards, however, the tendency of infection shifts increasingly to adulthood. The disease seldom follows a biphasic or cholestatic course. A fulminant course of disease is very rare (ca. 0.01%). Transition into chronic hepatitis need not be feared. (s. p. 422!) There is no causative correlation with primary liver cell carcinoma. Healthy HAV carriers are not known. The disease leaves the patient with life-long immunity.

3.2 Pathogen

Up to now, one serotype has been identified. Seven genotypes of HAV are known to show serological cross-reactions. Three geno- types are deemed to be HAV strains, stemming from the simian virus. Recently, a new genotype 1 B variant was described. (43) By means of genotyping, it is possible to explain the geographic origin of the virus, the individual source of infection, etc. HAV since been characterized in greater detail. (74, 114) (s. p. 112!) (s. fig. 5.4!)

3.2.1 Inactivation

HAV survives for up to 3 months in freshwater or sea water. It is completely inactivated by heat at 75°C for 20 minutes or 85°C for

1 minute, but only partly inactivated at 60 °C for 4 hours. Boiling water (< 15 minutes) is not enough to inactivate HAV completely, particularly if the instruments have not been mechanically cleaned with due care prior to heating. Formalin (diluted solution, 37°C for 2 hours), β-propriolactone, sodium hypochloride and glutaraldehyde (2%) are suitable for inactivating HAV. • Alcohol, ether or acids (up to pH 3) do not inactivate HAV; the virus also remains stable down to ⫺70°C. (105)

3.2.2 Detection

Stools: With the aid of an electron microscope, HAV is detectable in the stools 7 to 11 days before the acute phase of disease begins.

The rate of detection in the 1

^st

week in no more than 50% of cases, in the 2

^nd

week about 29% of cases and in the 3

^rd

week merely 4%

of cases. After the 4

^th

week, HAV can generally no longer be found in the stools at all ⫺ by means of molecular hybridization (or PCR), PCR, however, it may be possible to detect the viruses up to 3 months following onset of the disease. In the event of clinical relapse, HAV is again apparent in the stools. (107) The presence of the virus (10

⁹

⫺10

¹¹

particles/g stool) clearly means infectiosity

⫺ yet a negative test does not definitely rule out infectiousness. It has hitherto not been possible to validate either the replication of the virus in stools or its permanent excretion. Some two weeks after the initial occurrence of dark urine, intestinal excretion of the virus has generally ceased, and in addition, patients are no longer infectious with respect to their environment.

Serum: At the same time as viruses are excreted in the stools, vir- aemia is apparent. The highest concentrations are found shortly before the onset of the disease (> 10

⁷

⫺10

⁹

particles/ml serum).

Using PCR, it was possible to show that viraemia can exist for longer than 3 weeks, and even up to 4 months.

Cells: The HA antigen is detectable as granular fluorescence in the

cytoplasm of the hepatocytes from the 2

^nd

week after infection,

about 1 week prior to excretion in the stools. HAV could also be

detected in the spleen and lymph nodes ( P. K arayiannis et al., 1986 ).

3.2.3 Replication

Replication of HAV is effected within the liver cell following its transportation into the interior via a

“receptor”: (1.) the capsid proteins are removed and the RNA is released; (2.) both are reproduced separately in the cytoplasm; (3.) new viruses are assembled from the RNA copies and the structural proteins; (4.) these viruses are packed into vesicles and released into the biliary pole; (5.) the viruses are excreted via the ductuli.

The viruses enter the bile by way of the ductules and are subsequently excreted into the bile and stool as early as 1 ⫺2 weeks before onset of the disease.

3.3 Transmission

Transmission of HAV is effected by a faecal-oral route.

The main danger, therefore, is poor hygiene, as is occa- sionally found in communal houses or flats, children’s homes, prisons, shelters for the homeless and homes for the mentally handicapped as well as among injecting drug users, etc. (45, 59, 73, 85, 91, 108) A similar danger prevails for those who are constantly exposed to mater- ial that contains viruses, such as sewage and water puri- fication plant workers (57) , medical personnel ( ⫽ noso- comial infection) (s. pp 428, 441) (70) , dentists (55) and staff in neonatal intensive care units. (97, 117) • An add- itional hazard exists in infected drinking water and foodstuffs, such as ice cubes, ice-cream, frozen strawber- ries and raspberries, raw bilberries, salads, green onions, raw milk, hamburgers, cold meat, bread, cakes and past- ries. (38, 43, 52, 66, 79, 80, 86, 90, 116) The warming up of food with microwave ovens (> 1 minute) has been shown to lower the risk of infection. (87) • Even chlorinated water in a swimming pool can serve as a vehicle for HAV infection. (82) Sexual transmission is rare, although an oral infection route may be responsible for infection in such cases, especially among homosexuals.

