Clinical Aspects of Liver Diseases 32 Cholangitis and cholangiodysplasia

32 Cholangitis and cholangiodysplasia

Page:

1 Definition 638

2 Systematics and aetiology 638

3 Cholangitis 639

3.1 Infectious cholangitis 639

3.1.1 Bacterial cholangitis 639

3.1.2 Parasitic cholangitis 639

3.1.3 Mycotic cholangitis 639

3.1.4 Viral cholangitis 639

3.2 Obstructive cholangitis 639

3.3 Toxic cholangitis 640

3.4 Clinical aspects 640

3.5 Morphology 640

3.6 Diagnostics 641

3.7 Complications and prognosis 642

3.8 Therapy 642

4 Primary biliary cholangitis 643

4.1 Definition 643

4.2 Epidemiology 643

4.3 Aetiology 643

4.3.1 Genetic susceptibility 643

4.3.2 Hormone theory 643

4.3.3 Mycotoxin theory 643

4.3.4 Bacterial or viral theory 644 4.3.5 Elevation of leukotrienes 644

4.3.6 Increase in Mn-SOD 644

4.3.7 Immunologic factors 644

4.4 Pathogenesis 644

4.5 Morphology 645

4.6 Clinical courses 646

4.6.1 Asymptomatic stage 647

4.6.2 Oligosymptomatic stage 647

4.6.3 Symptomatic anicteric stage 647

4.6.4 Icteric stage 647

4.6.5 Final stage 647

4.7 Complications 647

4.8 PBC-associated immunologic diseases 648

4.9 Diagnosis 648

4.10 Prognosis 649

4.11 Therapy 650

4.11.1 Symptomatic therapy 650

4.11.2 Approaches to causal therapy 650

4.11.3 Therapy concepts 652

4.11.4 Liver transplantation 652

Page:

5 Primary sclerosing cholangitis 653

5.1 Definition 653

5.2 Systematics 653

5.3 Epidemiology 653

5.4 Aetiopathogenesis 654

5.5 Morphology 654

5.6 Clinical aspects 655

5.7 Diagnosis 655

5.8 PSC-associated diseases 657

5.9 Complications 657

5.10 Course and prognosis 657

5.11 Therapy 658

5.11.1 Conservative therapy 658

5.11.2 Invasive therapy 659

5.11.3 Surgical measures 659

6 Autoimmune cholangitis 659

6.1 Clinical aspects 659

6.2 Hypothesis of autoimmune cholangitis 660

7 Overlap syndrome 660

7.1 Conversion syndrome 661

7.2 Therapy 661

8 Cholangiodysplasia 661

8.1 Cholangiogenesis 661

8.2 Definition 662

8.3 Aetiopathogenesis 662

8.4 Ductal plate malformation 662

8.4.1 Caroli’s disease 662

8.4.2 Congenital liver fibrosis 663 8.4.3 Childhood fibropolycystic disease 663 8.4.4 Adult polycystic disease 664 8.4.5 Solitary non-parasitic liver cyst 664

8.4.6 Microhamartoma 664

8.5 Alagille’s syndrome 664

8.6 North American Indian cirrhosis 665 8.7 Genetic-metabolic ductopenia 665 8.7.1 α

-antitrypsin deficiency 665

8.7.2 Mucoviscidosis 665

8.7.3 Zellweger’s syndrome 665

8.8 Acquired ductopenia 665

8.9 Idiopathic ductopenia 666

앫 References (1⫺537) 666

(Figures 32.1 ⫺32.18; tables 32.1⫺32.7)

1 Definition

The term cholangitis subsumes localized or diffuse inflammatory changes of diverse aetiology, i. e. be- tween the canal of Hering and the ampulla of Vater, affecting the intrahepatic and extrahepatic bile ducts.

Cholangitis can be acute or chronic; it may originate as a primary disease in the bile ducts or develop as secondary concomitant cholangitis in the course of another underlying disease. Forms of cholangitis which exclusively affect the intrahepatic bile ducts generally give rise to the clinical picture of liver disease.

2 Systematics and aetiology

䉴 The bile is sterile under physiological conditions. • Pathophysiological events can cause asymptomatic bac- teriocholia, which is of no clinical importance. Microor- ganisms are verifiable in bile in 75 ⫺100% of patients with obstruction of the large bile ducts ⫺ whereas this applies only to 0 ⫺10% of patients with obstruction due to pancreatic carcinoma. Diagnostic or therapeutic endoscopic interventions in the bile ducts are often fol- lowed by bacterial cholangitis, attributable to the im- portation of microorganisms, particularly as a result of a (usually temporary) hindrance of bile flow. • Cholan- gitis caused by infection is not a separate entity.

Initially, ascending cholangitis has to be considered on account of its pathogenetic development. This condition originates in the gall bladder, duodenum or pancreas.

Moreover, the bile ducts are liable to infection by bacte- ria or parasites as a consequence of cholestasis and/or achylia. • Descending cholangitis is considered to be less frequent, with the infection descending from a chroni- cally infected gall bladder or from a primary infection of the liver, for example in the case of salmonellosis. • An infection of the bile ducts may cause pyogenic cho- langitis, which can take an acute, relapsing or chronic course, the latter mainly being caused by a hindrance of bile flow. • Depending on the time taken for an obstruc- tion to develop, obstructive cholangitis manifests as either acute or chronic disease. In the case of obstruc- tion, the increase in intraductal pressure (> 15 ⫺20 cm H

O) causes a cholangiovenous or cholangiolymphatic reflux of bacteria or endotoxins into the blood circula- tion. As a result, signs of systemic and, in severe cases, septic disease appear. • Toxic cholangitis may be trig- gered by chemicals, medicaments or toxins. • Further-

more, there is also the clinical picture of immunological cholangitis. This form includes (1.) primary biliary cho- langitis, (2.) primary sclerosing cholangitis, (3.) autoim- mune cholangitis, and (4.) overlap syndromes. (s. tab.

32.1)

1. Aetiology

• Infections

⫺ bacteria ⫺ parasites

⫺ mycoses ⫺ viruses

• Obstruction

⫺ benign stenoses

(stenosis of the papilla of Vater, Mirizzi’s syndrome, postoperative strictures, chronic pancreatitis, juxtapapillary diverticula, etc.)

⫺ blood clots

⫺ mycoses

⫺ gallstones

⫺ malignant stenoses

(histiocytosis X, Hodgkin’s disease, CCC, etc.)

⫺ oriental cholangitis

⫺ parasites

⫺ suture material, clips, sponges

⫺ highly viscous mucus (e.g. mucoviscidosis)

• Immunological causes

⫺ primary biliary cholangitis

⫺ primary sclerosing cholangitis

⫺ autoimmune cholangitis

⫺ graft-versus-host disease

⫺ rejection reaction

⫺ sarcoidosis

⫺ pharmacons

• Toxic causes

⫺ burn injury

⫺ cytostatics

⫺ pharmacons

• Caroli’s disease

2. Clinical forms

• acute • non-suppurative

• chronic • suppurative

• relapsing

䉴 asymptomatic 䉴 symptomatic

3. Pathogenesis

• primary development

⫺ genetic/congenital

⫺ immunological

⫺ toxic

• secondary development

⫺ ascending ⫺ periductular lymphogenic

⫺ descending ⫺ septicaemic via hepatic artery

Tab. 32.1: Classification, causes and pathogenesis of cholangitis

3 Cholangitis

3.1 Infectious cholangitis 3.1.1 Bacterial cholangitis

Based on the number of reported cases, bacterial cholang- itis is by far the most frequent type. It can take an acute, relapsing or chronic course, and it may have a purulent (pyogenic, suppurative) or non-suppurative form. • There are four routes for bacteria, and hence infection, to spread: (1.) ascending, (2.) descending, (3.) periductular lymphogenetic, and (4.) in the case of sepsis, via the hepatic artery. The condition following Billroth’s anasto- mosis II exposes patients to a particular risk, because the duodenal stump serves as a bacterial reservoir. Bilio- digestive anastomoses are also regarded as risk factors.

