Clinical Aspects of Liver Diseases 35 Liver cirrhosis

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35 Liver cirrhosis

Page:

1 Definition 716

2 Classification 716

2.1 Aetiological classification 716

2.2 Morphological classification 717

2.2.1 Liver size 717

2.2.2 Regeneration nodes 717

2.2.3 Progression 718

2.2.4 Completion 719

2.2.5 Pathogenetic development 720

2.2.6 Postdystrophic cirrhosis 720

2.2.7 Necrosis, fibrogenesis, regeneration 720

2.2.8 Morphological diagnostics 720

3 Epidemiology 720

4 Aetiology 720

5 Clinical classification 722

6 Diagnosis 723

6.1 Anamnesis 723

6.2 Complaints 723

6.3 Clinical findings 724

6.4 Laboratory findings 724

6.5 Imaging procedures 725

6.5.1 Sonography 725

6.5.2 Colour-encoded duplex sonography 726

6.5.3 Computer tomography 726

6.5.4 Magnetic resonance imaging 726

6.5.5 Radioisotope scanning 726

6.6 Liver biopsy and laparoscopy 726

6.7 Endoscopy 727

7 Prognostic classification 727

8 Differential diagnosis 728

9 Consequences and complications 728

9.1 Negative energy balance 728

9.2 Carbohydrate metabolism disorders 728

9.2.1 Hypoglycaemia 729

9.2.2 Hepatogenic diabetes mellitus 729

9.2.3 Glycogenolysis disorders 729

9.3 Protein metabolism disorders 729

9.3.1 Catabolism 729

9.3.2 Amino-acid imbalance 729

Page:

9.4 Lipid metabolism disorders 730

9.5 Hypovitaminoses 730

9.6 Endocrine disorders 730

9.7 Bacterial and viral infections 731

9.8 Hepatic osteopathy 731

9.8.1 Definition 731

9.8.2 Frequency 731

9.8.3 Pathogenesis 731

9.8.4 Clinical symptoms 732

9.8.5 Treatment 732

9.9 Hepatic encephalopathy 732

9.10 Ascites 733

9.11 Pleuropulmonary complications 734

9.11.1 Hepatopulmonary syndrome 734

9.11.2 Portopulmonary hypertension 735

9.11.3 Hydrothorax 736

9.12 Gastrointestinal bleeding 736

9.12.1 Portal hypertensive gastroenteropathy 736

9.12.2 Oesophagofundal varices 737

9.12.3 Ectopic varices 737

9.12.4 Anorectal varices 737

9.13 Febrile phases of disease 737

9.14 Cholelithiasis 738

9.15 Hepatocardiovascular syndrome 738

9.16 Hepatocellular carcinoma 739

10 Prognosis 740

11 Treatment 740

11.1 Causal treatment 740

11.2 Treatment of pathogenic reactions 741

11.3 Treatment of progression 741

11.4 Symptomatic treatment 741

11.4.1 Nutrition 741

11.4.2 Physical activity 742

11.4.3 Psychological guidance 742

11.4.4 Drug therapy 743

11.5 Monitoring 744

11.6 Liver transplantation 745

앫 References (1⫺205) 745

(Figures 35.1 ⫺35.17; tables 35.1⫺35.8)

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䉴

^A retaeus

(2^nd century AD) coined the term “skirros”, because he thought that inflammation of the liver led to its

hardening (ⴝ skirros). •

In 1543

A. V esal

described the granula- tion of the liver surface as being responsible for the compres- sion of the small hepatic vessels. Even at that time, he associ- ated these changes, which were thought to accompany a shrinking of the liver, with alcohol consumption.

•

When

J. P osthius

(1590) described ascites, he said that the changed liver was “all granulated inside”. A drawing by

J. B rown

(1685) shows coarse nodular liver cirrhosis.

G. B. M orgagni

(1761) also wrote a treatise on cirrhosis, in which he described the small vessels as being compressed due to a shrinking and hardened liver.

M. B aillie

(1818) wrote an excellent description of the morphology of liver cirrhosis and, like

A. V esal

, he also pos- tulated a causal connection with excessive alcohol consumption.

•

The first accurate report on atrophic, portal cirrhosis was given by

R. T. H. L aennec

(1819) as an incidental inclusion in his book «Traite´ d’auscultation». Because of the

yellow colour of the liver (ⴝ kirros), he coined the term cirrhosis. •

The first microscopic examinations were carried out by

F. K iernan

(1833),

R. C arswell

(1838) and

E. H allmann

(1839).

F. T h

.

F re- richs

differentiated between two stages of the cirrhotic course:

the stage of inflammation and the stage of shrinking with formation of nodes. In 1911

F. B. M allory

defined cirrhosis as a

“chronic, destructive, progressive process” with regeneration, accompanied by scarring and shrinking of the connective tissue.

A. G hon

(1928) recognized the transformational processes in the liver as being an essential feature of cirrhosis.

•

In 1930

R. R össle

provided a morphological definition of cirrhosis by stat- ing

three criteria: (1.) destruction of liver parenchyma, (2.) con-

nective tissue proliferation, and (3.) nodular compensatory hyperplasia together with regeneration of liver parenchyma. In the following years, a

fourth criterion was added: (4.) distur-

bance of the intrahepatic vascular system with consecutive formation of arteriovenous and portovenous anastomoses

(H. T ha- ler, 1952, 1957, 1968

;

H. P opper et al., 1958

;

P. P. A nthony et al., 1977

;

A. M. R appaport, 1980)

.

1 Definition

Cirrhosis is a gradually developing, chronic disease of the liver which always involves the organ as a whole. It is the irreversible consequence and final stage of various chronic liver diseases of different aetiology or the result of long-term exposure to vari- ous noxae. • The extent of the morphological changes depends on the cause and stage of cirrhosis. Accord- ingly, there is a wide spectrum of morphological find- ings and clinical symptoms. The variations of this dis- ease range from symptom-free conditions, non- characteristic complaints and different laboratory findings through to life-threatening complications.

Since, in most cases, no clear dividing line can be drawn between cirrhosis and the preceding liver dis- ease, it is very difficult to determine the point where the cirrhotic stage begins; as a rule, the transition is fluent.

䉴 Localized transformation processes such as those observed in scarred liver (s. p. 405) are not considered to be cirrhosis. The loss of parenchyma in scarred liver is generally the result of reduced blood supply in the respective area. Deep-set scars create the picture of a funnel-shaped liver (s. p. 406). Similarly, pronounced liver fibrosis (s. p. 405) does not fulfil the criteria of cir- rhosis, since the lobular architecture as well as the intra- hepatic and intra-acinar vascular supply are uncompro- mised. While fibrosis constitutes a precirrhotic stage, it does not necessarily progress to cirrhosis itself. Fibrosis can regress! • Thus, liver cirrhosis is characterized by the following five criteria:

1. Pronounced, insufficiently repaired necroses of the parenchyma (with or without inflammatory pro- cesses)

2. Diffuse connective tissue proliferation

3. Varying degrees of nodular parenchymal regener- ation

4. Loss and transformation of the lobular structure within the liver as a whole

5. Impaired intrahepatic and intra-acinar vascular supply

2 Classification

Definitive classification of cirrhosis is difficult. It can be categorized according to its (1.) aetiology, (2.) morph- ology, (3.) pathogenetic development, and (4.) clinical features.