(47, 110) The hands, in particular, are vehicles of HAV transmission to animate and inanimate surfaces. (84)

HAV infection of an animal keeper at a zoo, transmitted for example by the apes he cares for, is accepted as an occupational disease. (100)

Oyster hepatitis: The ingestion of oysters cultivated in pools or harbour basins has led to oyster hepatitis (B.

R oos, 1956) . This is due to their mode of life: filtration of approx. 40 litres water/hr, whereby coliform bacteria are excreted again, leading to a 100-fold concentration of HAV. Usual boiling of oysters in water does not guaran- tee inactivation of such highly concentrated HAV. (54, 95) The terrible epidemic in Shanghai in 1988 caused a sensation, with 292,301 cases of disease (4,083 per 100,000 inhabitants) being registered. The infection was brought on by the ingestion of inadequately boiled Venus oysters (Anadara subcrenata Lischke). (63, 112) 䉴 Posttransfusion transmission was observed for the first time by T. F rancis (1946) and A. G. H arden (1955). In isolated cases (e. g.

collection of blood and blood plasma during viraemia), a haema- togenic mode of transmission is conceivable (65, 103) (see earlier observations of H. V oegt [30], S. K rugman et al. [17]). Infection of haemophiliacs from factor VIII preparations is likewise considered rare (61), as is infection in haemodialysis units. However, a total of more than 80 cases have actually been reported. • There have been no reports of perinatal infection.

3.4 Epidemiology

HAV is a ubiquitous virus, especially since it retains its stability in heat and cold under normal environmental conditions and is highly resistant to external influences.

The risk of infection correlates with a low standard of hygiene. For this reason, a 7 to 10-fold increase in fre- quency of the disease must be anticipated when travel- ling to certain countries (some 20 cases of infection out of 1,000 travellers per month). The risk of infection is even greater with so-called adventure trips (overland trekking, backpacking) in those countries. The same also applies to persons engaged in humanitarian or development projects. Given these factors, prior active vaccination is a necessity, unless immunity already exists. (78, 109)

The seasonal frequency of infection in the late autumn and winter, which used to be most pronounced in the wake of dry summer months (at least in northern latitudes), is less evident today. It is possible that closer physical contact resulting from unfavourable weather conditions played a part here ⫺ especially since such sea- sonal fluctuations were not observed in southern regions.

䉴 Recent decades have witnessed large-scale epidemics in several countries, generally caused by poor hygiene conditions and/or infected food or drinking water. (51, 63, 112) • This is also true of the great epidemics and pandemics with their impact on the battle fronts and across the frontiers during the Second World War: from 1939 ⫺1945, between 5 to 6 million German soldiers and 3 to 4 million civilians (i. e. about 13% of the German population at that time) contracted an HAV infection. These figures do not include the undoubtedly large number of unidentified anicteric courses of disease. • A wide-scale regrouping of troops had to be carried out as a result of the losses in manpower due to HAV infection, as I experienced myself when I likewise contracted the disease in Russia in 1942. (s. p. 414)

The infection rate among the population of a country correlates with age, hygiene standards, socio-economic status and individual risk factors (drug addiction, homosexuality, close contact with infected persons, etc.). Men and women are subject to the same frequency of infection, irrespective of age or race and seasonal or regional factors. • In Germany, there has been a rapid decrease in natural immunity, because far fewer juve- niles become infected with HAV today. Consequently, when people contract the infection at a more advanced age, there is a higher complication rate and greater mor- tality (2.7% vs. 0.004%).