Older people are more frequently affected by cholangitis.

In general, bacteriocholia only results in cholangitis in the case of disrupted bile flow. (s. tab. 32.1)

In bacterial cholangitis, bile culture is positive in 90 ⫺100% of cases, whereby several species of microor- ganisms are verifiable in 45 ⫺60%. Escherichia coli, Klebsiella pneumoniae, Aeromonas (11) , Streptococcus faecalis and Pseudomonas are found most frequently. In up to 10% of cases, anaerobes may be the causative agents of cholangitis. Yersinia enterocolitica (42) , Sal- monella and tuberculosis bacilli are seen as rare causal pathogens. • Under normal circumstances, bacteria from the intestinal tract sometimes enter the portal blood. Migration of microorganisms into the bile is pre- vented by different defence mechanisms (e. g. intactness of tight junctions, normal phagocytic function of RES cells). Development of cholangitis is likewise impossible in the case of normal biliary flow and normal secretion of IgA into the bile. (7, 11, 14, 20, 33, 36, 49, 52) (see chap- ter 24)

3.1.2 Parasitic cholangitis

Ascaris lumbricoides, Clonorchis sinensis, Lamblia intestinalis, Fasciola hepatica, Opisthorchis felineus and viverrini, Lymnaea trunculata, Cryptosporidium, etc.

have been identified as parasitic causes of cholangitis.

The development of cholangitis is mainly due to a hin- drance of bile drainage. Parasites induce inflammation and fibrosis of the bile ducts with partial or intermittent obstruction. During their migration into the biliary tree, parasites may physically introduce bacteria into the bile ducts, which often leads to secondary bacterial cholang- itis. Cholangitis induced by Opisthorchis and Clonor- chis predisposes to cholangiocarcinoma and liver cell carcinoma. Echinococcus cysts may break in the bile ducts. (7, 15, 17, 51) (s. tab. 32.1) (see chapter 25) 3.1.3 Mycotic cholangitis

Various fungi have also been found to cause (obstruct- ive) cholangitis, e. g. Cryptococcus neoformans (3) , Can-

dida (9) , Microsporidium (40) , Blastomyces. (43) (s. tab.

32.1) (see chapter 26) 3.1.4 Viral cholangitis

Viral cholangitis is rare. It can be caused by primary hepatotropic viruses, such as HCV or HBV, and may also occur in systemic viral diseases. (4) Both immuno- competent and immunocompromised patients are affected. The effect on the bile ducts depends mainly on the status of the host immune system. Generally, bile ducts of 50 ⫺70 µm diameter are targeted. The cholan- gitic lesions can be divided in four types: granulomatous, lymphoid, fibrous and pleomorphic (J. L udwig et al., 1984) . It is postulated that damage to the bile duct leads to an increase in alkaline phosphatase. • In adults, cyto- megaly is the sole cause of viral cholangitis, especially in the case of HIV infections ( ⫽ HIV-associated cholan- giopathy) and in patients who have undergone liver transplantation. In the course of AIDS, biliary infec- tions are frequently caused by opportunistic microorga- nisms, e. g. cryptosporidiosis, microsporidiosis (2, 10, 16, 27, 40, 51) and sclerosing cholangitis. (17, 45) • ERCP is very important in the diagnosis of HIV-associated cho- langiopathy. In acute viral hepatitis, HCV is more fre- quently associated with cholangitis (20 ⫺30%) than is HBV. There is mostly evidence of lymphocytic cholan- gitis, which is, as a rule, reversible and does not adversely influence the course of disease or response to therapy. The intraepithelial lymphocytes are of the T- cell type. • During the foetal period, viral cholangitis due to reoviruses (type 3) can cause bile-duct atresia, which may also be the result of rotaviruses (types A and C) and RS viruses. (see chapter 23)

3.2 Obstructive cholangitis

An obstruction in the bile ducts does not always result in cholangitis; however, a disorder of bile drainage is considered to be a prerequisite for the manifestation of cholangitis. In this case, the defence system is of particu- lar importance with regard to bacterial infections. Fur- ther risk factors include advanced age and alcohol abuse. The causes of obstruction are manifold, with cholangiolithiasis being the most frequent. • An impac- tion of a gallstone in the cystic duct or neck of the gall bladder can narrow the choledochus, a condition known as Mirizzi’s syndrome (P. L. M irizzi, 1948) , with subse- quent development of obstructive cholangitis or cholecystobiliary fistula. (13) (s. fig. 32.1)

During cholecystectomy, choledocholithiasis was found in 12 ⫺24% of cases. A stone-free gall bladder does not exclude cholangiolithiasis. About 80% of the bile-duct stones are found in the choledochus, 15% in the com- mon hepatic duct and 5% in the intrahepatic bile ducts.

In obstructive cholangitis, the recognition and removal

Fig. 32.1: Cholesterol-calcium-pigment stone: a rare specimen showing a striking coloured/chemical development (here: a so- called tiger-eye stone) (at our disposal). Diagnosis: obstructive cho- langitis due to Mirizzi’s syndrome

of the obstruction constitutes causal therapy and is de- cisive for prognosis. (9, 15, 21, 25, 34, 35, 39, 50, 56)

Oriental cholangiohepatitis: This particular type of chol- angitis was first described by K. D igby in 1930. It de- velops from the formation of calcium bilirubinate stones, especially with intrahepatic localization. It is mainly found in China, Japan, Malaysia and Taiwan. A nutritional cause together with a deficiency of glucaro- 1,4-lactone is assumed, so that deglucuronidated biliru- bin precipitates. Migration of parasites, especially Asca- ris lumbricoides, into the bile ducts is probably an ini- tiating event. (s. fig. 25.8!) Suppurative cholangitis develops. ERCP and MRCP are excellent diagnostic tools for depicting and examining the biliary tree. • Treatment consists of endoscopic stone removal, which often has to be repeated. The insertion of an expandable metallic stent has not proved effective in the long term.

Surgical procedures include sphincteroplasty, biliointes- tinal bypass or hepatic resections. (6, 32, 47) • So-called recurrent pyogenic cholangitis is thought to be identical to oriental cholangiohepatitis. (12, 22, 26, 48, 55, 56)

3.3 Toxic cholangitis

Toxic (especially sclerosing) cholangitis (5, 8, 17 ⫺19, 24, 38, 39, 44 ⫺46) has been attributed to the effects of aromatic amines. Likewise, this condition can be caused by lithocholic acid. It may also be triggered by various medi- caments acting as facultative toxins, e. g. allopurinol, anti- biotics, carbamazepine, phenylbutazone, tolbutamide. (s.

tab. 29.6) • Such a type sometimes occurs after intra-arte- rial administration of cytostatics (18, 19, 24, 38) and as a result of burn injuries. (44) (s. p. 651) (s. tab. 32.4)

3.4 Clinical aspects

Acute cholangitis: The acute course is initially diagnosed clinically. It is characterized by Charcot’s triad: (1.) sud-

den onset of pain (epigastric, right-sided), (2.) fever (also with shivers), and (3.) jaundice (J. M. C harcot, 1877 :

“intermittent gall fever”). This triad was expanded by

B. M. R eynolds et al. (1959) to a pentad, which points to sep- tic cholangitis: (4.) confusion, and (5.) coagulation disor- der, occasionally with the development of disseminated intravascular coagulopathy (DIC). The course can be intermittent, or it may rapidly progress to sepsis with septic shock (in about 5%). However, a severe course of disease does not necessarily confirm the existence of sup- purative cholangitis. In younger people, Charcot’s triad is more clearly marked than in older patients, in whom jaundice is absent in 20 ⫺30% of cases. The liver is enlarged and tender upon pressure; splenomegaly is occa- sionally found. (33, 36, 52)

Suppurative cholangitis: Pyogenic (suppurative) cholang- itis has the most severe course with a very poor progno- sis. In general, there is complete bile obstruction with expanded pus-filled bile ducts ( ⫽ bile-duct empyema).