2.1 Aetiological classification

Classification of cirrhosis according to its aetiology would be desirable, as this approach may help determine prophylactic and therapeutic measures as well as prog- nosis. If all diagnostic options are employed and the patient cooperates optimally, an aetiological identifica- tion of cirrhosis is possible in almost all cases today. • Due to improved detailed diagnostics, the group of so-called cryptogenic cirrhoses has been consistently reduced (< 10% of cases). (s. tab. 35.2)

However, classification of cirrhosis based on aetiology

is limited for several reasons: (1.) the cause of cirrhosis

cannot be determined in many cases, (2.) a certain

cause gives rise to different morphological forms in

individual patients, (3.) there may be several causes

for the same form of cirrhosis, and (4.) various causes

may frequently coincide in diverse combinations.

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2.2 Morphological classification

Cirrhosis is an alteration which affects the whole liver. It is characterized by septa-forming fibrosis and the transformation of the lobular/acinar architecture into insular or nodular parenchyma.

Up to now, the classification of cirrhosis according to its morphology has met with the most approval.

⁽¹⁰⁾

Classification is based on: (1.) liver size, (2.) size of the regeneration nodes, (3.) fine-tissue structure, (4.) pro- gression, and (5.) completion of cirrhosis. (s. tab. 35.1)

(10, 179)

(see chapter 21.5.2)

I.

Size of liver

1. Normotrophic cirrhosis 2. Hypertrophic cirrhosis 3. Atrophic cirrhosis (s. fig. 35.1) II.

Size of regeneration

1. Fine-nodular (granular) cirrhosis (s. fig. 28.13) 2. Coarse-nodular (nodular) cirrhosis (s. fig. 35.2) 3. Coarse-bulbous (lobular) cirrhosis (s. fig. 35.3) 4. Mixed-nodular cirrhosis (s. fig. 35.6)

5. “Smooth” cirrhosis (s. fig. 14.3) III.

Structure of the fine tissue

1. Multilobular (multiacinar) cirrhosis 2. Monolobular (monoacinar) cirrhosis 3. Mixed forms

IV.

Progression of cirrhosis

1. Active (⫽ progressive) form 2. Inactive (⫽ stationary) form V.

Completion of cirrhosis

1. Complete form 2. Incomplete form

3. Incomplete septal cirrhosis

Tab. 35.1: Criteria for the morphological classification of cirrhosis (see chapter 21.5.2)

2.2.1 Liver size

Liver size is determined by sonography (or CT). In cir- rhosis, it varies from case to case and presents as hepato- megaly, normal-sized liver or atrophy. There may even be deviations due to a disproportion between the two lobes resulting in asymmetric enlargement or reduction in size. Usually, there is more functional parenchyma pre- sent in hypertrophic or normotrophic cirrhosis than in atrophic cirrhosis. The majority of cirrhoses are assigned to the atrophic group. A progressive reduction in liver size tending towards atrophy is to be interpreted as a prognos- tically unfavourable sign, particularly when the trans- aminase values decrease to a subnormal level. Deter- mination of the liver size enables the course of disease to be evaluated in terms of the remaining parenchymal mass or its potential for regeneration.

Atrophic cirrhosis as described by

^{R. T. H. L}aennec (1819)

was compared with hypertrophic cirrhosis as described by

A. Gubler (1853)

and

P. Olivier (1871)

; the latter condition was identified as biliary cirrhosis by

V. Hanot (1875)

.

2.2.2 Regeneration nodes

While the formation of nodes is a typical finding on the liver surface (s. figs. 28.13; 35.2 ⫺35.4), in sectional prep- arations (s. fig. 35.5) and under the microscope (s. fig.

35.4), it is not an obligate criterion. It is hardly recog- nizable in many cases, such as in haemochromatotic, bil- iary and alcoholic cirrhosis. • Smooth cirrhosis, showing a smooth liver surface despite complete transformation, is likewise found; it is micronodular and poor in fibres.

(s. fig. 14.3)

䉴 Proliferation is characterized by enlarged cells with great variability in the size of the nuclei (⫽ anisonucleosis), occurrence of hepatocytes with 2⫺3 nuclei and cell plates of varying thickness. The parenchyma which has remained undamaged is capable of regenerative proliferation. The vulnerability of the acinus structure is the prerequisite for the criterion “transforma-

tion”, and the tendency to proliferate is the criterion for

“nodes”. •

The

blood vessels are also involved in this process:

(1.) reduction in the distance between presinusoidal and post- sinusoidal vessels, (2.) development of shunts, and (3.) forma- tion of a perinodular plexus

(E. G audio et al., 1993)

. This plexus consisting of arterioles guarantees the arterial blood supply within the nodes. Due to the displacement effect of the nodes, arterial vessels also become compressed. This is particularly critical since the cirrhotic liver is almost exclusively supplied by arterial blood, so that some areas become increasingly hypoxic and are thus more prone to coagulation necrosis. This happens mainly under conditions of circulatory collapse caused, for instance, by haemorrhage or toxicosis.

•

In contrast, a very favourable local arterial blood supply may lead to the formation of

gigantic regeneration nodes similar to “proliferations”.

(s. fig. 35.1)

Fig. 35.1: Atrophic liver cirrhosis with pronounced, thick capsule

callosity. Gigantic regeneration node “proliferating” from the underside of the right liver lobe, displacing the (duplicated!) gall bladder

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The following forms of cirrhosis are differentiated according to the size of the regeneration nodes: (1.) micronodular (granular), (2.) coarse-nodular (nodular), (3.) coarse-bulbous (lobular), and (4.) mixed-nodular.

The classification into granular, nodular and lobular forms was proposed by

A. H. Baggenstoss et al. (1952)

. Despite complete transformation processes, cirrhosis with a smooth surface, completely or largely without intrahepatic nodes, is occasionally found. Various syno- nyms have been used for this kind of classification according to the type and size of the nodes.

(quot. 88, 90)

Macronodular cirrhosis: In multilobular cirrhosis, the nodes develop from parts of several lobules or from larger parenchymal areas with intact lobular architec- ture. This group with nodes of > 0.3 cm up to the size of a walnut is also called postnecrotic cirrhosis or Nagayo type A

(M. Nagayo, 1914)

. The liver is predom- inantly atrophic. The pseudolobules contain parts derived from several acini ( ⫽ multiacinar or multilobu- lar cirrhosis). Portal fields and central venules are pre- sent, however, in an abnormal topography. (s. fig. 35.2)

Fig. 35.2: Complete, coarse-nodular liver cirrhosis due to chronic

viral hepatitis B

A special form is incomplete septal cirrhosis; it is found especially as a result of chronic hepatitis B or in Wege- ner’s granulomatosis.

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The thin septa, which invade the parenchyma from the portal fields, contain no or only very few inflammatory infiltrates ( ⫽ passive septa).

(s. p. 407) • Lobular coarse-bulbous cirrhosis can likewise be assigned to this group, which, as posthepatitic cirrho- sis, is also called Nagayo type B or may be referred to as Marchand’s hyperplasia

(F. Marchand, 1895)

or potato liver

(H. Kalk, 1957)

in the literature. Lobular nodes can reach such a size that they are mistaken for a normal hepatic lobe. (s. fig. 35.1) Macronodular forms may fol- low chronic viral hepatitis, chronic autoimmune hepati- tis, metabolic diseases and toxic-necrotizing processes as well as alcohol abuse. (s. fig. 35.3)

Fig. 35.3 Complete, coarse-bulbous cirrhosis after years of alcohol

abuse and superimposed acute viral hepatitis B, showing a chronic course. Mild tendency towards cholestasis; pronounced subcapsu- lar vascularization and vascular stasis. Occasional funnel-shaped parenchymal depressions

Micronodular cirrhosis: Monolobular (monoacinar) cir- rhosis consists of individual hepatic lobules separated by connective tissue, with the central vein maintained in the interior. In pseudolobular cirrhosis, no elements of the lobular architecture and no central vein can be detected; the nodules in this type of cirrhosis are small.