3.4.1 Frequency of disease

The infection rate is established by determining anti-

HAV IgG in the serum. Prevalence depends upon the

epidemiological situation in a particular country. At

40 ⫺50%, Germany ranks in the middle, with a clear dependence on age: some 5% of eighteen-year-olds and about 75% of seventy-year-olds are positive. Currently, 30 ⫺40% of those older than fifty are HAV-negative in Germany. The infection rate is about 4 to 5 times higher than the number of cases actually registered. (56, 76)

3.4.2 Obligation for notification

Germany’s 4

^th

Federal Epidemic Control Act (1992) requires that all cases involving primary hepatotropic viruses (A, B, C and others) which result in disease or death are reported to the local Public Health Depart- ment. (s. tabs. 23.1, 23.2; 24.3; 25.1)

There has been a continuously declining tendency in the number of HAV cases in numerous countries as a result of improved hygiene and active vaccination. • In Ger- many, the following frequencies of HAV disease were registered ⫺ although the actual figures were probably much higher. (s. pp 426, 440)

1992 ⫽ 6,990 1998 ⫽ 3,811

1993 ⫽ 5,839 1999 ⫽ 3,131

1994 ⫽ 5,488 2000 ⫽ 2,820

1995 ⫽ 6,639 2001 ⫽ 2,274

1996 ⫽ 4,911 2002 ⫽ 1,479

1997 ⫽ 4,596 2003 ⫽ 1,365

Mortality in the same period (1992⫺2002) was as fol- lows:

1992 ⫽ 13 1998 ⫽ 9

1993 ⫽ 14 1999 ⫽ 13

1994 ⫽ 12 2000 ⫽ 11

1995 ⫽ 12 2001 ⫽ 17

1996 ⫽ 19 2002 ⫽ 11

1997 ⫽ 15 2003 ⫽ 4

3.5 Pathogenesis

In principle, differentiation is made between two phases: (1.) initial non-cytotoxic reaction with a high HAV replication rate and (2.) cytopathogenic reaction with low virus production, histological signs of inflammation and development of immunity. • Liver cell necrosis is caused by T lymphocytes (CD

^8⫹

) specific to the virus, with T cell-induced cytolysis occurring in the course of the immun- ological response. The virus is subsequently neutralized by anti- bodies. • Given the right predisposition, HAV is deemed capable of triggering autoimmune hepatitis. (96, 115)

3.6 Serological diagnostics

Direct detection of HAV and HAAg in the blood or stools is only necessary for scientific purposes. • Sero- logical diagnostics is based on the specific detection of anti-HAV IgM, the presence of which confirms acute viral hepatitis A. In differential diagnosis, it is necessary to rule out acute viral hepatitis E, with which anti-HAV IgM may likewise occur! Anti-HAV IgM rises in the serum during the first 2 weeks of the disease, i. e. 3 to 4 weeks after infection. It persists for about 2 or 3

months, and in single cases for up to 12 months (71) , with slowly diminishing titre values. A clinical relapse is usually accompanied by a renewed increase in anti-HA IgM; in protracted courses of disease, the drop in titre values is generally delayed. • A rise in anti-HAV IgG is observed four to six weeks after infection. This finding points to a subsiding HAV count or one which has long since run its course. The IgG specific to the virus per- sists for a lifetime and reflects the HAV immunity of the carrier (and the infection rate of the population or community). (78) (s. p. 113) (s. fig. 5.5)

The mere detection of anti-HAV only implies the pres- ence of virus-specific IgG or IgM and offers no infor- mation on acuity or immunity. For this purpose, it is necessary to determine the antibodies of the IgG or IgM. Maternal HA-antibodies pass to the foetus via the placenta and provide the infant with postnatal immunity for a certain period of time. The most sensi- tive method of detecting hepatitis A is by RT-PCR.

HAV-RNA can also be detected with high sensitivity using molecular hybridization (up to approximately 10

⁴

copies per ml).

3.7 Stages of disease Incubation period

The period of time between HAV infection and the manifestation of symptoms ranges from 15 to 49 days, the mean period varying between 25 and 30 days. A shorter incubation period is often accompanied by a severe course of disease, i. e. fluctuations in the period of incubation depend on the respective quantity of the virus uptake and on the individual immune response.

Prodromal stage

Generally, the onset of the prodromal stage is charac- terized by nausea, vomiting, lack of appetite, a feeling of repletion and diarrhoea (or constipation), followed by weakness, fatigue, fever, headaches, itching, sore throat, painful joints, impaired sense of smell and taste, light sensitivity and coughing ⫺ in various degrees of intensity and frequency. These symptoms often take the form of a “febrile influenzal infection”. In children and juveniles, the “gastrointestinal” symptoms predominate, whereas adults more frequently present with jaundice as well as aching joints and muscles.