Clinically, Reynold’s pentad is present in most cases.

Hepatosplenomegaly, pronounced leucocytosis and hyperbilirubinaemia (in general > 9 mg/dl) are found.

Suspected severe or suppurative cholangitis requires instant diagnostic measures and, on confirmation of diagnosis, immediate therapeutic endoscopic (occasion- ally also surgical) intervention. (11, 14, 21, 30, 31) • Severe or suppurative cholangitis is always an emergency!

Chronic cholangitis: The symptomatology is bland ⫺ particularly in older people. Younger people mostly suf- fer from a chronic relapsing course. Clinical symptoms include pain in the right upper abdomen, possibly also inappetence and nausea as well as occasionally verifi- able hepatomegaly. Laboratory tests provide evidence of cholestasis with or without slight jaundice. Symptom- free intervals and exacerbations with fever and jaundice can alternate. • Both acute and chronic cholangitis have a variable clinical picture with a wide spectrum of sever- ity, including cholangitis lenta.

3.5 Morphology

Acute cholangitis: Thickened bile-duct walls with inflam- matory infiltration as well as focal ulcerations are found histologically. The portal fields are expanded by oedema and reveal pericholangiolar and intracholangiolar in- filtrations from leucocytes. Ductal tortuosity reflects increased pressure in the biliary ducts. Periductular abscesses can develop during the course of cholangitis. (s.

fig. 32.2)

Chronic cholangitis: This disease shows dilated, prolifer- ated, peripherally located ductules, which contain con- centrated bile with degenerative epithelial changes.

Large numbers of polymorphonuclear leucocytes are

verifiable in the lumen and in the bile-duct wall; leuco-

cytic infiltrations spread to the neighbouring paren-

chyma. Increasing (lamellar) periductular fibrosis and

biliary strictures develop. (s. fig. 32.3) • Laparoscopi- cally, progressive portal and portoportal fibrosis with cholestasis is characteristic of the macroscopic picture of chronic cholangitis. (s. fig. 32.4)

Fig. 32.2: Ascending, suppurative, destructive, relapsing cholang- itis with abscess formation; the loose periportal fibre cuff (arrow) points to previous cholangitic episodes (HE)

Fig. 32.3: Periductal, portoportal slight fibrosis. Clinically: history of previous bile-duct inflammation (Sirius red)

Fig. 32.4: Chronic cholangitis. Periportal fibrosis; dark red/brown- ish discolouration of the liver with greenish patches: finely nodular surface ( ⫽ scattered light reflection)

If it is not possible to remove the obstruction and achieve defect healing (i. e. with fibrous residues) of the chronic (relapsing) cholangitis, the inflammatory destruction of periportal liver parenchyma will result in portoportal bridge formations and thus isolation of hepatic lobules by means of connective tissue. • Monolobular, mostly micronodular biliary cirrhosis develops. (41, 54) (s. fig. 32.5)

Fig. 32.5: Biliary cirrhosis following chronic relapsing and abscess- forming cholangitis; green and grey “dirty” colouration of the deformed micronodular surface. (Chronic cholecystitis with formation of a shrunken gall bladder)

3.6 Diagnostics

The diagnosis is initially based on detailed anamnesis focusing on the biliary system (preceding hepatobiliary diseases, endoscopic examinations, operative interven- tions). Previous examination results and surgical reports (if applicable) should be obtained. • With regard to clin- ical findings, the liver can be enlarged and/or tender on pressure, and jaundice may also be present. • Laboratory investigations reveal leucocytosis with inflammation cri- teria in the differential blood count, increased values for the erythrocyte sedimentation rate and CRP, elevated γ- GT, AP, LAP and bile acids, hyperbilirubinaemia, aug- mented α

- and γ-globulins and IgM as well as increased GPT, GOT and GDH (pointing to involvement of the lobular periphery in the form of cholangiohepatitis).

Occasionally, the amylase value and the tumour marker

CEA 19 ⫺9 (due to cholestasis) are elevated. • Bacteri-

aemia is verifiable in 20 ⫺40% of patients during a fever

episode, with the result that an antibiogram guarantees a

more targeted therapy in these cases. • Sonography shows

dilated bile ducts; normal bile ducts, however, do not

exclude cholangitis! As a rule, the type and localization of

an obstruction are verifiable and gas can occasionally be

detected in the portal veins. Abscess foci are easily recog-

nizable. (16, 30) • Computer tomography provides valuable

evidence in difficult cases, for example in malignant

obstruction. (1, 12) More recently, good results have been

obtained by means of MRC. (26, 53) (s. p. 183)

䉴 Direct cholangiography by means of ERCP (s. p. 183) and PTC (s. p. 185) is a decisive examination with very high diagnostic reliability. However, these techniques should be carried out under antibiotic prophylaxis, the duration of which depends on the clinical picture. The important factor here is the well contrasted and com- plete visualization of the bile ducts. Using these two methods, it is possible to implement simultaneous thera- peutic procedures, such as decompression of bile ducts, flushing with antibiotics, papillotomy with stone extrac- tion, nasobiliary or bilioduodenal drainage, stent implantation, etc. • If there is no suspicion of suppura- tive cholangitis (which calls for immediate invasive or surgical intervention!), antibiotic therapy for 1 (or 2) day(s) is carried out prior to ERCP and the result awaited, because ERCP can trigger complicative cholan- gitis in rare cases. • An inconspicuous cholangiogram now requires further diagnostic efforts to find the still unresolved cause of cholangitis, such as serological ex- amination for viruses or bacteria, evidence of parasitic larvae or eggs in the bile or stool, autoantibodies (e. g.

AMA, pANCA), toxins and colour-encoded Doppler sonography of the portal system.

Aerobilia may have various causes, e.g. biliodigestive anastomosis or fistula, ERCP, cholangitis due to gas- forming bacteria. In aerobilia, there are sonographically echogenic, strand-like gas bubbles in the respective bile ducts. (s. fig. 32.6)

Fig. 32.6: Aerobilia: Sonography shows echogenic, strand-like gas bubbles in the respective bile ducts

This diagnostic programme, which has proved its worth in the case of cholangitis, can be incorporated into a flow diagram for the clarification of cholestasis or jaundice. (s. fig. 13.7) The individual characteris- tics of each case always have to be considered!

3.7 Complications and prognosis

The mild form of cholangitis frequently subsides spon- taneously, mostly with antibiotic therapy, and can even

be cured without morphological residues. • Severe and progressive courses have a poor prognosis due to the development of complications: (1.) suppurative cholang- itis, (2.) sepsis, possibly with septic shock, (3.) DIC, (4.) infected portal thrombosis, (5.) acute renal failure (so- called biliorenal syndrome), and (6.) liver abscesses or metastatic abscess formation. • However, complications also have to be feared when using ERCP and PTC, since the inherent risks of these invasive techniques are greatly increased by bacterial infection of the bile duct (e. g. phlegmon, retroperitoneal or subphrenic abscess, pleural infection). There is a particular risk involved in the application of contrast medium under pressure (!) into the bile ducts, which may even result in death. • The prognosis is based on establishing whether (1.) the causal obstruction can be removed, (2.) decompression of the bile ducts can be achieved, (3.) effective drainage is guaranteed, and (4.) antibiotic therapy is effective.