The monolobular and pseudolobular forms are classi- fied as micronodular cirrhosis, or Nagayo type C (with node size < 0.3 cm). A striking feature is the uniformity of the nodules. (s. figs. 35.4, 35.5)

Fig. 35.4: Complete, micronodular, progressive liver cirrhosis with

formation of pseudoacini (Sirius red)

The micronodular form can develop into a macronodu- lar form, but not vice versa. Generally, micronodular cirrhosis contains more fibrosis than parenchyma;

therefore it is firmer than macronodular cirrhosis. The

development of micronodular cirrhosis, e. g. in alcohol

abuse, may be caused by the fact that continuous alco-

hol intake blocks the protein synthesis, and thus the

parenchyma has no time or chance for cellular prolifera-

tion. This form of cirrhosis mainly results from alcohol

abuse, but may also be found in haemochromatosis,

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congestive liver, biliary cirrhosis, toxic liver damage due to pharmacons, metabolic diseases and chronic viral hepatitis. The liver is generally enlarged.

Fig. 35.5: Complete, micronodular to medium-nodular liver cir-

rhosis after chronic viral hepatitis B (section, native preparation)

Mixed-nodular cirrhosis is considered to be a transi- tional form between micronodular and macronodular cirrhosis

(V. J. Desmet et al., 1990)

. Due to variations in the regenerative capacity of the cirrhotic liver, 50% of

Fig. 35.6: Complete, mixed-nodular (toxin-induced) liver cirrhosis

due to years of alcohol abuse and long-term oxyphenisatin abuse

micronodular forms with a diameter of 1.5 mm develop into macronodular forms after 2 ⫺4 years, whereas after 10 years, the rate is as high as 90%. • Atrophic cirrhosis is the most common form with regard to size, whereas mixed-nodular cirrhosis is the most common form with regard to nodes. (s. tab. 35.1) (s. figs. 35.2 ⫺35.7) 2.2.3 Progression

The question as to the progression of cirrhosis is of cru- cial importance clinically and can only be answered by means of histology. Progressive cirrhosis shows dense, chronic inflammatory infiltration of the connective tis- sue; the boundary between connective tissue and paren- chyma is blurred. Groups of damaged hepatocytes, liver cell necroses as well as nodules formed from the prolif- eration of Kupffer cells and round cells are found within the parenchyma. In places, piecemeal necroses infiltrate the parenchymal islands. A great number of cirrhoses only take a progressive course because of circulatory disturbances. • Stationary cirrhosis is predominantly found in macronodular forms. It frequently exhibits round, clearly defined, nodular parenchymal areas within scar tissue. The boundary between the paren- chyma and connective tissue is (relatively) clear-cut. (s.

fig. 35.2) The scar tissue contains a small number of chronic inflammatory infiltrates of moderate and slightly varying density. The hepatocytes are conspicu- ously enlarged. Fully developed stationary cirrhosis may result, which is defined morphologically as defective healing. • Remission of the cirrhosis is possible, provided the cause of the disease is eliminated (e. g. abstention from alcohol, iron depletion in haemochromatotic cirrhosis, removal of biliary obstruction). However, nod- ular transformation processes cannot be reversed ⫺ restoration of normal lobular architecture is no longer possible. • The morphological dynamics of progression or full-scale stationary cirrhosis has to be strictly dif- ferentiated from the respective clinical course. Clinical progression frequently, but by no means always, corres- ponds to morphological progression.

Fig. 35.7: Scheme of possibilities for hepatic transformation after

parenchymal necroses: (1) formation of pseudolobuli, (2) nodes with enclosed portal field, (3) formation of parenchymal garlands, (4) development of a coarse node from several hepatic lobules which are, in part, completely intact, (5) scar formation after total lobular necrosis

(H. T haler, 1975)

(179)

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2.2.4 Completion

Another important criterion is to determine whether the nodular transformation in the liver is complete or incomplete. This morphological characteristic can be found both in progressive and stationary cirrhoses. • In complete cirrhosis, the parenchyma is completely parti- tioned by connective tissue septa. The collapse of fibres (due to portocentral bridging necroses) results in the development of portocentral septa ( ⫽ passive septa).

Due to the spreading of the inflammation to the peri- portal parenchyma, septa develop and branch out from the portal fields ( ⫽ active septa). Generally, they lead to capillarization of the sinusoidal walls as well. (s. fig.

35.7) Incomplete cirrhosis only displays the formation of short septa ( ⫽ subsepta), so that there are areas of incomplete (partial) subdivision of the parenchyma.

2.2.5 Pathogenetic development

The development of cirrhosis can easily be understood by analysing the morphological findings. Differentiation is made between: (1.) regular cirrhosis (where the cause has a constant, long-term and strong effect, e. g. in alco- hol abuse, haemochromatosis, Wilson’s disease), (2.) irregular cirrhosis (where the cause has an intermittent effect interposed by inaction), (3.) mixed forms, (4.) bili- ary forms, and (5.) vascular forms.

2.2.6 Postdystrophic cirrhosis

In the course of massive subacute liver necrosis (or hepatic dystrophy), large parts of the hepatic paren- chyma can be destroyed within a few months. Extensive regenerative nodes form from the remaining epithelium.

Within these regenerations, the lobular architecture is either still maintained or has been partially restored.

Areas of parenchymal loss are converted into fibre- dense scar tissue with embedded pseudoductuli and duct proliferations as well as irregularly located residual hepatocytes. This course is extremely rare. In the litera- ture, it is also called incomplete postnecrotic cirrhosis.

2.2.7 Necrosis, fibrogenesis, regeneration

The mechanisms leading to cell degeneration and cell death have been described in detail. (see chapter 21.3.4) The processes of regeneration (see chapter 21.3.5) and fibrogenesis (see chapter 21.3.6) have also been dis- cussed in depth. These three important events ⫺ cell death, regeneration and fibrogenesis ⫺ are involved in the development of cirrhosis.

Fibrogenesis commences with the activation of Ito cells by cyto-

kines such as TGFβ1, PDGF, TNFα, IGF1. This induction of Ito cells leads to quantitatively increased (up to 10 times the norm) and qualitatively altered synthesis of the extracellular matrix, which consists of collagens, glycoproteins, proteoglycans and glu- cosaminoglycans.

•

At the same time, degeneration of the matrix is reduced by a decrease in matrix metalloproteinases (MMP) with simultaneous increase in the tissue inhibitors of metalloproteinases

(TIMP). Both factors reduce further degradation of connective tissue.

•

The hepatocytes are now multilayered instead of normal single-layered cell plates and lose their microvilli. Fenestration of the sinusoids disappears, whereas the sinusoidal extracellular matrix increases, leading to

capillarization of the sinusoids. (s. pp 406,

526) In this way, the distance between the hepatocytes and the blood becomes greater, and the clearance of macromolecular substances is reduced. Stronger flow resistance in the liver leads to portal hypertension.

•

Portoportal and portocentral bands of connective tissue form, in which portosystemic intrahepatic shunts develop.

Regeneration after liver resection follows a coordinated and limited

course. This is not the case in cirrhosis: isolated and excessive regenerations of hepatocytes and bile ducts are formed, from which adenomas and carcinomas may develop.

2.2.8 Morphological diagnostics

In order to evaluate cirrhosis in terms of morphology, certain requirements have to be fulfilled. Occasional diagnostic uncertainty or divergent classification may arise from the fact that the biopsy material is insuffi- cient and therefore not representative. This, in turn, is probably due to the fact that the techniques used in obtaining these inadequate samples were faulty or unsuitable. (s. pp 160, 161, 408, 726)

3 Epidemiology

Cirrhosis of the liver is a disease found all over the world, affecting all races, age groups and both sexes. • However, there are geographical differences regarding the most important causative factors: (1.) rate of alcohol consumption and (2.) frequency of viral hepatitis. Few reliable figures concerning its incidence and prevalence are available, since cirrhosis is often symptom-free.