Clinical stage

In approx. 90% of all patients, acute viral hepatitis A is

subclinical, i.e. it frequently goes undetected. The end

of the prodromal and the beginning of the clinical phase

is indicated by a brown colouration of the urine. Urobili-

nogenuria persists for a longer period of time than bili-

rubinuria. Mild proteinuria and microhaematuria can

develop. Stools are usually acholic. • With the occurrence

of jaundice (60 ⫺70% children, 80⫺90% adults), most of

the subjective symptoms of the prodromal stage subside,

whereas fever and exanthema often occur. There is evi- dence of hepatomegaly in 70 ⫺80% of cases (whereby the liver is sensitive to pressure due to capsular distension and has a soft consistency) and splenomegaly in 20 ⫺30%, more rarely also cervical lymphadenopathy (10 ⫺20%). • Children often show a moderate or asymp- tomatic course.

From the end of the incubation period, laboratory parameters show a rise in LDH as an expression of viro- cyte duplication. They reach their maximum value in the prodromal stage and decline from the beginning of the icteric stage. • Already in the prodromal phase, the indicator enzymes GPT, GOT and GDH begin to rise, the increase in GPT being evident at an earlier point (“liver cell damage”) and that of GOT somewhat later.

The transaminase values (usually between 800 ⫺1,200 U/l GPT and 500 ⫺700 U/l GOT) do not necessarily correlate with the degree of severity. In approx. 95% of cases, the transaminases show one peak. Generally, the DeRitis quotient is < 1 (“inflammation type”). (s. p. 95) (s. tab. 5.6) (s. fig. 5.5) The y-GT rises until the end of the icteric phase and then recedes to the normal range at a slower rate than the indicator enzymes ⫺ also reflecting regeneration of the liver cells. (s. p. 97) A rise in serum iron is always an expression of liver cell dam- age. (s. p. 98) The AP and LAP only increase minimally.

Conjugated bilirubin is elevated, where the bilirubin values ⫺ and to a far greater extent the duration of the jaundice ⫺ correlate with the degree of morphological severity. IgM in the serum is clearly higher. The haemo- gram initially reflects leucopenia and lymphopenia, the latter often developing into relative lymphocytosis with the production of atypical lymphocytes. All other par- ameters (electrophoresis, Quick’s value, cholinesterase, autoantibodies, etc.) are normal. Zinc and selenium, which are important for the body’s own defence, are often reduced; copper levels are elevated. (71) Viraemia may be longer-lasting than previously assumed: HAV RNA is detectable about 17 days before GPT increases and several days before HAV IgM appears. Viraemia persists for an average of 79 days after GPT increase, i.e. the main duration of viraemia is 95 days. (41)

Convalescence phase

The icteric phase lasts for some 2 to 6 weeks. Labora- tory parameters become completely normalized after 4 to 6 months. Normalization of the serum bile acid is also deemed to be a reliable parameter of recovery. The regression phase is often characterized by pronounced diuresis. (56, 76, 113)

3.8 Extrahepatic manifestations

Extrahepatic manifestations have repeatedly been de- scribed in viral hepatitis A. (78) They can complicate the course of disease and cause considerable clinical diffi- culties. (s. tab. 22.2)

Acute renal failure (60, 93, 120) Aplastic anaemia

Arthralgia (68) Ascites (48, 77)

Cholecystitis (39, 88, 92) Cryoglobulinaemia (67, 68) Encephalitis (64)

Exanthemas

Guillain-Barre´ syndrome (42) Haemolysis (81)

Myalgia

Pancreatitis (50, 75, 104) Pleural effusion (106) Purpura (44)

Thrombocytopenia (44) Urticaria (102) Vasculitis (49, 67, 68)

Tab. 22.2: Extrahepatic manifestations with acute viral hepatitis A (with some references) (s. tabs. 22.7, 22.8)

3.9 Clinical courses of disease

䉴 Acute viral hepatitis A usually pursues an uncompli- cated course (in children mostly mild or asymptomati- cally) and heals without sequelae (90 ⫺99%). About 13%

of the elderly patients need clinical therapy. • Neverthe- less, some particular courses of disease are worth men- tioning:

Cholestatic course

Characteristic of this course of disease ⫺ mainly in elderly patients

⫺ are the greatly increased bilirubin values (15⫺30 mg/dl) lasting between 2 ⫺5 months, accompanied by elevated AP (and LAP) val- ues. Transaminase activity is relatively low (generally below 500 U/

l). Clinical symptoms include itching, fever, malaise, bradycardia and a loss of weight. This complicated course of disease finally heals without sequelae. (46, 49, 62, 64, 101, 118) (s. pp 416, 432) (s. fig. 22.4)

