Clinical Aspects of Liver Diseases 38 Systemic diseases and the liver

38 Systemic diseases and the liver

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1 Systemic haematological diseases 812

1.1 Extramedullary haemopoiesis 812

1.2 Acute leukaemia 812

1.3 Myeloproliferative syndrome 812

1.3.1 Chronic myeloid leukaemia 813

1.3.2 Osteomyelofibrosis 813

1.3.3 Polycythaemia vera 813

1.3.4 Essential thrombocytosis 813

1.4 Haemolytic syndrome 814

1.4.1 Sickle-cell anaemia 814

1.4.2 Thalassaemia 814

1.4.3 Paroxysmal haemoglobinuria 814

2 Systemic lymphatic diseases 814

2.1 Hodgkin lymphoma 814

2.2 Non-Hodgkin lymphoma 816

2.2.1 Low-grade malignant NHL 817

2.2.2 High-grade malignant NHL 818

3 Systemic rheumatic diseases 818

3.1 Rheumatoid arthritis 818

3.2 Still’s disease 819

3.3 Adult Still’s disease 819

3.4 Sjögren’s syndrome 819

3.5 Felty’s syndrome 819

3.6 Polymyalgia rheumatica 819

3.7 Polymyositis 819

3.8 Periarteritis nodosa 820

3.9 Lupus erythematosus 820

3.10 Wegener’s granulomatosis 820

3.11 Eosinophilic granulomatous vasculitis 820

4 Mastocytosis 820

5 Histiocytosis X 821

앫 References (1⫺123) 821

(Figures 38.1 ⫺39.13; tables 38.1⫺38.4)

Systemic diseases originating in the haemopoietic or lymphatic systems and those belonging to the cate- gory of rheumatic diseases can affect the liver directly or indirectly.

Haematopoietic system 1. Direct effects on the liver

⫽ pathological extramedullary haemopoiesis in the liver

⫽ disturbed liver haemodynamics following haemolysis 2. Indirect effects on the liver

⫽ reduced defence against infections facilitates bacterial, viral or mycotic liver damage

⫽ toxic liver damage caused by drugs (e. g. cytostatics, immunosuppressants)

⫽ graft-versus-host reaction in bone-marrow transplants Lymphatic system

1. Direct effects on the liver

⫽ pathological formation and deposition of lymphocytes or lymphoblasts with formation of infiltrates or focal lesions

⫽ cholestasis following mechanically mediated biliary dys- kinesia

2. Indirect effects on the liver

⫽ reduced defence against infections facilitates bacterial, viral or mycotic liver damage

⫽ toxic liver damage caused by drugs (e. g. cytostatics, immunosuppressants) Rheumatic diseases

1. Direct effects on the liver

⫽ rheumatism-related inflammatory or immunologically in- duced intrahepatic vasculitis with sequelae

⫽ non-specific reactive hepatitis 2. Indirect effects on the liver

⫽ toxic liver damage caused by drugs

(e. g. antirheumatic agents, immunosuppressants)

Tab. 38.1: Relationship of the liver to the haematopoietic and lymphatic systems and to the category of rheumatic diseases

1 Systemic haematological diseases

1.1 Extramedullary haemopoiesis

䉴 Intrahepatic haemopoiesis is a physiological process in foetuses and neonates. From 6

to 24

week of pregnancy, haemopoiesis takes place in the liver (and spleen) in a diffuse manner within the sinusoids. Thereafter, focal haemopoiesis may still continue in the liver up to about the second week of life.

Myeloid metaplasia beyond this physiological endpoint of intrahepatic haemopoiesis is regarded as a pathological event. Haemopoietic foci are seen in the sinusoids, in Disse’s spaces and sometimes to a minor degree in the portal fields; they consist of erythropoietic and myelo- proliferative precursors as well as polynuclear giant cells of the megakaryocyte type. This variety of cells provides important evidence in histological differential diagnosis for excluding leukaemic infiltrates and mononuclear

hepatitis. Myeloid metaplasia accompanies displacement of the bone marrow, e. g. in osteomyelofibrosis, bone- marrow carcinomatosis and myeloproliferative diseases.

Occasionally, megakaryocytes are also present in the liver. Naphtol-AS-D chloracetate esterase-positive cells of granulopoiesis are a striking feature in this context.

Hepatomegaly is generally found. Ascites can develop due to portal hypertension. (s. fig. 38.1)

Fig. 38.1: Extramedullary haemopoiesis in the liver with erythro- poiesis precursors and intrasinusoidal megakaryocyte ( 앖) due to the so-called marrow-replacement syndrome or chronic myelopro- liferative disease (HE)

1.2 Acute leukaemia

In acute myeloid leukaemia or lymphatic leukaemia as well as in acute leukaemic episodes in non-Hodgkin lymphoma, involvement of the liver may only be detect- able clinically by the presence of hepatomegaly and sub- icterus. • Laboratory parameters usually show slightly elevated transaminase as well as bilirubin values, and distinct cholestasis is occasionally observed. (7) Acute hepatic failure can occur during the course of acute leukaemia. (1, 8, 26, 65) • Histologically, there are massive, yet uniform blast-cell infiltrates; these are found mainly within the portal fields in acute lymphatic leukaemia (about 95%) and within the sinusoids in acute myeloid leukaemia (about 75%). • Involvement of the liver is of no consequence with regard to the underlying disease and its therapy. Secondary infections require systemic treatment with antibiotics and/or antimycotics.