Autopsy examinations suggest a prevalence of 4⫺10%.

The incidence is about 240/million inhabitants/year. • The number of people suffering from cirrhosis in Ger- many is estimated at 600,000 ⫺700,000; some 25,000 patients die of cirrhosis every year, with mortality being twice as high in men as in women. Thus cirrhosis ranks ninth as a cause of death, and even fifth for the age group 45 ⫺65 years. • Generally, the increasing mortality rate runs parallel to regional alcohol consumption. This correlation between alcohol consumption and mortality as well as morbidity due to cirrhosis applies equally to men and women. • The slight decrease in mortality in some countries observed during the past 10 ⫺15 years may be due to more effective prophylaxis and improved treatment options for complications.

(61, 157)

4 Aetiology

The causes of “liver cirrhosis” are numerous; some of

them are rare, appearing even in childhood (e. g. drink-

ing water from copper pipes). Cirrhosis can be acquired

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or genetically based. Aetiological clarification, particu- larly with early diagnosis, should always be a priority, since it may aid treatment and thus prognosis. Cirrhosis comes in many different forms! • There is still no unequivocal answer to the question as to why these causal factors are responsible for the development of cirrhosis over such a widely varying period or why they may not cause cirrhosis at all in some individuals. There are even cases where cirrhosis develops despite effective elimination of the causes ⫺ probably as a result of self- perpetuation due to induced immunological mecha- nisms. • Although there are numerous causes with vary- ing pathogenesis, it is possible to differentiate between three forms of cirrhosis from an aetiological viewpoint:

(1.) parenchyma-related cirrhosis, including the so- called “common” cirrhosis

(H. W. Altmann et al., 1986)

as well as metabolic cirrhosis, (2.) bile duct-related cirrho- sis ( ⫽ biliary cirrhosis), and (3.) vessel-related cirrhosis ( ⫽ vascular cirrhosis). (s. tab. 35.2)

Biliary cirrhosis: Biliary cirrhosis can be detected in 5 ⫺15% of cases. (s. pp 641, 646, 655) (s. figs. 32.5;

35.8, 35.9)

Fig. 35.8: Biliary liver cirrhosis after long-term chronic-recurrent

cholangitis

Fig. 35.9: Liver cirrhosis due to chronic-recurrent, ascending

cholangitis

Alcohol abuse: Alcohol abuse is the most common cause of cirrho-

sis. Nevertheless, no more than 40⫺60% of alcoholics contract the disease. Thus genetic factors must also be involved in the development of alcoholic cirrhosis. Alcohol itself can be a facilitative factor or cofactor. Moreover, so-called “additives” contained in various alcoholic beverages in widely different quantities may also be of greater importance than has hitherto been assumed. (100, 171, 186) (s. pp 528, 532) (s. fig. 28.13, 28.14)

Chronic autoimmune hepatitis: If untreated, AIH (especially type

2) develops almost inevitably into cirrhosis; the condition is further aggravated by the presence of multilobular necrosis and bridging necrosis. In bridging necrosis, development of cirrhosis is more rapid between the portal fields and the central vein than between the portal fields themselves. (s. p. 683) (s. fig. 33.4)

Chronic viral hepatitis: Within a period of 5⫺6 years, cirrhosis is

caused by chronic viral hepatitis B in 15⫺30%, chronic viral hepatitis C in 20⫺50% and chronic viral hepatitis B/D in up to 60% of cases. The risk of cirrhosis is 4.2 times higher in HBsAg carriers and 2.3 times higher in carriers of anti-HCV than in people without these serum markers. (68, 78, 114, 144)

Haemochromatotic cirrhosis: Untreated idiopathic haemochro-

matosis has an insidious course and, as a rule, leads to (micronodular) cirrhosis. Spontaneous remission has not been observed. The survival rate in haemochromatotic cirrhosis is 60⫺65% after 10 years. (s. pp 620, 623) (s. figs. 31.24⫺31.26)

䉴 We do not consider the terminological demarca- tion of “primary” cirrhosis or the differentiation into

“primary” and “secondary” cirrhosis to be accept- able because any kind of biliary cirrhosis constitutes the final stage of a preceding chronic biliary disease.

(s. p. 646!)

Cryptogenic cirrhosis: Cirrhoses which cannot (yet) be clarified by means of current investigation techniques are subsumed under the term cryptogenic cirrhosis.

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Earlier data regarding the frequency no longer apply.

As a result of the methods of detailed diagnosis used nowadays, only a small number of cirrhoses remain truly “cryptogenic”.

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Modern hepatological detailed diagnostics yield an aetiological clarification rate of nearly 95% of all patients! (s. tab. 35.2) • In most of the remaining cases, chemical substances, which are still unknown or which have not yet been identified as hepa- totoxins, are probably involved, so that the patient con- cerned remains unaware of them; furthermore, they might occur in combination with other noxae that can- not be identified. (see chapter 30) Medication may like- wise cause chronic hepatitis as well as cirrhosis. This also applies to herbal remedies, e. g. wild germander.

(see chapter 29) Knowledge in this field has been greatly improved by cooperation between clinicians, toxicologists and specialists in industrial and environ- mental medicine. AIH was the cause of cryptogenic cir- rhosis in 20 ⫺25% of cases. • Non-alcoholic steatohepa- titis is of particular aetiological importance in crypto- genic cirrhosis, especially in cases where obesity and dia- betes coexist (30 ⫺35%).

(15, 138, 143)

(see chapter 31.3.6)

• Owing to modern diagnostic options (and assuming the

patient co-operates!), cryptogenic cirrhoses today consti-

tute no more than 5 ⫺10% of cases.

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1. Alcohol (see chapter 28) 2. Infections

Congenital syphilis (see chapter 24) Schistosomiasis (see chapter 25) Toxoplasmosis (see chapter 25) Viral hepatitis B, C, D (see chapter 22)

3. Autoimmune diseases

Autoimmune hepatitis (see chapter 33) Autoimmune cholangitis (see chapter 32) Primary biliary cholangitis (see chapter 32) Primary sclerosing cholangitis (see chapter 32) Wegener’s granulomatosis

4. Pharmaceuticals (see chapter 29)

Amiodarone Methotrexate

Dantrolene Methyldopa

Halothane Nitrofurantoin

Isoniazid Perhexiline

MAO inhibitors Propylthiouracil

5. Chemical agents (see chapter 30)

Arsenic Phosphorus

Carbon tetrachloride Phytotoxins

Copper Trichloroethylene

Mycotoxins

6. Cholestatic diseases (see chapters 13, 32)

Aagenaes syndrome Byler’s syndrome Arteriohepatic dysplasia Caroli’s syndrome Bile-duct atresia Choledochal cyst Bile-duct stenoses Chronic cholangitis

7. Venous congestion (see chapters 14, 39)

Budd-Chiari syndrome Constrictive pericarditis Right-sided heart failure Veno-occlusive disease

8. Metabolic diseases (see chapter 31)

α1-antitrypsin deficiency

Abetalipoproteinaemia Acute intermittent porphyria Atransferrinaemia syndrome Cystinosis

Erythrohepatic protoporphyria Fructose intolerance

Galactosaemia Gaucher’s disease

Glycogenosis (types I, III, IV) Haemochromatosis

Hurler’s disease Hypermethioninaemia Mucoviscidosis

Neonatal adrenoleucodystrophia Nieman-Pick disease

Non-alcoholic steatohepatitis Porphyria cutanea tarda Seip-Lawrence syndrome Thalassaemia

Tyrosinosis (type I) Wilson’s disease Wolman’s disease Zellweger syndrome

9. Intestinal bypass

10. Rendu-Osler-Weber disease 11. Indian childhood cirrhosis 12. Cryptogenic cirrhosis (<10%) Tab. 35.2: Possible causes of liver cirrhosis

5 Clinical classification

The following stages or courses of cirrhosis can be dif- ferentiated according to clinical criteria:

1. Latent cirrhosis 2. Manifest cirrhosis

앫 active form 앫 inactive form

Latent cirrhosis: There are no subjective complaints or clinical symptoms. This stage is identified by laboratory parameters, imaging procedures or histological examin- ation of the liver. Frequency is between 10 and 20%.