Fulminant course

Very rarely (0.01%), albeit more frequently in elderly patients and people with a compromised immune system (0.1 ⫺1.0%), viral hepatitis A takes a fulminant course. About 1.0% of all cases of fulminant viral hepatitis are caused by HAV. The survival rate is

> 90%. (53, 83) (s. pp 377, 433)

Protracted course

Delayed courses of disease lasting between 6 and 18 months (2 ⫺3%) have been observed repeatedly (also by us in three cases).

The frequency is estimated at 5 ⫺20%. (101) (s. p. 432) • This pro- tracted course of HAV infection can, however, be a sporadic, recur- rent HEV infection, since HAV IgM also reacts positively here! •

With both a protracted as well as a cholestatic course, thought must always be given to the combination of acute viral hepatitis with the Dubin-Johnson syndrome when drawing up a differential diagnosis. In one protracted and cholestatic case, we observed that it was ultimately the typical histological finding which produced the diagnosis. In such cases, percutaneous biopsy is essential for differential diagnosis. (s. pp 223, 415) (s. fig. 12.1) Generalized lym- phadenopathy can be considered as a marker of ongoing inflam- mation. (89)

Anicteric (subclinical) course

The anicteric course is mainly found in children. However, it gen-

erally remains unidentified due to the multifarious complaints. For

this reason, the condition can give rise to a chain of infections,

particularly in nursery centres and schools. (94) (s. pp 416, 432)

Recurrent course

For reasons that cannot be explained (reinfection? reactivation?), relapse occurs in 5 ⫺15% of cases, especially in children. There may be renewed HAV excretion in the stools (with the danger of infec- tion for the environment) and a more pronounced increase in anti- HAV IgM in the serum. The clinical course is usually milder than in the first phase of the disease, yet is more frequently accompa- nied by cholestasis and extrahepatic manifestations. Despite this relapse, the disease heals completely. (40, 107)

Chronic course

䉴 A report on the (possibly) first case of acute hepatitis A developing into chronic active hepatitis (CAH) and cirrhosis has already been published. (69)

3.10 Formation of granulomas

As with various viral, bacterial or parasitic diseases, with Hodg- kin’s disease or after the intake of allopurinol, etc. (s. tab. 21.1), acute viral hepatitis A can be accompanied by intrahepatic fibrin- ring granulomas. (99)

3.11 Prophylactic measures

In principle, consideration has to be given to any meas- ure that prevents faecal-oral HAV infection, e. g. correct hygiene procedures ⫺ particularly in risk situations.

Generally, for water and food, is required: “Cook it, peel it or forget it!” This includes the (worldwide) purifica- tion of drinking water and the operation of reliable sew- age plants. (45, 47, 73, 78)

3.11.1 Passive immunization

Passive immunization by means of standard immuno- globulin (J. S tokes et al., 1945) requires an absence of HAV antibodies. The detection of anti-HAV renders immun- ization superfluous. Such protection is temporary, last- ing approx. 2 ⫺4 months. It is effective as both a pre- exposure measure (almost to 100%) and postexposure measure (in over 80% up to 14 days after exposure and possible infection). Passive immunization should also be given to pregnant women who have been exposed to infection. • Immunization is indicated to protect HAV- antibody-free persons in their contact with diseased per- sons or prior to a stay in high-risk regions. The immun- ization of antibody-free persons also makes it possible to develop a temporary protective ring of immunity, preventing the infection from spreading when diseased persons are being cared for. This so-called vaccination seal is recommended for families and schools or insti- tutions where there is close physical contact. Such pass- ive immunization should be extended to simultaneous vaccination as well. (45, 58, 80, 111)

Immunoglobulin A: The specific human immunoglobulin A is injected i.m. deeply at body temperature (0.02 ⫺0.06 ml/kg BW).

With continued exposure, it is necessary to repeat the injection after 6 ⫺8 weeks. Because of the known HAV IgG content, the effect is better and lasts longer than with standard immuno- globulin, in particular since batches of immunoglobulin can differ

in antibody titre. Approximately 1% of vaccinated persons display side effects in the form of fever, rash, aching joints or local sore- ness at the site of injection. All of them are without consequence and disappear rapidly. There are no contraindications. • Should a pregnant woman be suffering from an acute HAV infection at the time of delivery, the newborn should be immunized simul- taneously.