1.3 Myeloproliferative syndrome

The term myeloproliferative syndrome encompasses the

following: (1.) chronic myeloid leukaemia, (2.) idio-

pathic osteomyelofibrosis and sclerosis, (3.) polycyth-

aemia vera, and (4.) essential thrombocytosis. Inter-

mediate forms of these manifestations are possible. The pathogenesis is based on the transformation of a stem cell and its clonal proliferation. • Chronic lymphatic leukaemia is classified as malignant non-Hodgkin lym- phoma. Overlaps between the different forms of disease are frequent. There is a tendency for fibrosis to develop in all types of the myeloproliferative syndrome with sub- sequent sclerosis of bone marrow in later stages. Certain forms may progress to acute leukaemia, which is termed blast crisis.

1.3.1 Chronic myeloid leukaemia

In CML, granulopoiesis is markedly accelerated, with increased formation of immature precursors. This oc- curs predominantly in the bone marrow. Accordingly, there is only a rare and slight involvement of the liver in CML, with the exception of a terminal myeloblast crisis. (s. fig. 38.2) Hepatomegaly may be very pro- nounced in some cases. Massive splenomegaly is gen- erally evident; it often presents as a sugar-icing spleen (perisplenitis cartilaginea). (s. fig. 38.3) Infiltrations of immature granulocytes and erythrocytes as well as of megakaryocytes are identifiable above all in the (gen- erally dilated) sinusoids. Biochemically, there is an eleva- tion of alkaline phosphatase and LDH. Complications include portal hypertension following obstruction of the sinusoids and as a result of increased hepatic blood flow.

(18) Acute liver failure has been observed. (15) In the final stage, metastasis-like structures can appear in the liver (so-called chloroma). Imaging procedures reveal no abnormalities in the area of the liver parenchyma. (5, 11)

• Therapy with imatinib was recently reported as being successful.

1.3.2 Osteomyelofibrosis

Osteomyelofibrosis is a chronic, progressive, fibrous obliteration of the bone marrow. Greyish-white discol- ouration appears with an increase in collagenous fibrils and later also in reticular fibrils. Clinically, there is hepatomegaly (and generally also splenomegaly) correl- ating with the stage of disease. Arthralgia also occurs occasionally. • Laboratory parameters may show a slight elevation of γ-GT, AP, transaminases and bilirubin.

Leucocyte alkaline phosphatase is enhanced. • Histolog- ically, extramedullary haemopoiesis, comprising eryth- rocyte and granulocyte precursors as well as dysplastic megakaryocytes, is found in the liver in > 90% of cases.

(13, 16) (s. fig. 38.1) Infiltrates appear in the sinusoids, which are partly dilated and display fibrosis and de- posits of haemosiderin. This results in portal hyperten- sion (6, 12) ; ascites (10) and oesophageal varices are rare (about 7% of cases). Further potential complications in- clude cholelithiasis (its relationship has not been clari- fied so far), Budd-Chiari syndrome and portal vein thrombosis. (2) • The diagnosis is established by liver

Fig. 38.2: Terminal blast crisis of chronic myeloid leukaemia:

numerous myeloid blasts in the sinusoids (HE)

Fig. 38.3: Splenomegaly with perisplenitis cartilaginea (sugar-icing spleen) in chronic myeloid leukaemia

histology. Imaging procedures are of no significance here.

1.3.3 Polycythaemia vera

Liver involvement in Osler-Vaquez disease is rare or not detectable at all. There is, however, evidence of hepato- splenomegaly due to extramedullary haemopoiesis. Of importance here is the association with Budd-Chiari syn- drome and veno-occlusive disease. Polycythaemia vera should be considered in cases of aetiologically unclari- fied portal vein thrombosis.

1.3.4 Essential thrombocytosis

With the exception of occasional hepatosplenomegaly,

liver involvement is rare. There is again an association

with Budd-Chiari syndrome and veno-occlusive disease.

1.4 Haemolytic syndrome

Numerous congenital or acquired diseases lead to haemolysis. (s. p. 218) (s. tab. 12.3) They are sub- sumed under the term haemolytic syndrome. Particu- larly, sickle-cell anaemia, thalassaemia and paroxys- mal nocturnal haemoglobinuria are worthy of men- tion in this context.

1.4.1 Sickle-cell anaemia

This form of genetic haemoglobinopathy is characterized by chronic haemolysis and haemolytic crises. • Acute haemolysis is associated with acute right upper quadrant pain, leucocytosis, jaundice and elevated transaminases, AP and LDH. This hepatic crisis can mimic acute chole- cystitis. It lasts 2 ⫺3 weeks. The condition is caused by a slowing down of the sinusoidal blood flow, which con- tains sickle cells, and, in addition, by a multiplication of the Kupffer cells. The liver is enlarged, rich in blood and violet-red. The sinusoids are dilated and contain agglutinates of sickle cells. The Kupffer cells contain ceroid and siderin as well as phagocytosed erythrocytes.