Manifest cirrhosis: Manifest cirrhosis is characterized by subjective complaints and clinical findings. Hepatic haemodynamics are significantly altered, and other organs and organ systems as well as hormonal and humoral functions are affected. Liver cirrhosis orches- trates a complex array of altered biochemical and physiological processes. • Manifest cirrhosis can present in two forms:

1. Stage of compensation 2. Stage of decompensation

앫 portal decompensation 앫 metabolic decompensation

Apart from histological activity (⫽ progressive) or in- activity (⫽ stationary), biochemical activity must also be defined. The latter is determined by (1.) enzymatic activ- ity, (2.) mesenchymal activity, and (3.) immunological activity. (s. p. 121) • Compensated cirrhosis may be either active or inactive. Even decompensated cirrhosis can sometimes be kept in an inactive (stationary) stage for a limited period of time. Jaundice (> 3 mg/dl) is a typical sign of decompensation.

䉴 Portal hypertension derives from microcirculatory disorders, with increasing flow resistance in the sinusoids and postsinusoids. This condition is a consequence of the narrowing, rarefaction and com- pression of the sinusoids or central veins due to collagen deposi- tion, fibrosis and nodulation as well as the presence of intrahepatic arterio-portovenous shunts. Elevated endothelin levels are involved in these processes. (13) Portal hypertension is also evoked or increased by (relatively common)

portal vein thrombosis. (7, 20,

127, 194) Nitric oxide (4, 12, 19), endotoxins (33, 35), platelet- activating factor, prostacyclin, histamine, adenosine, serotonin, bile acids, secretin, glucagons, etc. are all considered to be media- tors of

hyperdynamic splanchnic circulation. (s. p. 738) The resulting

portal hypertension with splenomegaly and collateral varicosis become detectable with progressive cirrhosis of the liver. An important factor is that in alcohol-induced liver diseases, portal hypertension may be present before cirrhosis develops. (see chap-

ter 14)

Portal decompensation: The various forms manifest as

(1.) hypersplenism, (2.) increasing collateral varicosis

with a simultaneous rise in the splanchnic flow due to

hyperdynamic circulation and vasodilatation in the area

of the splanchnic vessels, (3.) hepatic encephalopathy,

and (4.) oedema and ascites. (see chapters 14, 15 and 16)

(9)

Portal decompensation

앫 Hypersplenism 앫 Collateral varicosis

앫 Portal hypertensive gastropathy 앫 Hepatic encephalopathy 앫 Oedema and ascites

䉴 By fulfilling a multitude of metabolic functions, the liver guaran- tees the survival of the organism. Some 70 metabolic partial functions grouped into 12 main metabolic areas need to be constantly maintained with the help of some 500 biochemical processes carried out separately within the hepatocytes. (s. p. 32)

Metabolic decompensation: Pronounced functional decrease or dysfunction in several metabolic areas result in partial metabolic insufficiency. With the failure of additional metabolic functions, there is a risk of global metabolic insufficiency. Development of metabolic insuf- ficiency (also known as cellular decompensation) is due to a significant loss of hepatocytes (e. g. mass necroses) and/or a loss of function of the hepatocytes (e. g. insuffi- cient numbers of hepatocytes and accumulation of waste products in cirrhotic transformation with the development of shunts).

Metabolic decompensation

Disturbance of some or almost all biochemical func- tions, also with a negative energy balance ( ⫽ partial or global insufficiency) (see chapter 20):

• Jaundice (see chapter 12)

• Encephalopathy (see chapter 15)

• Oedema, ascites (see chapter 16)

• Disturbed coagulation (see chapter 19)

• Impaired protein metabolism

• Impaired carbohydrate metabolism

• Disturbed biotransformation

• Hormonal dysbalances

• Altered pharmacokinetics

• Bacterial and viral infections

• States of deficiency (vitamins, trace elements, electrolytes, energy carrier substances) 1. HE and hepatic coma (see chapter 15) 2. Ascites (see chapter 16)

3. Spontaneous bacterial peritonitis (see chapter 16) 4. Hepatorenal syndrome (see chapter 17)

5. Hepatopulmonary syndrome (see chapter 18) 6. Coagulopathy (DIC) (see chapter 19)

7. Acute varix bleeding (see chapter 19) 8. Hepatocellular carcinoma (see chapter 37) 9. Hepatic osteopathy

10. Cholelithiasis

11. Impaired protein, carbohydrate, lipid, vitamin and hormonal metabolism 12. Portosystemic myelopathy and neuropathy

Tab. 35.3: Possible complications in liver cirrhosis

Complications: Generally, complications can occur dur- ing the stages of compensation and decompensation.

Some complications predominantly arise from a decom- pensated situation, whereas others do not necessarily occur at all in the natural course of cirrhosis. However, in view of the cirrhosis-induced lability of the metabolic functions, they may easily be provoked by the patient’s inappropriate behaviour or by iatrogenic measures.

Viruses, such as CMV or influenza A

(50)

, may cause deterioration of the liver function or decompensation.

(59, 157)

(s. tab. 35.3)

6 Diagnosis

䉴 Liver cirrhosis is the final stage of a hepatic disease which has generally run a chronic course for several years.

• Some 60 ⫺65% of cirrhoses are alcohol-induced (long- standing alcohol abuse does not go unnoticed!). Some 25 ⫺30% of cirrhoses are thought to be posthepatitic events. Although a very small number of anicteric HBV and particularly HCV infections remain unrecognized (the exact figure is impossible to estimate), most acute and icteric courses are diagnosed. • With today’s diag- nostic possibilities, chronic liver disease is generally detected at an early stage, either due to general com- plaints by the patient or during medical examinations.

Its course is then carefully monitored. • The point at which a chronic liver disease, particularly cirrhosis, is first detected depends on the patient’s general attitude and the diagnostic interview, which nowadays is far more effective than the standard 20 ⫺30 years ago!

䉴 Thus (subjectively and clinically symptom-free) latent cirrhosis, the frequency of which is 10⫺20% of cases, need not remain undetected. Looking back on almost 40 years of experience, we can state that cirrhosis itself constituted the first diagnosis in no more than 10% of cases. The first diagnosis of cirrhosis at such a complica- tive stage as oesophageal varix bleeding or decompensa- tion has fortunately become a rare event. • The course of cirrhosis (progressing, stationary, or regressing) is monitored by clinical findings, liver function tests and sonography.

6.1 Anamnesis

Targeted anamnesis can yield valuable diagnostic infor- mation as soon as liver disease is suspected. This may require insistent and intense questioning, involving additional consultations. Such an approach is especially helpful in determining risk factors concerning viral hepa- titis infection and toxic effects. (s. p. 76) (s. fig. 4.21) 6.2 Complaints

The subjective complaints of cirrhosis are non-charac-

teristic and ambiguous. Even determination of the

(10)

severity of cirrhosis is only possible to a limited extent.