3.8 Therapy

1. Standard therapy: Intensive care treatment and moni- toring is accepted as standard therapy; complications may appear unexpectedly and rapidly. In about 75% of patients with mild cholangitis, therapeutic success can be achieved by the substitution of fluid, electrolytes and zinc as well as vitamins, glucose (possibly also amino acids) and the (indispensable) administration of anti- biotics. Analgesics and spasmolytics are generally neces- sary. • In addition, the administration of fresh plasma is recommended to stabilize haemostasis.

As long as there is no positive bacteriological result from the bile (or blood), antibiotics are administered on empirical and plausible principles. In this case, mezlocil- lin or piperacillin is initially recommended, 3 x 2 ( ⫺4 or

⫺5) g/day, i.v. ⁽⁵⁵⁾ These antibiotics are effective against virtually all bacteria in acute cholangitis, since they can reach high biliary concentrations. Once the course of disease has entered a more severe stage, an additional dose of tobramycin, for example, is indicated (e. g. 3 x 80 mg/day, i.v.). A septic clinical picture requires a course of triple therapy with ureidopenicillin ⫹ amino- glycoside (see above) ⫹ metronidazole (3 x 500 mg/

day, i.v.).

2. Invasive therapy: If clinical improvement and defer-

vescence do not occur within 12 (to 36) hours, decom-

pression of the bile ducts becomes necessary. Decom-

pression is carried out endoscopically by means of

papillotomy. Providing there are no reasons against

doing so, bile drainage should also be carried out at the

same time via a nasobiliary tube or bilioduodenal endo-

prosthesis. Early decompression is recommended with a

thrombocyte count of < 100,000/mm

and an albumin

value of < 3.0 g/dl. (23, 29, 31, 47, 56) Under these circum-

stances, we regard the simultaneous administration of

fresh plasma as a necessity. • If the bile ducts cannot be

reached by retrograde endoscopy, PTC is available as an

ideal alternative for decompression and drainage (and, occasionally, antibiotic instillation). Nevertheless, because of the bacterial (suppurative) situation, a higher complication rate also has to be expected. (23, 37, 47) • Surgical measures carry a substantially higher risk than endoscopic papillotomy ⫹ drainage, which is why they are restricted to particular situations in special cases (e. g. Caroli’s syndrome, liver abscess). (23, 28, 48)

4 Primary biliary cholangitis (PBC)

䉴 In 1826 ^{P. F. R} ayer reported on the peculiar appearance of xanthelasmas and xanthomas in middle-aged women. • In 1851 T. A ddison et al. assumed a correlation between skin changes and liver disease. (58) In 1857 R. V irchow pointed to a connec- tion between these skin changes and cholestasis and cirrhosis.

V. H anot (1876) described the clinical picture of hypertrophic cirrhosis with chronic jaundice. (134) S. G. T hannhauser et al.

(1938) postulated the combination of xanthomas and biliary cir- rhosis as a separate entity. (271) In 1949 H. E. M acMahon et al.

used the term “xanthomatous biliary cirrhosis”. (193) • A detailed description of this disease was presented by J. A. D au- phinee et al. ( 1949) (98) and E. H. A hrens jr. et al. (1950) , who coined the term “primary biliary cirrhosis”. (60) • In 1965 the group of H. P opper introduced the expression “chronic non-sup- purative destructive cholangitis” (CNDC). (247)

4.1 Definition

Primary biliary cholangitis (PBC) is characterized by chronic, non-suppurative, destructive cholangitis (CNDC) of the small and medium-sized bile ducts (ductule, interlobular and septal). The cause is not yet known. • PBC proceeds slowly and does not cause any clinical symptoms for a long period of time.

However, antimitochondrial antibodies (AMA) already appear at the preclinical stage, which allows a very early diagnosis to be made. During the further course of disease, the symptoms are those of chronic cholestasis. The final stage is characterized by the total destruction of the bile ducts. • In the case of a progressive (or unsuccessfully treated) course, pri- mary biliary cholangitis gradually develops into bili- ary cirrhosis ⫺ as is also the case with primary and secondary sclerosing cholangitis.

4.2 Epidemiology

PBC is found in all races and social classes, although it is virtually unknown in Africa. Its prevalence ranges between 25 ⫺40/100,000 inhabitants (with regional differences). The incidence is 2.7 ⫺3.5 cases per 100,000 inhabitants/year. The disease predominantly affects women (in about 90% of cases); the prevalence among women between the ages of 35 and 60 is >90/100,000.

PBC is nearly always witnessed in adults; it is a very rare event in children. (97) Close relatives have a preva- lence of 4 ⫺6%. Patients with ulcerative colitis are

affected thirty times more frequently than the general population. (108, 148, 188, 190, 204)

4.3 Aetiology

The aetiology of PBC is still unknown. Possible causal factors include genetic susceptibility, infections, environ- mental influences and immunological reactions. • Prob- ably, there is an individual concurrence of endogenous and exogenous factors.

4.3.1 Genetic susceptibility

Isolated instances of familial aggregation of PBC involv- ing siblings, twins, mother and daughter or father and daughter have been reported. The occurrence of AMA as well as an increase in IgM and γ-GT, or deficiency of IgA has been observed in relatives of PBC patients (genetics? close physical contact?). It is not a hereditary disease, however. (59, 66, 83, 85, 87, 89, 90, 117, 127, 144, 148, 163, 275)

There is a certain association with HLA, such as HLA- DR8, -DR3, -DR4, -DPB1, -B8 or -DQB1, as well as with the formation of isohaemagglutinins ⫺ but not with the AB0 blood-group system or the Rhesus groups.

The HLA-A class 2 antigen is significant in reducing susceptibility to and affording protection against PBC.

HLA-DR8 is deemed to be a risk factor, particularly in the combination DR8/C4B2 and DR8/C4AQ0. (270, 278)

4.3.2 Hormone theory

䉴 The so-called hormone theory ^{(J. A} hlqvist, 1980) is based on the impact of hyperoestrogenaemia on the biliary/canalicular system and bile acid metabolism. The question of sequential causality remains open. (quot. 75)

4.3.3 Mycotoxin theory

䉴 The so-called mycotoxin theory ^{(E. K} untz, 1984) emerged from our examinations of stools for the presence of fungi in 54 fe- male patients. (170, 171) • Normally, the lumen of the bile capil- laries is surrounded by a network of actin-like filaments which radiate into the microvilli. The bile flow is essentially steered by this network. The mycotoxin cytochalasin B (possibly also other mycotoxins) causes loss of microvilli and dilatation of the canali- culi (M. J. P hillips et al., 1975) ⫺ and as a result, probably also reten- tion of leukotrienes. (see 4.3.5) Mycotoxins can penetrate the intes- tinal mucosa and reach the liver cells through the portal vein. The frequent evidence of antiactin antibodies in PBC patients may be attributable to this. A (myco)toxic canalicular impairment as an

“initiator” may result in self-perpetuation in connection with

(secondary) hyperoestrogenaemia due to a (tertiary) defect in the

immunoregulatory mechanism. The formation of mitochondrial

antibodies can be induced by a mycotoxic (?) (possibly bacterial?)

antigen, which culminates in the formation of AMA with subse-

quent T-cell infiltration into the small bile ducts. Yet, the question

remained unanswered for us as to whether this applies to (1.)

markedly increased fungal colonization of the intestinal tract in

individual cases, (2.) specific fungal species, (3.) increased pervi-

ousness of the (predamaged?) intestinal mucosa with regard to

mycotoxins, or (4.) insufficient clearance function of the hepatic

RES. • We were subsequently able to confirm this marked associ-

ation on the basis of numerous mycological stool examinations ⫺ however, no further evidence could be obtained to substantiate our mycotoxic hypothesis at that time. • It is of interest that AMA also react with PDH-E2 contained in mycoses.