(s. fig. 38.4) Single-cell necroses of hepatocytes with Councilman bodies are detectable. Acute liver failure, usually with cholestasis and deep jaundice, is a rare event. • Chronic haemolysis can lead to mostly asymp- tomatic gallstones (approx. 25% in children, 50 ⫺70%

in adults). Furthermore, portal hypertension and portal fibrosis may develop. (3, 4, 9, 14, 19) Therapy: Exchange transfusion is indicated. Surgery must be avoided in cases where acute cholecystitis is only mimicked. • Suc- cessful liver transplantation has been reported.

Fig. 38.4: Erythrophagocytosis in Kupffer cells (arrows) in haemo- lytic anaemia

1.4.2 Thalassaemia

As a result of the crises entailing destruction of the red blood cells and the frequently required blood transfu- sions, liver siderosis develops. This may subsequently lead to fibrosis in some cases. Episodic cholestasis can be witnessed. In progressive siderosis, treatment with deferoxamine is indicated. Pigment gallstones (s. figs.

35.16, 35.17) can appear in the course of chronic haemolysis. (4)

1.4.3 Paroxysmal haemoglobinuria

Paroxysmal nocturnal haemoglobinuria may also give rise to chronic haemolysis. This membrane defect of the erythrocytes is due to mutation of the PIG-A gene on chromosome X resulting in deficient biosynthesis of the glycosylphosphatidlinositol anchor. The erythrocytes are sensitive to lysis when the pH of the blood becomes more acidic during sleep. This clinical picture can lead to hepatomegaly, a rise in transaminases, iron deficiency and siderosis as well as centrizonal necrosis. Thrombosis of the portal and splenic veins as well as Budd-Chiari syndrome are possible complications. Sclerosing cholang- itis is likely to develop due to ischaemia. (17)

2 Systemic lymphatic diseases

Hodgkin’s disease and non-Hodgkin’s lymphomas belong to this group. Liver involvement as a result of these diseases consists of infiltrates of lymphocytes or their precursors as well as the formation of lymphatic tissue nodes. The liver itself has no organ-specific lymphatic tissue.

2.1 Hodgkin lymphoma

䉴 ^T h . H odgkin described the so-called Hodgkin’s lymphoma in 1832; in 1865 S. W ilks coined the term Hodgkin lymphoma. R.

P altauf reported on lymphosarcomatosis in 1897. • The aeti- ology of this malignant systemic disease is unknown. Hodgkin’s lymphoma invariably begins in the lymphatic tissue ( ⫽ lympho- granulomatosis), mainly in the neck and mediastinum. The lymph node swelling is not painful.

Typical Hodgkin cells derive from undifferentiated retic- ular cells. They have a slightly basophilic cytoplasm and 1 or 2 glowing red or violet nucleoli in a very light, almost unstained nucleus. These cells are the mononu- clear precursors of the polynuclear Paltauf-Sternberg gi- ant cells ^{(R. P} altauf, 1897 ; C. V. S ternberg, 1936) . Such re- ticular giant cells are considered to be a reliable symp- tom of Hodgkin lymphoma in the liver (stage IV) when they are found in the typical cellular environment of a Hodgkin’s granuloma. • Five forms of Hodgkin lym- phoma are distinguishable histologically (1965, 1971):

1. nodular sclerosis 40ⴚ80%

2. mixed cellular form 20ⴚ40%

3. lymphocytotic type 2ⴚ10%

4. lymphocytopenic type 2ⴚ5%

5. unclassifiable form 1ⴚ5%

The liver is the most frequently affected non-lymphatic

organ in Hodgkin lymphoma (30 ⫺50% of cases). Liver

involvement is highest in the lymphocytopenic type

(which also has a particularly unfavourable prognosis) and in nodular sclerosis. Liver involvement is lowest in the lymphocytotic type. There is evidence of large, irregu- larly delineated tumour nodes and multiple, diffusely distributed nodules or even subcapsular miliary nodules.

These macroscopic forms can also occur in combin- ation; their histological properties are largely identical.

Acute liver failure can develop. (35, 38) Hepatomegaly is frequently observed. Splenomegaly is generally associ- ated with liver involvement. Non-involvement of the spleen is extremely rare (34) ; a normal-sized spleen gen- erally rules out involvement of the liver. • Hodgkin in- filtrates originate in the portal fields; they are arranged irregularly. Numerous reticulin fibres and dilatations of the sinusoids are frequently found in zones 2 and 3. The infiltrates consist of focally arranged histiocytes, epithe- lioid cells, eosinophils and small lymphocytes as well as Hodgkin cells and Sternberg cells. Central venous ob- struction and endophlebitis can appear as a conse- quence of Hodgkin lymphoma in the liver. (20, 27, 39, 51, 57) (s. figs. 38.5 ⫺38.9)

Fig. 38.5: Hodgkin lymphoma: portal granuloma with Paltauf- Sternberg giant cell ( 앖) (HE)

Fig. 38.6: Hodgkin lymphoma: relatively well-defined, large intra- lobular granuloma with numerous Hodgkin cells (HE)

Clinically, there is loss of weight (>10% within 6 months), fever ( ⫽ Pel-Ebstein type, i.e. periodic fever at short intervals), night sweats, weakness, pain in the lymph nodes (following intake of alcohol) and pruritus