Most often, fatigue (“pain of the liver”) (60 ⫺80%), sleep disturbance (possibly due to an impaired melato- nin rhythm)

(40, 173)

and gastrointestinal complaints (50 ⫺60%) as well as mental disorders are mentioned by the patient. The most important subjective complaints can be noted quickly by using a check list. • Frequently, however, the patient does not mention any subjective complaints. (s. p. 77) (s. fig. 4.21)

6.3 Clinical findings

As a rule, all of the cirrhosis-typical findings occur in the late course of the disease. Occasionally, patients report striking findings such as changes in the consis- tency, colour or smell of faeces, cutaneous or mucous bleeding and unexplained febrile episodes. The senses of taste and smell are both impaired.

(25)

Eyelid retraction and eyelid lag are often increased. • The liver becomes harder; hepatomegaly is present in about 60% of patients, while in about 20% of cases, the liver is atrophic and therefore usually no longer palpable. Sin- gle nodes are sometimes detectable. • Splenomegaly is present in 50 ⫺75% of cases. Splenic infarction may occasionally be detected (e. g. laparoscopically). (s. fig.

35.10) Generally, there is development of hypersplenism ( ⫽ reticuloendothelial hyperplasia with increased fibro- sis and hyperaemia). • Muscle cramps

(F. Konikoff et al., 1985)

sometimes occur. Zinc deficiency or the admin- istration of diuretics are not considered to be possible causes. These painful cramps occur mostly at night and mainly affect the gastrocnemius muscle and small muscles of the foot. They are often accompanied by increased activity of the renin system with a decrease in the effective blood volume. As a rule, they respond to BCAA supplements in the late evening

(152)

, quinine sulphate (oral application) or i.v. albumin infusion (1 x per week).

(9)

Hepatic myelopathy with spastic parapare- sis is a rare event, especially in the advanced stage of cirrhosis. Pathogenesis is not yet clarified. Liver trans- plantation leads to complete recovery. • Symptoms of peripheral neuropathy have also been observed.

(16, 83, 172)

There is often meteorism (“first the wind ...”) and in many cases ascites develops (“... and then the rain”).

Tachycardia, hypotension and systolic murmur point to hyperdynamic circulation. Evidence of pronounced spi- der naevi is generally a sign of a significant disturbance of the systemic and pulmonary circulation.

(19, 113, 115)

Occasional murmurs may be perceptible in the umbilical area (Cruveilhier-Baumgarten syndrome). Men often display symptoms of feminization, while women display symptoms of hypogonadism. • Numerous skin stigmata of liver disease, which may be partially pathognomonic, are visible in varying intensities and combinations; they can be rapidly and clearly documented by using a check list. (s. tab. 4.3) (s. figs. 4.6⫺4.11, 4.18⫺4.21) (s. pp 79 ⫺86)

Fig. 35.10: Splenic infarction in splenomegaly due to complete

liver cirrhosis. (Postpartum blood transfusion into the umbilical vein, with subsequent severe viral hepatitis B and rapid transition into early infantile cirrhosis)

6.4 Laboratory findings

Enzymatic activity: The enzymatic activity depends upon the extent of (1.) inflammatory or necrobiotic damage to the hepatocytes and (2.) residual parenchy- mal mass. Accordingly, subnormal, normal or dif- ferently increased values of GPT and GOT, and in some cases also of GDH, are found. Enzyme quotients may be used for establishing the diagnosis. (s. tabs. 5.6, 5.7) Cholestasis parameters are moderately elevated; in bili- ary diseases, however, the rise is significant. A pro- gressive increase in γ-GT and AP suggests hepatocellu- lar carcinoma and requires determination of 움

1

- foetoprotein. Disproportionally elevated γ-GT values generally indicate alcoholic or chemical-toxic aetiology or even HCV infection ⫺ but sometimes also regener- ation of the hepatocytes.

(88, 90, 140, 169)

With the pro- gressive loss of liver parenchyma, the transaminase values fall to the normal range, and occasionally even to subnormal levels. This prognostically unfavourable sign correlates with a deterioration of the liver function test.

Mesenchymal activity: Mesenchymal activity is accom-

panied by an increase in γ-globulins and immunoglobu-

lins. There is a broad-based, often dromedary-like

humped γ-globulin peak (typically 22⫺35 rel.%). Albu-

mins can be reliably determined by means of immuno-

nephelometry. Generally, IgA is elevated in alcoholic

cirrhosis, IgG in autoimmune cirrhosis and IgM in pri-

mary biliary cholangitis or CDNC-related cirrhosis. The

rise in γ-globulins is due to reduced clearance of bacter-

ial antigens in the RES, with increased antibody forma-

tion against intestinal bacteria, mainly E. coli. At the

same time, elevated γ-globulins have a depressor effect

on albumin synthesis and are indicators of the degree

(11)

Coagulation factors Coagulation inhibitors Fibrinolytic system

Fibrinogen (I) 앗 Antithrombin III 앗 Plasminogen 앗

Factors II, IX, X 앗 Protein C 앗 α2-antiplasmin 앗

Factor VII 앗앗 Protein C inhibitor 앗 Prekallikrein 앗

Protein S 앗

Factors V, IX, XII, XIII 앗 HRGP 앗

Heparin cofactor 앗

Factor VIII 앖 t-PA 앖

TPT 앖 D dimer 앖

Quick’s value 앗

PTT 앖

Tab. 35.4: Abnormal coagulation factors, coagulation inhibitors and fibrinolytic system values in hepatic cirrhosis (TPT

⫽ thromboplastin time; PTT⫽ partial thromboplastin time; HRGP ⫽ histidine-rich glycoprotein; t-PA ⫽ tissue plasminogen activator)

of portacaval anastomoses. The serum value of copper may be increased. In correlation with the dynamics of fibrogenesis, there is often a rise in P-III-P and hyaluro- nan.

(87)

• Increased γ-globulins and decreased cholines- terase may point to cirrhosis.

(88, 90)

Liver function parameters: The most common endogen- ous liver function parameters, such as lowered cholin- esterase, albumin

(17)

and Quick’s value, are helpful for diagnosis. Since 1982, we have included the determin- ation of bile acids as a relatively sensitive and specific follow-up procedure. Abnormal coagulation factors and fibrinolysis values are of particular diagnostic and prog- nostic importance. Factor 5 has a short half-life. (s. tab.

35.4) • These endogenous parameters can provide add- itional help in evaluating the remaining liver function, especially when used in combination, and may thus facilitate prognostic evaluation. An increase in bilirubin and subsequent permanent jaundice are unfavourable prognostic signs.

(140)

Urobilinogenuria is mostly pre- sent. • Galactose elimination capacity

(150, 153)

and the indocyanine green test are reliable exogenous liver func- tion tests.

(68, 167)

Good results have also been obtained using the caffeine test, aminopyrine breath test

(43)

(s. pp 108 ⫺109) and MEGX test.

^{(124, 162)}

The formation of portosystemic collaterals can sometimes be assessed with the help of the ammonium tolerance test. (s. p. 107)

• In a more advanced cirrhosis, there is a decrease in BCAA (valine, leucine, isoleucine) and an increase in AAA (phenylalanine, tyrosine, methionine).

Additional parameters: Decreased serum values of zinc

(105, 196)

and selenium

(27, 181)

, thrombopenia or throm- bopathy

(128)

as well as increased values of endotoxins

(33, 35)

and homocysteine are also considered to be important laboratory parameters. Increased values of anticardiolipin antibodies are a hint of existing portal vein thrombosis. • Determination of 움

1

-foetoprotein (s.

pp 106, 778) or des-gamma-carboxy prothrombin (s. p.

779) should be carried out to obtain a basic value, then checked at longer intervals; if values increase, they must be monitored at shorter intervals. This also applies if there is a progressive rise in AP and γ-GT.