3.11.2 Active vaccination

Active vaccination (P. J. P revost et al., 1975) with an HAV live vac- cine as well as with an inactivated HAV vaccine has produced a higher antibody titre as well as a longer period of efficacy than passive immunization.

The usual commercially obtainable vaccine is highly immunogenic and low in side effects. The former 3-phase administration (i.m.) with a single dose of 720 IU can be replaced by a 2-phase admin- istration (i.m.) at zero and 6 ( ⫺12) months with a single dose of 1,440 IU. On average, an antibody titre of > 4,000 IU/l is reached.

Given an annual drop in the titre of 14%, a period of protection of some 10 years can be expected. The vaccine protection expires at about 20 IU/l, which is why a booster inoculation ought to be carried out in due course. An immunity of almost 100% is achieved.

By controlling the antibody titre, the time point for a booster inoc- ulation can be established. The success rate is highest among youn- ger people (under 40 years). If protection has to be provided sooner, both injections may be administered within a period of 2 weeks. Side effects are very rare and without consequence, and disappear rapidly (tendency to diarrhoea, nausea, slightly in- creased transaminases, local soreness). (58, 72, 80, 98, 119)

The indications for active inoculation are (1.) people who are planning a stay in areas with a high HAV infec- tion risk, (2.) those who are working in such areas or have close contact with HAV sufferers (including clean- ing and kitchen staff in medical facilities), (3.) homosex- uals, and (4.) patients with severe or chronic HAV-nega- tive liver disease, since a superimposed HAV infection can result in a life-threatening situation.

In principle, hepatitis A inoculation should be a routine measure already carried out in childhood.

3.11.3 Simultaneous vaccination

In a situation in which rapid protection is required and at the same time long-term immunity is to be established as well, it is possible to carry out an active-passive vac- cination with immunoglobulin A and active vaccine A.

This is also indicated in the case of a newborn if the mother was suffering from acute viral hepatitis A during pregnancy. After the 3

^rd

inoculation with vaccine, all individuals displayed a good formation of antibodies to HAV.

3.12 Therapy

A causal therapy (with antiviral agents) is not yet pos-

sible. • Bed rest is usually kept in line with the situation

of the patient and, as with other acute diseases, is

recommended. • With inadequate oral intake, the substi-

tution of fluid, calories (glucose infusions), electrolytes,

trace elements and (water-soluble) vitamins is advisable.

Cholestyramine may prove necessary for severe pruritus due to a cholestatic course of disease (4 ⫺8 g prior to breakfast) ⫺ if antihistamines were unsuccessful. With such a cholestatic course of disease, the application of ursodeoxycholic acid (2 ⫺3 ⫻ 250 mg) is most suitable.

(166) In some cases with a fulminant course, interferon alpha has been successfully used. “Special diets”, gluco- corticoids or other medication are not necessary.

4 Acute viral hepatitis B

4.1 Definition

A 42 nm DNA virus causes acute liver inflammation, which heals in the majority of cases; in 5 ⫺15% of cases, it becomes chronic or develops into a long- term virus carrier status. Occasionally, posthepatitic cirrhosis may occur, and there is a close correlation with the development of primary liver cell carcinoma.

4.2 Pathogen

The hepatitis B virus (HBV) belongs to the hepadna virus group. • This includes e.g. woodchuck hepatitis virus (WHV) and ground squirrel hepatitis virus (GSHV) (⫽ orthohepadnaviruses) as well as Peking duck hepatitis virus (DHBV), and heron (HHBV) (or crane [CHBV]) hepatitis virus (⫽ avihepadnaviruses).

(205, 206, 217, 220, 224, 230, 261)

There are at least 7 genotypes of HBV (A⫺G). Serologically, 9 subtypes of HBsAg can be distinguished, all of which have compo- nent “a” in the main HBsAg. HBV can only infect mature hepato- cytes in humans and chimpanzees. HBV DNA is a direct param- eter of viral replication and infectivity, with a magnitude of 10

¹¹

to 10

¹³

per day; replication of HBV is extremely high. It is possible to detect 10 ⫺100 viruses/ml using PCR. (119, 137, 164, 173, 188, 189, 199, 232, 239) • (s. p. 113!) (s. figs. 5.6, 5.9!)