Fig. 38.7: Late stage of lymphocyte depleted in Hodgkin lym- phoma (HE)

Fig. 38.8: Hodgkin lymphoma: node at the margin of the left liver lobe; clear, diffuse (reticular) fibrosis of the liver

Fig. 38.9: Hodgkin lymphoma: several foci up to the size of a lentil

as well as a 1.5 cm tumour node in the greatly enlarged spleen

(particularly in the later stages). The so-called B-symp- tomatology (occurrence of weight loss, fever, night sweats) is mostly present when the liver is involved. (33)

Laboratory investigation reveals highly pathological “in- flammatory criteria”, which probably point to a con- suming or malignant process. Alkaline phosphatase and bilirubin rise in the further course of disease (in about 80% of cases). Lymphopenia and eosinophilia are often in evidence. (36, 38, 41) (s. tab. 38.2)

Non-specific “inflammatory criteria”

(or indicators of a consuming process)

ESR 앖 α-globulins 앖

CRP ⫹ haptoglobin 앗

fibrinogen 앖 copper 앖

iron 앗 cholinesterase 앗

haemoglobin 앗 D-dimer 앖

Tab. 38.2: Non-specific “inflammatory criteria” (or indicators of a consuming process) (s. tabs. 37.6, 37.11, 37.12)

Imaging procedures display focal lesions, which appear hypoechoic and generally without a halo in sonography;

in the further course of disease, the centre can yield a more hyperechoic structure. MR-SPECT has proved es- pecially reliable in this connection. (25, 58, 62) • The diag- nosis is established morphologically. This can be achieved most reliably by laparoscopy and targeted biopsy. (22, 51) Percutaneous biopsy has a low specificity;

it must be carried out, if at all, under US or CT guid- ance (several samples should be obtained from both liver lobes). Liver involvement always corresponds to Hodgkin stage IV ( ⫽ non-localized, diffuse or dissemin- ated disease of one or more extralymphatic organs or tissues, with or without involvement of the lymphatic system). (43) • Therapy consists of polychemotherapy and/or intercurrent small-field irradiation, if applicable.

The recurrence rate can be significantly reduced by mild chemotherapy prior to irradiation. In the case of recidi- vation, however, high-dose chemotherapy clearly shows greater efficacy. (53)

2.2 Non-Hodgkin lymphoma

The term non-Hodgkin lymphoma (NHL) subsumes a large number of different malignant diseases of the lymphatic system. Taken together, they have about the same frequency as Hodgkin’s lymphoma. The annual incidence of the disease in Germany is about 15 per 1 million inhabitants.

䉴 According to their clinical progression, they are classified into lymphomas of low and high malignancy. Classification is based on the Kiel Classification (K. L ennert, 1978) , the USA Classification (H. R appaport et al., 1978) or the New Working Formulation (1980).

Staging corresponds to that of Hodgkin lymphoma (1971), i. e.

liver involvement represents the prognostically critical stage IV. (s.

tab. 38.3) • NHL occurs in three macroscopic forms:

1. micronodular, disseminated infiltrates 2. macronodular multiple nodes 3. solitary tumour masses

There is (primary or secondary) involvement of the liver in about 50% of patients with NHL (initially in approx.

20%, postmortem in > 60%). The liver is seldom affected without simultaneous involvement of the spleen. How- ever, liver involvement in NHL is of less importance than in Hodgkin lymphoma. In most cases, lymphocytic lymphomas result in miliary foci, whereas histiocytic lymphomas predominantly develop into tumour nodes.

Macronodular, greyish-white nodes and solitary, grey- ish-white tumour masses are rare. Micronodular, dis- seminated infiltrates are produced by involvement of the portal fields, mainly in low-grade malignant forms of NHL. They appear as barely recognizable, fine-grained, white foci on the cut surface of the liver. • Diagnosis is confirmed morphologically with the aid of laparoscopy and targeted biopsy or forceps biopsy (22, 51) , or by per- cutaneous biopsy under US or CT guidance. The use of immunohistochemical methods allows further differen- tiation and a more reliable diagnosis. (20, 21, 37, 52) (s.

tab. 38.3)

Low-grade malignant NHL I. Derived from lymphatic cells

1. Chronic lymphatic leukaemia

⫺ B-cell type (B-CLL)

⫺ T-cell type (T-CLL) 2. Prolymphocyte leukaemia 3. Hairy cell leukaemia 4. Mycosis fungoides 5. T-zone lymphoma

II. Derived from cells secreting immunoglobulin 1. Immunocytoma

2. Plasmacytoma

III. Derived from germ centre cells 1. Centrocytic lymphoma

2. Centroblastic-centrocytic lymphoma

High-grade malignant NHL 1. Centroblastic lymphoma

(lymphoblastic lymphosarcoma) 2. Lymphoblastic lymphoma

⫺ B-type (EB virus-induced Burkitt lymphoma)

⫺ T-type

3. Unclassified lymphoma 4. Immunoblastic lymphoma

(chiefly reticulosarcoma)

Tab. 38.3: Classification of non-Hodgkin’s lymphomas according to K. L ennert, 1978 (Kiel/Germany)