6.5 Imaging procedures

Imaging techniques have significantly improved the diagnosis of cirrhotic diseases. They supply detailed

information on (1.) structural changes in the liver, (2.) development of portal hypertension and formation of collaterals, (3.) occurrence of ascites at a very early stage, (4.) haemodynamics, and (5.) vascular changes. (s.

tab. 35.5)

6.5.1 Sonography

Portal hypertension can be reliably detected and evalu- ated by way of sonographic criteria. (s. pp 129, 251) The sensitivity of sonography is limited by the extent of the cirrhosis-induced changes and reaches 85 ⫺90% in pro- nounced stages of cirrhosis. Specificity is high. The nod- ularity of the liver surface is, in general, easily visible, especially using a 7.5 MHz annular-array transducer.

(120)

Occasionally, however, the surface is so finely undulant that it appears smooth in sonography. The reflex pattern is inhomogeneous, irregular and coarse;

the vessels are rarefied and tortuous. Splenomegaly as well as dilated portal vessels with collaterals are in evi- dence. Any reduction in size of the quadrate lobe (seg- ment IV) (<3 cm in diameter) is an important indicator.

The caudate lobe is enlarged (especially in alcoholic cir- rhosis) in relation to the right lobe. Regeneration nodes can appear as focal lesions; they may be misinterpreted as malignant foci. (s. figs. 6.6; 35.11)

Fig. 35.11: Liver cirrhosis with ascites (

䉱). Re-opened umbilical vein (ᎏ䉴), hepatic bifurcation and hilum of the liver with ramifi- cation of the portal vein (ᎏᎏ䉴)

Sonography is also considered to be a routine technique

for evaluating the course of cirrhosis. It does not, how-

(12)

Diagnosis of portal hypertension

Diagnosis Diagnosis

of cirrhosis Portal vein Splenomegaly Collaterals of HCC

1. Sonography ⫹⫹ ⫹ ⫹⫹⫹ ⫹⫹ ⫹

2. Colour-encoded duplex sonography ⫹⫹ ⫹⫹ ⫹ ⫹⫹ ⫹

3. CT ⫹⫹ ⫹⫹ ⫹⫹ ⫹⫹ ⫹⫹⫹

4. MRI ⫹⫹ ⫹⫹⫹ ⫹⫹ ⫹⫹⫹ ⫹⫹

5. Angiography (⫹) ⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹

Tab. 35.5: Diagnostic reliability of imaging techniques in liver cirrhosis

ever, provide any information about the activity of dis- ease, degree of fibrosis or initial stage of a malignant process.

(14, 38, 48, 80, 92, 93, 101, 120, 168, 174, 191)

• EUS has proved successful in evaluating varices in the distal oesophagus and cardia area.

(23)

(s. pp 137, 354) 6.5.2 Colour-encoded duplex sonography

Colour-encoded duplex sonography facilitates charac- terization of the portal and hepatovenous haemodynam- ics and differentiation between the hepatofugal and hepatopetal direction of flow.

(56)

There is a flattening of the flow wave in hepatic veins. CEDS can show a shortened liver transit time (using sonographic contrast medium), collaterals, thrombosis or the reopening of vessels, spontaneous portosystemic shunts

(60, 147)

and arterioportal fistulas

(22)

as well as determining the por- tacaval pressure gradient.

(22, 60, 96, 113, 147, 169)

(s. figs.

14.13; 35.12) (s. p. 137) • Colour-encoded duplex sono- graphy is indispensable for establishing indications and excluding contraindications regarding TIPS; it is also used for monitoring a TIPS placement.

Fig. 35.12: Colour-encoded duplex sonography: retrograde portal

flow (flow inversion) in both branches and in the trunk of the portal vein due to arterioportal shunts

6.5.3 Computer tomography

CT scanning basically provides the same information as sonography, but the surface tubers or inhomogeneous internal structure are usually represented more clearly.

Generally, regeneration nodes cannot be differentiated.

The portal system and hepatic veins as well as collateral vessels are discernible. Even small collections of ascitic fluid and some increases in density are recognizable. The caudate lobe is more enlarged in compensated than in decompensated cirrhosis.

(80, 195)

CT is particularly valuable in detecting small hepatocellular carcinomas.

(79, 103)

Fig. 35.13: Cirrhosis with regenerative node (

䉳ᎏᎏ), recanalized umbilical vein (⫽ caput Medusae) (씯) and ascites (䉳•••) in CT

6.5.4 Magnetic resonance imaging

No further diagnostic information is gained by MRI, even though histological results can be improved to a certain extent by applying special techniques. By measuring the signal intensity of the liver, it is generally possible to quantify the extent of liver cirrhosis. Even the uptake of contrast medium as an expression of the still func- tioning proportion of the parenchyma can facilitate quantification.

As a rule, liver perfusion is reduced in relation to the increase in arterial blood flow. The relative reduction in the volume of the right lobe of liver compared to the caudate lobe correlates closely with the extent of the cirrhosis. However, this has no relevance in the context of cirrhosis. (75, 76, 79, 80, 103, 106, 108, 172, 192)

6.5.5 Radioisotope scanning

This technique reveals decreased uptake of the radioisotope with an irregular pattern. Regeneration nodes cannot be visualized.

There is enhanced storage in the spleen and bone marrow. (s. fig.

9.1)

6.6 Liver biopsy and laparoscopy

Laparoscopy: The direct visualization of the nodular

liver by laparoscopy is the procedure with the greatest

value for primary morphological diagnosis. The diag-

nostic margin of error regarding percutaneous biopsy in

cirrhosis is so high that there can be no indication for

biopsy using a Menghini needle! Only a compact biopsy

sample turns histology into a diagnostic gold standard;

(13)

furthermore, such a sample allows all other specific eval- uation techniques to be carried out, if necessary. • It is particularly important to obtain photolaparoscopic doc- umentation of the liver surface, regeneration and scar areas, portal hypertension, spleen (or splenic infarction) (s. fig. 35.10) and other relevant, individual, abdominal findings.

(89, 91, 129, 137)

Although percutaneous biopsy using a Vim-Silverman needle usually produces a com- pact biopsy punch, it entails a higher and less control- lable bleeding risk. Only an adequate biopsy sample yields the necessary results: (1.) confirmation of diagno- sis, (2.) assessment of the degree of activity ( ⫽ grading), (3.) evaluation of the extent of fibrosis ( ⫽ staging), and (4.) specific histochemical examinations if a certain aeti- ology of cirrhosis is given.

Connective tissue collagen in biopsy specimens can be shown, for

example, by the following staining:

elastic fibres (e.g. sinusoids)

ⴝ elastin

reticulum fibres

ⴝ silver

portal and central zones

ⴝ van Gieson

basal membrane

ⴝ PAS

Both the risks and the possibility of obtaining uncertain results are far greater with percutaneous biopsy than with laparoscopically directed biopsy. The latter produces a detailed diagnosis in 97 ⫺100% of cases, a result also confirmed by our own observations.

(46, 90, 123, 129)

• Insufficient training in laparoscopy or the non-availabil- ity of this examination technique do not constitute an indication for percutaneous biopsy in liver cirrhosis, at least for initial diagnosis. (s. figs. 7.8, 7.15; 16.5; 28.13;

35.2 ⫺35.4) (s. pp 160, 161, 408)

6.7 Endoscopy

Gastroscopy (s. figs. 14.10, 14.14; 19.7, 19.9), rectocol- oscopy (s. fig. 19.13) and, in certain cases, rectal endoso- nography are required for evaluating oesophageal vari- ces, portal hypertensive gastroenteropathy

(41, 55, 64, 130, 133, 141, 190)

, gastric antral vascular ectasia

(133)

, peptic ulcer

(55, 134, 170, 205)

, intestinal

(21, 158)

and anorectal

(70)

varices, etc.