4.3.4 Bacterial or viral theory

䉴 The group of ^{U. H} opf also examined the question of an infec- tious toxic factor, since there is a great similarity between bacterial and mitochondrial membranes. (75, 139, 254, 261, 267, 293) Evi- dence of so-called R forms of E. coli could be found in all PBC patients in the stool (with no relation to the severity of cholestasis), and A lipid could be detected very frequently in hepatocytes and Kupffer cells. Mitochondrial antigens were present in the bacterial wall of Enterobacteriaceae. • Evidence of AMA in tuberculosis patients is of interest (R. K lein et al, 1993) . Urinary tract infections with E. coli may also play a role in the development of anti-M

(A. K. B urroughs et al., 1984) . • Anti-M

has also been observed after infections with EBV, cytomegalovirus, Salmonella sp., toxo- plasma, Chlamidia sp. (57), etc. Hepatitis viruses may also be “ini- tiators”. Propionibacterium acnes could be detected in granulo- mas. • PBC is possibly caused by a coated retrovirus. This as yet unnamed virus has been detected in the epithelia of small bile ducts. It contains neither human nor viral DNA. Therefore, it is deemed to be an exogenous virus. Thus antiviral treatment of patients with PBC may be considered a new therapy option. (198)

4.3.5 Elevation of leukotrienes

Leukotrienes can form in hepatocytes, Kupffer cells and masto- cytes. Their release, induced by endotoxins for example, correlates with the increase in AP, LAP and γ-GT. Leukotrienes have a marked inflammatory effect. Enhanced production together with reduced secretion of leukotrienes into the bile can result in severe lesions of the bile ducts. (203)

4.3.6 Increase in Mn-SOD

In PBC patients, manganese superoxide dismutase levels in the serum were found to be increased; it is secreted in greater quanti- ties from damaged bile-duct epithelia. Free radicals were therefore assumed to play an aetiopathogenetic role regarding immuno- logically induced lipid peroxidations. (229)

4.3.7 Immunologic factors

1. Antimitochondrial antibodies (AMA): ^{D. C. G} ajdusek (1957) and J. R. M ackay (1958) were able to determine different antibodies in the serum of patients suffering from PBC by means of a comple- ment fixation test (CFT). (s. p. 120) • In 1965 J. G. W alker et al.

reported the occurrence of antimitochondrial antibodies in PBC patients. (282) These were directed against the antigens of the inner mitochondrial membrane. The antigen specific to PBC and sensi- tive to trypsin was termed AMA-M

. The target antigen is an enzyme complex containing pyruvate dehydrogenase, keto acid dehydrogenase and branched chain keto dehydrogenase. In about 95% of cases, patients with PBC show a positive result. Four deter- minants (I ⫺IV) are attributed to M

: E

, X, E

, E

. (70, 74, 112, 137, 215, 264, 295) • The group of P. A. B erg identified an anti-M

(1984) in PBC patients as well as a trypsin-resistant anti-M

and a trypsin-sensitive anti-M

(1985). Anti-M

was found almost exclusively in the early stage, often in family members who did not have an anti-M

⫺ as well as in female laboratory assistants in frequent contact with AMA-positive serum. Anti-M

is verifiable in 10 ⫺15% of the population. (77, 285) (s. tab. 5.21) (s. p. 120) (s.

fig. 5.14) It is still not clear whether AMA-positivity is a sequela or a pathogenetic factor of PBC. • Further AMA subgroups have been verified: anti-M

against syphilis (D. J. W right et al., 1970) , anti-M

against pseudolupus (T. J. S ayers et al., 1981) , anti-M

against collagenosis, anti-M

against iproniacid (M. T. L abro et al.,

1982) and anti-M

against cardiomyopathies (R. K lein et al., 1984) .

• The typical antibodies for PBC (M

, M

, M

, M

) can be com- bined into four constellation types (A⫺D), which are probably of clinical importance. The sensitivity of detection ranges between 66 ⫺96%. • However, AMA are neither species nor organ-specific.

(76, 130, 152, 163 ⫺165, 199, 236, 263) (s. tab. 5.21)

2. Other antibodies: Antinuclear antibodies (ANA) in PBC are verifiable in 10 ⫺40% of cases. Antibodies to hepatocyte mem- branes (LMA) are present in about 40% of PBC patients. Further- more, antibodies to microfilaments, intermediary filaments and microtubuli as well as to antiactin have been detected. In approx.

100% of PBC patients, antibodies against parietal cells can be iden- tified (H. P. W irth et al., 1994) . In 25% of cases, antibodies to thyreo- globulin have also been demonstrated. (96, 104, 149, 263, 265) (s.

tabs. 5.19 ⫺5.21)

3. Immunocomplexes: It has also been suggested that complement activation with subsequent bile-duct lesions and an increased syn- thesis of immunoglobulins is evoked by immunocomplexes. They are even considered to be responsible for the formation of granulo- mas. However, they are certainly not the primary aetiological factors.

4. Immunoglobulin M: Virtually all PBC patients show increased serum IgM values. This IgM differs remarkably from the IgM of healthy persons. Elevated monomeric IgM was also detected in the skin, in hepatocytes and in the intestinal mucosa. Enhanced IgM serum values were likewise determined in relatives of PBC patients.

(see 4.3.1) However, there was no correlation between IgM serum values and the tissue level values, cholestasis or morphological changes. Progressive PBC courses result in augmented IgG as well.

5. Cellular immunoreactions: Increased IgM values are a character- istic sign of enhanced B-lymphocyte activity, namely of an IgM- secreting subgroup, as well as a restriction in the normal transfer from type IgM to type IgG. Infiltrations are found in the hepatic tissue and consist mainly of T lymphocytes (activated, cytotoxic CD8

as well as CD4

helper cells). The portal field infiltrations predominantly show CD4 T lymphocytes, while the ductuli are surrounded by CD8 T lymphocytes. It is still not known which mechanisms are responsible for the bile-duct lesions brought about by the T lymphocytes, mainly of the CD8 type. The latter are assumed to react with M

antigens, which are expressed from the ductulus cells. • So-called MHC antigens are found on the surface of the bile-duct epithelia of PBC patients, i. e. they act as antigen- presenting (target) cells. This leads to the stimulation and prolifer- ation of CD4 lymphocytes. These emit cytokines, which cause a proliferation of CD8 lymphocytes in the direct neighbourhood of the small bile ducts. However, the bile-duct epithelial cells are also target cells of the CD8 lymphocytes; the latter adhere to the bile- duct epithelia due to the expression of MHC antigens and adhe- sion molecules (ICAM), and enter the cells. Their cytotoxic impact destroys the small bile ducts and evokes an immunological inflam- matory process with further secretion of cytokines, which are con- ducive to inflammation. However, with regard to cytokine pro- duction and response in PBC, the findings are still contradictory.

Nor is it clear why these processes take place almost exclusively in the small bile ducts. (182, 215)

6. Selenium deficiency: The trace element selenium is also obliga- tory for the normal functioning of the immunological system.

Selenium deficiency has been proposed as one of the aetiological factors in PBC ⫺ although this has not yet been verified.

4.4 Pathogenesis

In the pathogenesis of PBC, cellular immunoreactions, particularly

the formation of autoantibodies, are probably of greater import-

ance than humoral reactions. Due to disturbed immunoregulation,

the immune response is ineffective against both cell and humorally

mediated cytotoxicity. On the one hand, therefore, causality is not eliminated and on the other hand, the initial damage still has an effect, so that the autoimmunological inflammatory reactions con- tinue to target the organ in a self-perpetuating process. • The fre- quent association with other autoimmunological diseases, infiltra- tions of activated CD4 and CD8 T lymphocytes in the portal fields and around the intralobular bile ducts as well as the expression of antigens of the MHC class II and ICAM class I on bile-duct cells point to the importance of autoimmunological reactions in the pathogenesis of PBC. • The involvement of M

antibodies in the pathogenesis of PBC has been discussed, but seems rather unlikely.