Clinically, general symptoms of illness, such as fatigue,

weakness, lack of appetite, loss of weight and fever are

in evidence. A tentative diagnosis is based on hepato-

(spleno)megaly and peripheral lymphadenopathy. • Lab-

oratory investigations reveal “inflammatory criteria” in

relation to the severity and form of NHL, as in Hodgkin

lymphoma. (s. tab. 38.2) LDH and alkaline phosphatase

are generally elevated; a slight rise in transaminase values is sometimes evident. There is a strikingly fre- quent association with HCV infection (28, 29, 32, 44, 55, 60) , with AIDS, and possibly also with azathioprine. • Imaging procedures can provide diagnostic evidence by displaying local lesions, usually as a singular space-oc- cupying process of varying echogenicity and density. (42, 54, 58, 62) • The majority of cases are not diagnosed until they have reached an advanced stage. The symptomato- logy, course and prognosis depend on the type of NHL.

Fulminant liver failure is relatively frequent ⫺ some- times as the initial manifestation. (24, 30, 31, 40, 45, 50, 63)

• New methods of treatment ⫺ in addition to or instead of interferon ⫺ are continuously being sought in the therapy of NHL. This includes transplantation of blood stem cells following whole-body irradiation combined with chemotherapy, chemoembolization or possibly tu- mour resection. Moreover, rituximab is available as an antibody against lymphoma cells.

2.2.1 Low-grade malignant NHL

The incidence of low-grade malignant lymphoma shows an increasing tendency. There are signs of a causal rela- tionship with environmental factors (e. g. pesticides).

Low-grade malignant NHL leads more often to liver involvement than do the other forms.

Chronic lymphatic leukaemia: CLL occurs as B-cell and T-cell types. B-CLL is the most common form (approx.

95%); it is based on the malignant transformation of B-lymphocytes and occurs mainly in older people. The surface of B-cells is coated with immunoglobulins of the heavy chain type. T-CLL results from malignant trans- formation of T-lymphocytes; it is comparatively rare (5%). All in all, CLL is the most common form of leuk- aemia (approx. 30%) and also the most common form of NHL. The liver is involved in > 40% of cases. • Histo- logically, there are dense, uniform portal field infiltrates of small lymphoid tumour cells, whereas lymphoblasts are generally not detectable. The portal fields are ex- tended, but the limiting plates usually remain intact and are only penetrated by the lymphocytic tumour cells in the later course of disease. (s. figs. 38.10, 38.11) Bridge- like infiltrates can then develop between the portal fields. Small infiltrates also occur in the liver lobule. The sinusoids show a cumulation of round cells. Jaundice and cholestasis develop following obstruction of the portal bile ducts. These findings can also be caused by compression of enlarged lymph nodes. (59) • Compli- cations include portal hypertension (following fibrosis)

(46) , nodular regenerative hyperplasia and cholelithiasis (due to chronic haemolysis). Micronodular cirrhosis may also develop. • Therapy is carried out in accordance with haemato-oncological guidelines, especially with alemtuzumal ( ⫽ antibody campath-1H).

Hairy cell leukaemia: This designation is based on the microvillar “hairy” surface of the tumour cells. It is con-

Fig. 38.10: Chronic lymphatic leukaemia: dense portal lymphoid cell infiltration (HE)

Fig. 38.11: Chronic lymphatic leukaemia: dense portal lympho- cytic infiltration extending into the liver parenchyma (HE)

sidered to be a special form of B-CLL. The disease be- gins insidiously, mainly at an advanced age, and it has a chronic progressive course. (23) Men are affected four times more often than women. Massive splenomegaly and panmyelophthisis are already detectable at an early stage. • In the liver, there is characteristic infiltration of the sinusoids with intralobular angiomatous changes, simulating the clinical picture of peliosis hepatis. (66)

The associated angiomatous lesions are covered by hairy cells. (49, 64) A special feature of the hairy cell infiltrates is the presence of tartrate-resistant acid phos- phatase, which is a reaction product of the tumour cells.

Hepatomegaly is often present (in 40% of cases), whereas lymphadenopathy is very rare. In severe forms of infiltration, the picture of a nutmeg liver can develop.

Colliquation of liver parenchyma with formation of lacunas can be detected as focal lesions by means of sonography and CT. Ascites can occur. • Therapy (with a generally favourable prognosis) consists of interferon- α or deoxycoformycin. Hairy cell leukaemia is resistant to radiation treatment and chemotherapy.

Mycosis fungoides: This malignant T-cell lymphoma be-

gins in the skin, but may also affect internal organs. The

liver is rarely involved; this is more frequently the case

with the leukaemic variant, the so-called Sezary syn- drome. In the final stage of mycosis, however, portal field infiltrations are frequently detectable. They consist of atypical polymorphic lymphoid Lutzner cells (M. A.

L utzner et al., 1971) and of larger cells containing hyper- chromic and highly polymorphic nuclei ( ⫽ mycosis cells). The disease is apparently caused by retroviruses.

The prognosis is unfavourable; radiation therapy and cytostatic agents are ineffective.

Immunocytoma: This tumour originates in three types of immunoglobulin-secreting cells: (1.) lymphoplasmo- cytic, (2.) lymphoplasmocytoid, and (3.) polymorphic.