4.2.1 Inactivation

Viruses are only deemed to be definitively inactivated once their nucleic acid has been irreversibly changed.

This can be determined with electron microscopy or by a negative PCR. The individual types of virus may differ considerably in terms of morphology and biochemistry, so that the efficacy of disinfectants can vary greatly, both in mode and degree. Hepatitis B viruses number among the most resistant types of virus. This is why the hepatovirucide potential of a disinfectant is largely considered to be a criterion of its general effectiveness.

Hepatovirucidal substances such as aldehyde derivatives, chlorine preparations (as long as chlorine is released at a low pH), glyoxal, n-propanol and iodine have proved to be effective. Virus destruc- tion is also achieved by heating (e.g. 100°C >10 minutes, or hot air 180 °C >2 hours, or steam 120°C >20 minutes at 1 bar). Just as effective in inactivating a virus is the boiling of instruments or equipment in a soda solution for 15 minutes. As far as possible,

linen should be disinfected by boiling, e.g. in an alkaline solution (pH 9 ⫺10 >30 minutes). Linen which cannot be boiled should be decontaminated by soaking for 12 hours in a 16% aqueous solution of formalin or in a 1.5% chloramine-T solution. Crockery and cut- lery should be boiled in a soda solution (> 15 minutes) or soaked in either commercially available aldehyde compounds (2% > 1 hour) or compounds of aldehyde glyoxal and ethylhexonal glyoxal (5% > 15 minutes). The careful cleaning of instruments prior to sterilization ⫺ any remaining blood must be removed ⫺ is of great importance. Instruments sensitive to heat are sanitized by gas steri- lization using ethylene oxide or placed in a 3% formalin solution for 6 hours. Endoscopes are sterilized by immersion in a commer- cially obtainable virucide disinfectant, by an ultrasound immersion method or in an endoscope disinfector. Frequent hand washing with soap (ca. 3 minutes) and subsequent disinfection using an ordinary commercially obtainable preparation (approx. 2 minutes) is deemed adequate (yet not reliable). • Reference should be made here to recognized disinfecting agents and procedures listed in the official guidelines of the individual countries.

4.2.2 Pathogenesis

Virus docking: According to current knowledge on pathogenesis, virus docking with the liver cells ensues directly via specific recep- tors (e. g. pre-S1 domain). This capsid protein, which contains HBV DNA, is transported into the cell nucleus with the help of a nuclear, localization signal. Now the development of the complete Dane particle starts, and the new viruses are secreted from the hepatocytes by the Golgi apparatus. About 5 x 10

¹³

viruses are produced per day. It is possible that new therapeutic paths could be opened up by using specific peptides to prevent the virus from docking with the target cell or to stimulate the antibody response.

The uptake of the virus is effected by endocytosis; the virus DNA reaches the cell nucleus.

Hepatocytolysis is caused by the cellular immune response to virus- coded or virus-induced antigens of the liver cell membrane. HBV itself is not directly cytopathogenic. The T lymphocytes are of prime importance for the cellular immune response to HBcAg (or HBeAg) at the liver cell membrane. The density of the virus deter- minants at the liver cell surface and the concentration of the anti- gens, determined by the human leucocyte antigen complex, are significant. Genetic factors and the individual endogenous pro- duction of interferon also influence hepatocytolysis. The virus par- ticles released by lysis are fixed by humoral antibodies and then phagocytized. (214, 221, 232)

4.3 Antigens and antibodies

HBsAg is coded by the pre-S gene. Pre-S

1

and pre-S

₂

antigens are detected in high concentrations in the serum. HBV expresses three forms of HBsAg: large (l), medium-sized (m) and small (s) proteins. Small HBsAg is the main component of mature HBV. (appr. 90%) (153)

In uncomplicated courses of disease, the elimination of

these surface antigens is generally achieved well in

advance of the decrease in the HBsAg titre. The elimin-

ation of HBsAg can be swift but also delayed and is

usually effected within 2 ⫺4 months. Smooth endoplas-

mic reticulum containing HBsAg is histochemically

detectable by orcein or aldehydethionine staining. How-

ever, this is only true for half of the hepatocytes. HBsAg

can also be detected in the liver cells by fluorescence

microscopy. The affected hepatocytes have no prefer-

ence for a particular site in the liver lobule. Nor is there

any correlation with the respective HBsAg serum titre.