A possible aspect would be the pathogenetic significance of AMA through antibody-transmitted cytotoxicity and the incorporation of complement factors. (100, 125, 144, 150)

Aetiopathogenetic hypothesis

The primary provocation of immunological phenomena by toxins, such as mycotoxins ^{(E. K} untz, 1984) (170, 171) , bacteria ^{(U. H} opf et al., 1989) (139, 261) and viral infection

(H. I. M ason et al., 1998) (198) ⫺ probably accompanied by hormone-induced bile-duct lesions (J. A hlqvist, 1980) ⫺ can therefore be interpreted in terms of subsequent self- perpetuation. The expression of relevant mitochondrial epitopes in the small bile ducts caused by an external antigen through molecular mimicry ^{(M. E. G} ershwin, 1991, 1997) (120, 267) may support the chronic inflammatory process by way of autoaggression. Immunologically induced lipid peroxidations may be significant here. (229)

Already in the year 1979, it could be demonstrated by means of electron microscopy that mitochondria multiply in the epithelial cells of the canaliculi of PBC patients; this finally leads to obliteration of the affected canaliculi. The longitudinal consolidations of intercellu- lar gaps point like fingers to the obliterated lumen (G.

S chwalbach, 1979) . • These results concurred with our concept at that time (171) which was based on the assumption that a primary mycotoxic factor (or molecu- lar mimicry) constitutes an “initiator”. (s. p. 643) 4.5 Morphology

䉴 The morphological changes in “primary biliary cir- rhosis” (PBC) (60) were described as “chronic non-suppu- rative destructive cholangitis” (CNDC) by the study group of H. P opper if the stage of cirrhosis had not been reached. (247) • The morphological classification of PBC, first proposed by P. J. S cheuer in 1967 (252), was modified in 1980. It differentiates four stages, which show fluid transition: ductal phase (I), ductular phase (II), fibrosing-cicatrizing (precirrhotic) stage (III), and cirrhotic stage (IV). (252) • Applying this classification,

H. P opper et al. (1970) described stage I as a cholangitic phase and stage II as a phase of ductular proliferation

⫺ they retained the original terms for stages III and IV.

• A modified classification was proposed by J. L udwig et al. in 1978. (191) They used the terms: portal hepatitis (I), periportal hepatitis (II), septal necrosis/fibrosis (III), and cirrhosis (IV).

Electron microscopy: Focal destruction of the numeric- ally diminished microvilli is evident. Spreading of the

peribiliary canalicular ectoplasm is attributed to an increase in filamentous structures. The mitochondria within the epithelial cells of the bile ducts multiply.

Finally, the affected bile canaliculi are completely ob- literated. • Thus it would seem that the primary damage, which results in CNDC, actually originates from the canaliculi (G. S chwalbach, 1979 ; K. T obe, 1982) . (213, 215, 294)

Stage I: Laparoscopically, the liver is of normal size and consistency. The surface colour is reddish-brown, pos- sibly with yellowish spots; it may even have a “tiger skin-like” colouring. • Histologically, there is evidence of ductular lesions similar to cholangitis as well as por- tal and pericanalicular infiltrations (lymphocytes, histio- cytes, plasma cells, eosinophilic leucocytes and, more rarely, polymorphonuclear granulocytes). The portal fields are affected regionally to different degrees and to a variably severe extent ⫺ sometimes, they are not affected at all. Mononuclear cells penetrate the walls of the small bile ducts. The histiocytes can form granulo- mas, mostly of the sarcoid type, which may also contain Langhans’ giant cells. At first, the florid, interlobular and septa bile-duct lesions with follicular elements only develop focally. The liver parenchyma is hardly affected.

The lesions are distributed irregularly in the liver. There is no evidence of cholestasis. (194, 214 ⫺216) (s. fig. 32.7)

Fig. 32.7: PBC stage I: Epithelioid cell granuloma ( 앖) related to a septal bile duct; focal inflammatory destruction of the bile-duct epithelium; granuloma-like nodule of macrophages entering the lu- men

Stage II: Laparoscopically, the liver now has a firmer

consistency (ascertained by pressure of the probe). With

the onset of cholestasis, the surface colour gradually

becomes reddish-yellow to speckled green. There are

clearly more subcapsular blood vessels. The surface is

finely rippled or granulated. (118, 184, 207) (s. fig. 32.8) •

Histologically, there is a reduction in the periductular

lesions, possibly with increasing proliferation of the cho-

langioles, and a drop in the number of portal bile ducts

( ⫽ increasing appearance of arteries without concomi-

tant bile ducts). There is often evidence of pigmentation

and PAS-positive material in the bile-duct endothelia. A dense collagenous fibre network develops. The liver cells occasionally contain Mallory bodies. Activated macro- phages cause secondary cellular necroses. Proliferation of stellate cells and lymphocytic infiltrations develop within the sinusoids. The inflammatory infiltrations spread to the lobules and present as piecemeal necrosis ( ⫽ interface hepatitis). (99, 110, 199, 234, 236, 251, 256)

Fig. 32.8: Primary biliary cholangitis: Map-like marking of the liver surface (stage I); still largely smooth surface (see light reflex), dark red/livid blue colouring; tiger skin-like pattern in the irregular reddish areas

Stage III: Laparoscopically, the liver has a markedly firmer consistency; the granular, in parts finely tuberous surface has a reddish-brown colour with greyish-green speckling. There are noticeably more subcapsular blood and lymphatic vessels. The first evidence of commencing portal hypertension is found in the ligaments. The spleen is enlarged and of a dark red colour. • Histologi- cally, periportal scarring and the formation of fibrosis predominate due to persistent stimulation of fibrogen- esis. The bile ducts are greatly reduced in number, and countless small arteries are apparent. The inflammatory infiltrations and bile-duct proliferations gradually become less obvious. (s. fig. 32.9) However, the different morphological stages can overlap in the same patient.

Copper is increasingly deposited in the lysosomes (10 ⫺60 mg/100 g/dry weight) and subsequently in the liver, spleen and kidneys (but not in the brain). Severe lobular central cholestasis now becomes pronounced.

Macrophages occasionally contain lipid and form pseu- doxanthomatous cells. (s. fig. 32.9)

Stage IV: Biliary cirrhosis, also described as stage IV, is the possible morphological final stage of PBC (or CNDC), in which the remaining biliary ductules are now subject to destruction, and consequently disappear.

Basically, CNDC is in itself “chronic cholangitis”. • Laparoscopically, the liver surface shows irregular, finely rippled, micronodular (at selective sites also macronod-

ular) cirrhosis. The vessels are more numerous and more clearly marked. The colour is brownish-grey to graphite- green, in some places more distinct. There are lymph cysts and signs of portal hypertension. • Histologically, one can find advanced scarred septation and regenera- tive growth in the form of a complete cirrhosis with almost no inflammatory activity. Cholestasis is severe.

There is virtually no evidence of bile ducts; granulomas are rare. (146, 234, 246) (s. fig. 32.9)

Fig. 32.9: Primary biliary cholangitis with cirrhotic transform- ation. Well-rounded parenchymal residues surrounded by collage- nous fibre tissue; hardly recognizable bile ducts in the residual round cell-infiltrated portal fields (stages III ⫺IV) (HE)

䉴 Strictly speaking, the historical term primary bili- ary “cirrhosis” (coined in 1950) (60) cannot be re- tained for primary biliary cholangitis with all its well- defined stages (CNDC I ⫺III) ⫺ because there is no sign of cirrhosis during the precirrhotic stages I ⫺III, and CNDC does not necessarily lead to cirrhosis. As early as 1965, E. R ubin et al. objected to the definition of PBC as “cirrhosis” on the grounds that it was a

“misnomer” (247) . • All forms of “chronic cholan- gitis” (e. g. obstructive, primary biliary, primary or secondary sclerosing and immunological) may develop into biliary cirrhosis ⫺ which can barely (or only unreliably) be differentiated histologically and in no way aetiologically. • It is not justified to use a pathologically incorrect term simply because it once became established in a historical context.