In isolated cases, patients with Waldenström’s macro- globulinaemia can also be assigned to this category. • Clinical symptoms include lymphadenopathy, spleno- megaly, infiltration of the skin, fever, night sweats and pruritus. Immunoglobulins M and G are elevated. • The liver is involved in > 90% of cases. The portal fields are only focally affected. The infiltrates are loosely and dif- fusely arranged. They frequently contain (50 ⫺80% of cases) PAS-positive, globular, nuclear and cytoplasmic inclusions, which represent retained immunoglobulins.

The infiltrates also contain a scattering of mast cells and eosinophils. The limiting plates remain intact. Increased flooding of the sinusoids is regarded as a sign of a leukaemic course.

Plasmocytoma: Extramedullary plasmocytic lymphoma likewise has its origin in immunoglobulin-secreting B- lymphocytes. It is also termed multiple myeloma. The condition occurs most frequently in 7

decade of life and ends fatally after 1 ⫺2 (⫺3) years. • In the liver, there are sometimes sinusoidal and portal infiltrations of B-lym- phocytes and plasmocytic tumour cells; nodular forma- tion can also occur. Generally, however, liver involvement is found in 40% of cases. (47, 61) (s. fig. 38.12) • Recently, patients with non-response or relapse after high-dose chemotherapy were treated successfully with thalidomide (starting with 200 mg daily, the dose was increased by 200 mg every two weeks until it reached 800 mg per day). (48, 56) • Plasma cell leukaemia is a rare complicative variant which tends to have its own individual course.

Fig. 38.12: Intrasinusoidal accumulation of atypical plasma cells in plasmacytoma (HE)

Centrocytic lymphomas: These have their origin in lymphatic germ centre cells. Liver involvement occurs in about 50% of patients. The portal infiltrates consist of small cells with bright, irregularly shaped, indented nu- clei. The portal fields are globularly distended as a result of the infiltration; the limiting plates remain intact, however, and the portal bile ducts are also undamaged.

Centroblastic-centrocytic lymphomas: This tumour type also develops from lymphatic germ centre cells. Liver involvement occurs in about 30% of cases. The portal fields are rounded due to infiltration; the limiting plates are penetrated in places. Follicular structures can occa- sionally be recognized.

2.2.2 High-grade malignant NHL

High-grade malignant lymphomas in the liver bring about destruction of the periportal limiting plates and fragmentation or neogenesis of the portal reticular fibres. All of these extremely malignant forms of NHL were classified as reticulosarcomas in the past, but only immunoplastic lymphoma can strictly be assigned to this category. High-grade malignant NHL is usually characterized by irregular portal infiltrates, which pene- trate the limiting plates and show (rapid) destructive growth. (28, 37) Fulminant liver failure has also been ob- served. There is usually far less liver involvement in high-grade malignant NHL than in low-grade forms. • Good results (complete remission in up to 75% of cases) could be achieved by shortened CHOP 14 therapy (cyclophosphamide ⫹ hydroxydaunorubicin ⫹ vincris- tine ⫹ prednisolone) in 6 cycles, every 2 weeks.

3 Systemic rheumatic diseases

Rheumatic diseases can also cause direct or indirect liver damage. A common denominator is the frequent occurrence of HLA type B8. There is frequently a close association between rheumatic diseases or collagenoses and chronic viral hepatitis (B, C), autoimmune hepatitis, primary biliary cholangitis as well as cirrhosis.

1. Rheumatoid arthritis 7. Polymyositis 2. Still’s disease 8. Periarteritis nodosa 3. Adult Still’s disease 9. Lupus erythematosus 4. Sjögren’s syndrome 10. Wegener’s granulomatosis 5. Felty’s sydrome 11. Churg-Strauss vasculitis 6. Polymyalgia rheumatica

Tab. 38.4: Rheumatic diseases causing direct or indirect liver damage

3.1 Rheumatoid arthritis

The cause of this systemic disease, which has a chronic

course, is unknown. Generally, several small and large

peripheral joints are affected, usually symmetrically.

Women suffer far more frequently than men. Clinically, there is arthralgia of varying intensity and symptoms of chronic proliferative inflammation of the synovial fluid in the diseased joints. Systemic manifestations can be recognized on the basis of haematological, neurological, pulmonary, renal, cardiovascular and hepatic symp- toms. Laboratory parameters show marked “inflamma- tory criteria” (s. tab. 38.2) as well as a rise in γ-globulins and immunoglobulins M and G. The rheumatoid factor is often detectable. (s. p. 118) Alkaline phosphatase may be elevated. (100)

Liver involvement occurs in 10 ⫺20% of cases. There is hepatomegaly and a slight elevation of transaminases.

Histologically, inflammatory infiltrates and fatty changes in the liver cells may be present together with non-specific reactive hepatitis. (s. fig. 21.1) Slight fibro- sis or rheumatic nodules may also occur in some cases after a lengthy period of disease. (67, 76, 79, 85, 91, 94, 101, 107)

3.2 Still’s disease

Juvenile rheumatoid arthritis is termed Still’s disease

(G. F. S till, 1897) . The disease begins in the finger joints and attacks the large joints and the cervical vertebral column in progressive steps. Lymphadenopathy is also present. • The liver and spleen may be considerably en- larged. Despite this, there are only very few histological findings, such as periportal lymphocytic infiltrates and Kupffer cell proliferations. (103)

3.3 Adult Still’s disease

Adult Still’s disease presents with seronegative polyar- thritis, febrile attacks, lymphadenopathy, skin symp- toms, hepatosplenomegaly, jaundice and involvement of the pleura and pericardium. • The liver is enlarged in about 30% of patients; transaminases may be slightly elevated. Periportal lymphocytic infiltrates and Kupffer cell proliferation can be demonstrated histologically.