Child-Turcotte stage and Pugh modification A B C

1 point 2 points 3 points

1. Bilirubin (mg/dl, µmol/l) ⬍2.0 < 35 2 ⫺3.0 35⫺51 ⬎3.0 > 51

2. Albumin (g/dl) ⬎3.5 2.8 ⫺3.5 ⬍2.8

3. Ascites none easy to treat difficult to treat

4. Encephalopathy none stages I, II stages III, IV

5. Quick’s value (%)*

⁾

(or INR) ⬎70 (<1.7) 40 ⫺70 (1.8⫺2.3) ⬍40 (>2.3)

Points score (used by Pugh) 5 ⫺6 7 ⫺9 10 ⫺15

Survival rate: 1 and 2 year(s) 100%; 85% 80%; 60% 45%; 35%

Tab. 35.6: Classification of hepatic cirrhosis according to Child-Turcotte (1964) and Pugh (1973) (stage A

⫽ good compensation, stage B ⫽ significant functional loss, stage C⫽ decompensation) *⁾Quick’s value is additionally used by Pugh (INR⫽ international normalized ratio)

7 Prognostic classification

The clinical picture of liver cirrhosis displays a great variety of forms. This makes it very difficult to judge the prognosis and to establish an appropriate treatment plan, particularly with regard to surgical intervention.

It was indeed surgeons who proposed a classification suitable for improved evaluation of the risks involved in surgery

(C. G. Child

,

J. G. Turcotte, 1964)

. By means of simple parameters, it is possible to assess the functional reserves of the liver with sufficient reliability. Some parameters show the severity of portal hypertension (e. g. ascites, encephalopathy), while others yield infor- mation about the metabolic functions of the liver (e. g.

jaundice, albumin value, hyaluronan)

(17, 87, 140)

; these criteria were extended by the addition of Quick’s value

(R. N. H. Pugh et al., 1973)

. Clinicians hope to improve the value of this classification by multiplying the criteria of class A by 1, of class B by 2 and of class C by 3, so that an overall score ranging from 5 ( ⫽ most favourable prognosis) to 15 ( ⫽ worst prognosis) is achieved. A close correlation between the deterioration of the Child- Pugh grade and the increasing size of the oesophageal varices could be shown.

(2, 35, 46, 59, 78, 107, 139, 140, 144, 157, 176, 203)

(s. tab. 35.6)

Criteria: Criteria such as ascites, encephalopathy and nutri-

tional status are obviously blurred and, to a certain extent, may be interpreted subjectively. For example, the degree of

ascites

(depending on the examination method chosen) as well as the determination of patient response to treatment (depending on the medication used) are criteria that are hard to standardize.

By contrast,

encephalopathy can be easily classified according

to its stages. (s. tab. 15.5)

• Liver function tests may provide

information about the severity of the functional disorder at an early stage of cirrhosis. We have always preferred to use the two liver function tests

GEC and ICG as additional methods of

evaluation, whereby ascites was determined sonographically and subjected to largely standardized treatment. Reproducible functional values make it much easier to distinguish between class A and B as well as between the scores 5⫺7 and 8⫺10.

They are no substitute for classification (s. tab. 35.6), but may provide valuable information in individual cases. These two function tests are reliable in quantifying the

liver cell mass (e.g.

by means of GEC) as well as the effective

liver blood supply

(e. g. by means of ICG) as prognostically useful parameters.

(14)

8 Differential diagnosis

Differential diagnosis of liver cirrhosis is concerned with two questions: (1.) confirmation of the diagnosis and (2.) clarification of the aetiology.

(59, 68, 90, 107, 114)

䉴 A diagnosis with an accuracy of almost 100% is guar- anteed by using laparoscopy and biopsy, whereby in the latter technique, samples are taken from both liver lobes, if necessary. It is important to obtain a compact biopsy sample ⫺ albeit in larger fragments. Crumbly material is of no use! If such tissue crumbs have been obtained by using a Menghini needle, the Vim-Sil- verman needle has to be used for a second biopsy (and should have been used in the first place in targeted biopsy in liver cirrhosis!). A reticulin preparation, which reveals the extent and distribution of connective tissue more clearly, is diagnostically valuable. • Differentiation has to be made between: (1.) focal nodular hyperplasia, which does not show any lobular areas cut off by con- nective tissue, (2.) liver fibrosis (s. figs. 7.16; 21.14; 22.15;

28.6, 28.7), and (3.) scar tissue within cirrhosis, e.g. in a scarred liver. (s. p. 405) (s. fig. 35.14)

Fig. 35.14: Postnecrotic scarred liver after severe viral hepatitis B.

Atrophy of the left liver lobe with regenerations, broad cicatricial areas and scarred furrows (s. figs. 21.13; 22.16; 35.1!)

Clarification of the aetiology of cirrhosis is usually no problem as long as the potential causes are investigated carefully. In this context, an overview of the numerous causes of cirrhosis as a check list in chart form is very useful. (s. tab. 35.2) The necessary diagnostic param- eters can then be applied efficiently. Specific histochem- ical investigations (e. g. in storage diseases) are carried out accordingly. It is important to categorize cirrhosis based on its aetiology as some forms can then be treated more effectively. • Certain sequelae or complications which impede a differential diagnosis are prevalent in some forms of cirrhosis; they are often the primary reason why the patient consults a physician. (s. tab. 35.2)

9 Consequences and complications

During the course of cirrhosis, it is almost impossible to differentiate between metabolic consequences and complications due to the fact that transitions are fluid both in terms of terminology and clinical features.

Metabolic consequences may be complications in themselves, or play a special role in the occurrence of acute sequelae, or even turn a complicative event into a deleterious situation. The initial cause of such developments often remains unknown. Usually, a vicious circle of impaired mechanisms precedes rele- vant metabolic insufficiency or other complications. • The development of such events can be triggered by the course of disease itself or by the patient’s behavi- our, or even by therapeutic interventions.

The clinical picture of cirrhosis is overlapped by the symptomatology of the respective metabolic sequelae, or in some cases the complicative event predominates.

Occasionally, a wide spectrum of symptoms and find- ings may be observed. This calls for detailed diagnos- tic clarification and varied medical treatment by an internal specialist as well as intensive care or some- times invasive measures.

In cirrhosis, both the overall hepatic intermediary metabolism (s. p. 32 and footnote *

⁾

; s. tab. 3.1) and the microcirculation are severely impaired.

9.1 Negative energy balance

Cirrhotic patients often suffer from a negative energy balance even at an early stage, predominantly due to protein deficiency, so-called protein-energy malnutrition (PEM). This pathological metabolic situation found in 70 ⫺80% of cases can be recognized by reduced oxygen consumption. The administration of β-blockers in patients with cirrhosis causes a favourable metabolic effect, whereby energy expenditure and catecholamine levels are decreased.

The energy required for hepatocellular metabolism is mainly provided by

oxidation of short-chain fatty acids and amino acids via

the citric acid cycle, usually in the mitochondria. Fructose and ethanol are also available for oxidation. In this process,

O

2

partial pressure falls from 13% in the periportal area to 6% in the peri-

central area, which means that the latter region is the most prone to hypoxic cellular damage.

The

energy supply required by cirrhotic patients is achieved by

mobilizing fats: the patient’s fatty tissue is reduced and body weight decreases; the continuing energy requirement is met by the breakdown of muscle proteins with the result that amino acids are formed, which in turn are used for gluconeogenesis in the liver.

Catabolism increases and leads to muscular atrophy, which is known as wasting syndrome. (29, 32, 62, 86, 104, 116, 117, 126)

9.2 Carbohydrate metabolism disorders

䉴 The central role of the liver in carbohydrate metabolism is underlined by the term

glucostate ^{(K. J} ungermann, 1986)

. The