Cirrhosis is never “primary”, but always has a rela- tively long developmental phase. Consequently, there is no “primary” and hence no “primary biliary” cirrhosis!

4.6 Clinical courses

In general, the three morphological stages I ⫺III (precir-

rhotic) are more or less equivalent to the clinical stages

I ⫺III, although fluid transitions understandably exist in

each case. Stage IV (cirrhotic) would correspond to the

clinical stages IV and V. • Assignment to a particular

disease phase also yields prognostic information. From a clinical and morphological point of view, the division into a precirrhotic and a cirrhotic stage is significant (and generally adequate).

4.6.1 Asymptomatic stage (I)

In general, there is no evidence of PBC in this initial phase. Occasionally, some patients complain of fatigue (s. p. 235) and weakness (116, 122, 140, 240, 242) as well as minor, short-term pruritus. (s. p. 235) • Often, an (ini- tially inexplicable) increase in γ-GT and AP is witnessed during investigations indicated for other reasons. The sulphated bile acids in the serum are elevated. • If the possibility of PBC is “taken into consideration” at this stage, evidence of AMA, especially of the subtype M

, can provide an early diagnosis. AMA are a very early marker of PBC ⫺ often a long time before other labora- tory or clinical findings become evident. (76, 77, 104, 112, 137, 149, 152, 163 ⫺165, 205, 225, 246, 260, 263, 285, 295) • How- ever, jaundice, gastrointestinal haemorrhages, bleeding oesophageal varices, osteoporosis and ascites have also been reported as initial symptoms. (65, 79, 91, 124, 242, 297)

4.6.2 Oligosymptomatic stage (II)

Clinically, pruritus becomes more and more pro- nounced, particularly at night, and is mainly localized in the extremities and perianal region. Pruritus is often the reason for a dermatological examination. Sub- jectively, arthralgia and steatorrhoea may also occur.

Hepatomegaly is verifiable in about 50% of cases. The cholestasis-indicating enzymes are elevated; this correl- ates with the release of leukotrienes. Occasionally, (nearly) normal values of AP are found. The metab- olism of bile acids is disturbed. • AMA are positive (ca.

95% of cases), so that the subtype M

can now be deter- mined. (s. tab. 5.21) (s. fig. 5.14) There is no difference in the frequency of AMA between men and women.

AMA are sometimes detectable also in urine, bile and tears. About 10% of cases show no evidence of AMA.

ANA appear in 25 ⫺50% of patients as a multiple nuclear dot type (MND-ANA) or a nuclear ring stand- ing form. Their presence confirms an AMA-negative PBC. Furthermore, antibodies against Escherichia coli proteases are found in ca. 30% and a typical pANCA in ca 15% of patients. Antibodies against parietal cells (anti-PCA) are detectable in nearly all cases. Simultan- eous negativity of AMA may be suggestive of an overlap syndrome. (s. p. 660) As a rule, IgM is clearly increased.

Elevated cholesterol and reduced HDL are often found with an additional rise in LDL. Generally, lipoprotein X is detectable. (61, 91, 205)

4.6.3 Symptomatic anicteric stage (III)

Pruritus and scratch wounds are a major impairment in daily life; the patients suffer enormously. With marked pruritus, a so-called butterfly sign is sometimes found

on the patient’s back, i. e. the area which cannot be reached by scratching (T. B. R eynolds, 1973) . (s. pp 85, 235) • Gradually, hyperpigmentation of the skin occurs due to melanin. Hepatomegaly is verifiable in 70 ⫺80%

of cases, splenomegaly in 20%. Portal hypertension develops, predominantly of the intrahepatic presinus- oidal type. Xanthelasmas and xanthomas form slowly, particularly on the lower and upper eyelids, on the ten- dons of the extensor muscles, on the elbows and heels as well as on the palms of the hands. (s. figs. 4.14 ⫺4.16) Biochemistry reveals increased values of AP, LAP, γ- GT and transaminases as well as enhanced values of cholesterol, LDL and IgM. In some patients, consider- able eosinophilia occurs ⫺ in correlation with the activ- ity of mast cells in the portal field. The galactose elim- ination capacity is reduced. Osteoporosis has reached an advanced stage. Up to now, no factors predicting progression from the presymptomatic to the symptom- atic stage are known. (91, 98, 146, 157, 205, 209, 225, 246)

4.6.4 Icteric stage (IV)

Jaundice develops within 6 months in rapidly pro- gressing forms or between 2 to 3 years after the onset of pruritus. In general, icterus suggests transition to the final stage. The bilirubin value mostly remains stable below 5.0 mg/dl for months or years, while clinical symptoms as well as hepatic erythema grow in intensity.

Dark urine and acholic stool are observed. The AP, LAP and γ-GT levels are (noticeably or even markedly) elevated; transaminases remain within the range of 30 ⫺100 U/l. The parameters relating to the rate of syn- thesis (cholinesterase, Quick’s value, albumin) decrease.

The galactose elimination capacity is significantly reduced. (244) The γ-globulins and P-III-P are elevated.

Serum copper is often increased, and copper secretion in urine is likewise higher.

4.6.5 Final stage (V)

Clinically, morphologically and biochemically, the over- all picture of cirrhosis prevails (in 4 years: 30 ⫺50%);

however, 20% of precirrhotic patients do not show any progression. PBC ends fatally either due to bleeding of oesophageal varices (50%) or liver insufficiency. This final stage is reached after a period of 8 to 15 years (depending on individual progression).

4.7 Complications

Owing to the greater sensitivity of PBC patients to pharmaceutical preparations, different pharmacons, e. g.

phenothiazines, contraceptives, oestrogens and anabolic

steroids, can reinforce cholestasis and the clinical symp-

toms, thus aggravating the course of disease. • Gallstones

are frequently detectable (35 ⫺40%); as a rule, they are

pigment gallstones. Administration of clofibrate is con-

traindicated; it gives rise to increased formation of gall- stones due to enhanced cholesterol secretion into the bile. • Xanthomas can lead to mechanically induced neu- ropathy. (272) Malabsorption of fat-soluble vitamins due to steatorrhoea resulting from bile acid deficiency causes corresponding deficiency symptoms. (168, 257) • Osteopathies occur in 20 ⫺60% (⫺100%) of cases; a decrease in bone density may be measurable at an early stage. Osteoporosis occurs twice as often as in the gen- eral population. The cause is multifactorial (e. g. defi- ciency of calcium, vitamin D and oestrogen, long dura- tion of disease, genetic factors). Osteomalacia is less frequent. In both forms of osteopathy, excretion of hydroxyproline in urine is increased as a sign of the enhanced rate of bone absorption. (78, 105, 113, 128, 129, 133, 208, 217, 228, 232) • About 20% of patients are suffer- ing from asymptomatic urinary tract infection. Hepato- cellular carcinoma develops in about 6% of PBC cases.