(68, 69)

3.4 Sjögren’s syndrome

Sjögren’s syndrome (H. S. C. S jögren, 1933) is characterized by reduced secretion from the salivary and lacrimal glands with parotid enlargement (and occasional forma- tion of calculi) together with chronic polyarthritis.

Women in the menopause are mainly affected. Hyperfi- brinogenaemia is common. The cause of the syndrome is unknown. • The liver is involved in 5 ⫺20% of patients with “sicca” syndrome. (88) Hepatomegaly and elevated alkaline phosphatase (25 ⫺40%) are detectable. Liver in- volvement can be ascertained on the basis of the find- ings of non-specific reactive hepatitis. (96, 99, 106, 107) An association with Budd-Chiari syndrome has also been reported. (89)

3.5 Felty’s syndrome

Felty’s syndrome (A. R. F elty, 1924) is a special form of seropositive polyarthritis. It leads to considerable changes in the articular structures. Characteristic find- ings include splenomegaly, leucopenia, lymphadenopa- thy and skin pigmentation. Men are mainly affected. • The liver is involved in about 70% of patients. Transamin- ases and γ-GT values are moderately elevated, and there is an occasional rise in alkaline phosphatase.

Lymphocytic infiltrates of the sinusoids, proliferation of Kupffer cells and periportal fibrosis are detectable histo- logically. Nodular regenerative hyperplasia can develop, which may subsequently cause portal hypertension and macronodular cirrhosis. (71, 95, 104)

3.6 Polymyalgia rheumatica

Clinically, this pathological picture is characterized by severe pain in the area of the shoulder/upper arm, pelvic girdle and femoral musculature. Symptoms include fa- tigue, weakness, fever and loss of appetite. Women are affected far more frequently than men ⫺ generally after the age of 50. Laboratory parameters show highly patho- logical “inflammatory criteria” (s. tab. 38.2) as well as greatly elevated AP, but no antibodies or rheumatoid serological findings. • Temporal arteritis, which is a spe- cial form of polymyalgia rheumatica, is frequently found. • If larger arteries emanating from the aortic arch are likewise affected, this condition is known as giant- cell arteritis. (78, 81, 86, 87, 92) The thickened intima and the media contain histiocytic, lymphocytic and epitheli- oid cell infiltrates with polynuclear giant cells and plasma cells. Thrombosis frequently occurs in the af- fected arteries.

Liver involvement is common. Granulomatous arteritis of the hepatic artery and its intrahepatic branches gives rise to the clinical picture of granulomatous hepatitis.

There are lymphocytic infiltrates in the portal fields to- gether with liver cell necroses, so that chronic persistent hepatitis is in evidence. Fatty changes in the liver cells together with hypertrophy of the perisinusoidal lipo- cytes can also be observed. • Therapy is with glucocorti- costeroids. (83, 86)

3.7 Polymyositis

Polymyositis can occur as a primary disease or a para- neoplastic syndrome. Clinically, there is weakness and pain in the shoulder and hip musculature, with muscular atrophy. Laboratory parameters show greatly elevated

“inflammatory criteria” (s. tab. 38.2) as well as a rise

in myosin AB. • Liver involvement is characterized by

hepatomegaly, inflammatory infiltration of the portal

fields, fatty changes in the liver cells and single-cell ne-

crosis as well as necrotic foci.

3.8 Periarteritis nodosa

Necrotizing inflammation of small and medium-sized arteries as well as of the perivascular tissue ( ⫽ periarter- itis) with inclusion of adjacent veins leads to nodular- aneurysmal changes in the diseased arteries. The arterial capillaries remain unaffected. The vessel walls are per- meated by polymorphonuclear leucocytes and mono- cytes; the inflammatory infiltration does not always in- volve the entire circumference of the vessel. Vascular branches are particularly affected. The aneurysmal dis- tensions of the vessels show a tendency to rupture. • Clinically, there is evidence of fatigue, weakness, fever, lack of appetite, myalgia and arthralgia, together with abdominal pain. Laboratory parameters show highly pathological “inflammatory criteria” (s. tab. 38.2), in particular greatly elevated ESR and alkaline phos- phatase.