Histologically, the HBsAg-containing hepatocytes have the appearance of so-called ground glass cells ^{(S. H} adzi- yannis et al., 1973) . (163) (s. figs. 5.7; 22.8) (s. pp 114, 396)

Fig. 22.7: HBsAg in the cytoplasm of hepatocytes (arrows) (s. fig.

5.7). Clinically: HBsAg carrier (former drug abuse) with moder- ately increased transaminases (immunoperoxidase reaction). These findings correspond to the so-called ground glass cells in HE (s.

figs. 5.7; 22.8)

HBeAg is cleared from the serum in acute disease after several days or a few weeks. The significance of HBeAg has not been clarified (viral persistence?). It is not neces- sary for HBV replication. It is considered to be a break- down product of HBcAg and, in conjunction with HBsAg and HBV DNA, determines the infectivity of the patient. The seroconversion of HBeAg to anti-HBe does not guarantee the active elimination of HBV in all cases, since viruses can still be detected by PCR in clin- ically healthy carriers of anti-HBe. In these cases, a decrease in the titre of anti-HBe is generally accom- panied by a reduction in the remaining virus load. Anti- HBe can persist for 10 ⫺20 years, even lifelong. Negativ- ity of HBeAg can be a sign of the formation of mutants due to the occurrence of a stopcodon (TGA) between the pre-core and core region. As a result, HBeAg cannot be produced. Infections with HBeAg-negative mutants usually show a high-replicative course. (137, 138, 182) (s.

p. 425) (s. tab. 22.3)

HBcAg is not detectable in the serum, yet can be demonstrated by immunofluorescence in the nuclei of the hepatocytes. (s. fig. 22.8) The excessive formation of intranuclear HBcAg is occasionally expressed in the form of a microvesicular, eosinophilic brightening of the karyoplasm and a shift of chromatin to the core membrane.

As a result of the metabolic strain on the liver cells due to the viral infection, functional core swelling occurs, subsequently leading to enlargement as well as basophilia of the nucleolus. HBcAg can be seen in the affected cores as an even, dense, finely granulated fluorescence. HBsAg and HBcAg are detectable in the liver cells both together and separate from one another. With serologically unresolved chronic hepatitis, the demonstration of HBsAg and HBcAg in the liver cells can bring clarity to the clinical picture.

Anti-HBs is found in the serum just 2⫺3 months after infection (“diagnostic window”) and probably remains detectable for life (due to mild, continuous boosting from persistent hepatitis B viruses?). It guarantees

Fig. 22.8: Immunohistochemical detection of HBcAg in the nuclei of liver cells shown by monoclonal antibody. Hepatocytes with ground glass-like homogenization of the cytoplasm, so-called ground glass cells (arrow). HBsAg in the cytoplasm is not pre- sented immunohistochemically in this case (s. figs. 5.7; 22.7)

immunity to HBV infection. Patients with anti-HBs titres are generally also anti-HBc-positive. Some 10 ⫺15% of hepatitis B patients form no anti-HBs. In previous infections which date back a long time, titre levels can fall below the detection threshold. About 2%

false-positive values are measured in the serum. (s. p.

114)

Anti-HBc IgM is the earliest immunological response of the body to HBV antigens. It is the most reliable marker, and once the disease is overcome, it can probably be demonstrated lifelong as anti-HBc IgG. In chronic hepa- titis B carriers, low titre anti-HBc IgG may also be pre- sent. It is the most suitable marker for the HBV contam- ination rate of a population (more reliable than anti- HBs). The absence of HBsAg and anti-HBc IgM rules out acute HBV infection. In healthy patients who test positive for anti-HBc, latent viral replication is usually still to be found. This can be detected with the help of PCR. Active vaccination does not result in positive anti- HBc IgM. (s. p. 114)

HBxAg: The significance of the smallest coded region of the HBV genome (17 k Da) ⫺ as well as of its protein, which comprises 154 amino acids ⫺ is still unclear. It is deemed to be an early marker of acute hepatitis B. HBx reinforces the replication of HBV in the liver cell. It has possibly something to do with the development of liver cell carcinoma, especially since it is most prevalent in HBV-related liver cirrhosis and even in liver cell car- cinoma. (146, 212)

Serological markers of the HBV antigens and anti- bodies facilitate reliable diagnostic and prognostic statements as well as an evaluation of the existing infectivity of the patient. (138, 188) (s. pp 112 ⫺116) (s.

tab. 5.17) (s. fig. 5.9)