PBC may sometimes be accompanied by severe compli- cations, leading to a poorer prognosis. (s. tab. 32.2)

1. Cholelithiasis

2. Exocrine pancreatic insufficiency 3. Hemeralopia (vitamine A deficiency) 4. Carcinoma (115)

⫺ HCC (male > female) (147, 169, 221, 292)

⫺ breast cancer ⁽²⁹²⁾

5. Coagulopathy (vitamine K

deficiency) 6. Paramenia

7. Osteopathy

with ostealgia, infraction of vertebral bodies, spontaneous fractures

(predominantly in associated sprue: 5 ⫺10%)

⫺ osteoporosis

⫺ osteomalacia

8. Portal hypertension (65, 153)

⫺ oesophageal varices (124, 266, 297)

⫺ ascites

⫺ hepatic encephalopathy 9. Renal tubular acidosis

10. Xanthomatous neuropathy (272)

Tab. 32.2: Complications of PBC (with some references)

4.8 PBC-associated immunologic diseases

Apart from complicative developments, the course of PBC is also aggravated by associated diseases, which occur almost exclusively as immunologic disorders.

About 25% ( ⫺40%) of all patients with PBC contract one or more such diseases. As a result, the quality of life is considerably impaired, further complications are induced or reinforced, and the prognosis worsens. (s.

tabs. 32.3, 32.6)

1. Anaemia perniciosa 2. Ankylosing spondylitis (279) 3. CREST syndrome (196, 239)

( ⫽ calcinosis cutis, Raynaud’s phenomenon, oesophageal motility disorder, sclerodactyly, teleangiectasia)

4. Dermatitis herpetiformis (119) 5. Dermatomyositis

6. Glomerulonephritis (211, 243) 7. Grave’s disease (220)

8. Haemolytic anaemia 9. IgA deficiency (144)

10. Immunocomplex capillaritis (243) 11. Intestinal manifestations

⫺ coeliac disease (69, 101, 119, 166, 167, 258)

⫺ ulcerative colitis (167)

⫺ jejunal villous atrophy 12. Lichen planus (126) 13. Lupus anticoagulant (367) 14. Lupus erythematosus (132, 142) 15. Lymphadenopathy (103, 109, 192, 230) 16. Mixed collagenosis (MCTD)

17. Myelitis (62, 248) 18. Polymyalgia rheumatica 19. Polymyositis (82)

20. Pulmonary manifestations (88, 259, 283)

⫺ interstitial pulmonary fibrosis (286)

⫺ granulomatous lung infiltrates

⫺ pulmonary infiltrations

⫺ sarcoidosis (259)

21. Retroperitoneal fibrosis (269) 22. Rheumatoid arthritis (123, 197) 23. Sclerodermia (206, 233)

24. Sjögren’s syndrome (62, 96, 104, 248, 274, 277) 25. Skin granulomas (145)

26. Teleangiectasia (135) 27. Thrombocytopenia (253)

28. Thyroiditis, hypothyroidism (96, 106)

Tab. 32.3: PBC-associated immunological diseases (with some references)

4.9 Diagnosis

First of all, the diagnosis of PBC is based on the patient’s discomfort in the form of fatigue, decline in functional capacity and pruritus, all of which, however, are uncharacteristic symptoms. PBC is verified if the following laboratory parameters can be demonstrated:

1. γ-GT 앖, AP 앖, LAP 앖 2. IgM 앖

3. Evidence of AMA

⫺ with subtypes (AMA profile)

The diagnosis of PBC should be supplemented by la-

boratory values, such as GPT, GOT, cholinesterase, cho-

lesterol (especially HDL fraction), LP-X and/or α-lipo-

protein, the galactose test, bilirubin as well as IgG and

electrophoresis, possibly also P-III-P and the MEGX

test. Because of their prognostic weighting, these values

(including γ-GT and AP) are considered to be the main

parameters for monitoring the course of disease and

success of therapy. Furthermore, they co-determine the

most suitable time for liver transplantation.

In the first instance, morphological diagnostics is based on laparoscopy, and, as a general principle, this method should be used for the initial diagnosis. All essential endoscopic findings are documented photographically.

Naturally, laparoscopy does not produce a diagnosis of PBC, but it facilitates classification into the respective stages I ⫺IV. (118, 184, 207) (s. p. 645) (s. fig. 32.8) • Targeted liver biopsy is then carried out by laparoscopy, whereby biopsy material is taken from both the right and left lobes of liver. The histological diagnosis of PBC is very unreliable because of the different patterns of morphological findings and the fact that criteria of the various stages can coexist. Nevertheless, targeted liver biopsy is imperative, even if the diagnosis is based upon reliable laboratory values: it facilitates an important additional assessment of inflammatory activity. (s. figs.

32.7, 32.9) • Ultrasound and CT do not yield any further diagnostic information. Lymphadenopathy is frequently present. (103, 109, 192, 230) Hepatobiliary sequential scin- tigraphy demonstrates a 7 to 10-fold prolongation of the excretory phase in stages III and IV. (174, 224, 256) (s. fig.

13.7) • The MRI periportal halo sign is deemed to be highly specific for PBC. (287) • Although ERCP plays an essential role in differential diagnosis, it cannot pro- duce a diagnosis of PBC in itself. In the later course of disease, the bile ducts show certain irregularities and rarefaction (as ambiguous findings). (s. fig. 32.10)

Fig. 32.10: ERCP shows smooth bile ducts of normal calibre; in later stages, there is rarefication of bile ducts, and certain irregular- ities appear

4.10 Prognosis

Life expectancy ranges from 9 ⫺15 years following the diagnosis of PBC. The patient’s life span is thus shorter than in the general population. The course of asymp- tomatic PBC is variable and difficult to predict. Some (25 ⫺35%) will never become symptomatic and others will run a progressive downhill course. The survival time of asymptomatic patients is generally longer than that of symptomatic patients; about 45% of cases were still asymptomatic at death. (242) Approximately 26% of PBC patients developed acute liver failure; in 39% of cases, liver transplantation could be kept until the cen- sor date. (241) An individual prognostic assessment is desirable for the initiation of therapeutic measures.

Indeed, several prognostic models have become estab- lished in recent years, e. g. Mayo model for survival (E.R.

D ickson et al., 1989) . (86, 125, 225, 249, 256) • Female patients (only a very low number of males are affected) contract PBC in middle age (between 35 and 60 years). Preg- nancy after the onset of PBC is very rare (so far < 20 cases have been reported). (222) • An early diagnosis in the presymptomatic or, at the latest, in the oligosympto- matic stage offers the best prognosis. This is also true if the stage of disease is identified at a relatively early age (between 35 and 45 years). The AMA profile is appar- ently of some significance in early diagnosis (s. p. 120):

in long-term follow-up over a period of up to 18 years, the poor prognosis of patients with profile C was only identifiable after 8 ⫺9 years, and with profile D after 6 ⫺7 years. In other studies, AMA profiles were not con- firmed as a prognostic parameter. The profile of AMA subtypes does not change during the course of PBC. (s.

tab. 5.21) • Those courses with less favourable prognoses showed a greater increase in IgG values as a sign of more distinct immunologic activity and correlated with increased TNF. • The presence of SLA/LP antibodies has a high specificity for the development of a second- ary AIH overlap syndrome. (s. p. 660)

With regard to laboratory parameters, an increase in bilirubin to > 5 ⫺6 mg/dl is considered to be an essential prognostic factor. In such cases, the average life expec- tancy is now less than 2 years. A decline in the synthesis rate of the liver (cholinesterase, Quick’s value, albumin) is usually also evident. Follow-up checks by means of the galactose test (244) are useful. Severe cholestasis, which can hardly or not at all be influenced, has to be rated just as poorly in terms of prognosis as a therapy- resistent and progressive pruritus. Increasing portal hypertension together with its complications, e. g.

oesophageal varices, ascites and/or oedemas and hepatic

encephalopathy, point to the final stage of PBC or to

decompensated liver insufficiency. • Based on the

pattern of these prognostic factors, important decisions

can be taken with regard to drug therapy and possibly

also the date of liver transplantation. • Histological

findings are not suitable for the prognostic assessment

of PBC.