If the liver is involved, the respective enzymes (GPT, GOT, γ-GT, GDH) are increased. There is frequently an association with HBV or HCV infection (50 ⫺75% of cases). Together with the skin and the kidneys, the liver is one of the most affected organs. There are cell necro- ses. Vascular involvement can lead to infarction, intra- hepatic bleeding (98) , acute cholecystitis (leading to per- foration) (72) and thrombosis. Nodular regenerative hyperplasia can develop. • Aneurysms in the area of the medium arteries are detectable by arteriography. Percu- taneous liver biopsy is not recommended because of the bleeding risk and the low success rate. • Therapy is with glucocorticosteroids in combination with azathioprine or cyclophosphamide. (70, 75)

3.9 Lupus erythematosus

Lupus erythematosus (LE) is a systemic autoimmune disease, occurring mainly in young women. Its aetiology is unknown. The clinical symptoms are chronic recur- rent arthralgia with febrile attacks, lack of appetite, fa- tigue, decreased performance, skin changes on areas of the body exposed to light, lymphadenopathy and renal findings following localized vasculitis. Its biochemistry is characterized by highly pathological “inflammatory criteria” (s. tab. 38.2) as well as by the detection of anti- nuclear antibodies, DNA-AB and the LE factor. LE cells may be present in the blood or bone marrow (M. M.

H argraves et al., 1948) . Anaemia, leucopenia and throm- bopenia are also frequently in evidence. In rare cases, jaundice due to haemolysis occurs.

The liver is involved in 40 ⫺60% of cases, but with greatly varying intensity. Hepatomegaly is frequently present. Even acute liver failure has been observed.

Discrete laboratory or histological findings relating to the liver can precede the diagnosis of LE by several years in some cases. The clinical picture of acute hepa- titis with cholestasis has also been observed. Histolog- ically, there is a broad spectrum of changes comprising

fatty degeneration in the liver cells, chronic persistent hepatitis, giant cell hepatitis (73, 77) , hepatic infarction

(82) , cholestasis, veno-occlusive disease (93) , nodular regenerative hyperplasia, and cirrhosis with portal and pulmonary hypertension. (108) Lupus anticoagulans (antiphospholipid antibody) can lead to hepatic vein thrombosis. The activity of LE correlates very well with the activity of the liver changes. It is a striking feature that patients with liver involvement complain less fre- quently of arthralgia, but more frequently have gastric, thyroid and haematological complications. It should be noted that there is hepatic idiosyncrasy towards non- steroidal antirheumatics. (90, 97, 102, 105)

3.10 Wegener’s granulomatosis

Wegener’s granulomatosis (F. W egener, 1936, 1939) is a necrotizing form of granulomatous vasculitis originating in the upper respiratory tract and lungs (rhinitis and sinusitis with sanguineous secretion, repeated nose- bleeds, ulcers, encrustations and pulmonary infiltra- tions). Glomerulonephritis subsequently develops. Fi- nally, generalized vasculitis can be detected. (80)

The liver shows vasculitis with necrotizing epithelioid cell granulomas. Non-specific reactive hepatitis is also present. Therapy is with cyclophosphamide (1 ⫺2 mg/kg BW/day). • We have given an extensive description of this clinical picture based on 132 cases in the literature as well as on our own experience. (84)

3.11 Eosinophilic granulomatous vasculitis Churg-Strauss vasculitis (J. C hurg et al., 1951) is charac- terized by angitis with extravascular granulomas, eosin- ophilia and bronchial asthma. Allergic factors are held to be responsible for this disease. Reports on about 200 cases have been published so far; men are affected twice as often as women. • Histologically, there is necrotizing inflammation of the small arteries and accompanying veins with paravascularly arranged granulomas deriving from macrophages and giant cells as well as leucocytes and lymphocytes; the centre of a granuloma is strikingly rich in eosinophils. • Such changes also occur in the liver. Concurrent involvement of the liver and the omen- tum can result in a palpable tumour. Therapy is with glucocorticosteroids. (74)

4 Mastocytosis

Mast cell hyperplasia can affect several organ systems.

Regarding the liver, 50% of cases present as hepato-

megaly. Mast cell infiltrates are found in the portal

fields. They can lead to occlusion of the small vessels

with subsequent fibrosis or cirrhosis. (112) Moreover,

there is evidence of marked lymphadenopathy and skin

lesions. Polygonal cells with eosinophilic granules are

present in the portal fields. On staining with Giemsa and toluidine blue, the typical metachromatic cyto- plasmic granules are sometimes identified. NRH, VOD and marked fibrosis have been reported and may be the cause of portal hypertension and ascites. (114, 116) Cir- rhosis occurs in 5% of cases. (112)

5 Histiocytosis X

In 1938 A. H. T. R obb - S mith mentioned this condition for the first time. One year later, he and R. B. S cott together described a disease characterized by “fever, wasting, generalized lymphadenopathy and hepatosplenomegaly, which in the final stages was associated with jaundice, purpura, anaemia and leucopenia”. This disease almost always resulted in death after an average duration of 15 weeks. The authors termed this condition “histiocytic medullary reticulosis”. (117) • The term “histiocytosis X” was introduced by L. L ichtenstein in 1953 (115) , sum- marizing (1.) Letterer-Siwe disease (reticulosis in in- fancy), (2.) Hand-Schüller-Christian disease (lipogranu- lomatosis), and (3.) eosinophilic granuloma of bone.

(120) Overlapping syndromes as well as mixed forms of these three diseases exist. The first two disease forms are mainly disseminated, while eosinophilic granulomas generally appear as solitary bone lesions (with a better prognosis). • The term “malignant histiocytosis” was in- troduced by H. R appaport in 1966. These disseminated forms were distinguished as being benign or malignant and acute or chronic by W. A. N ewton et al. in 1973.

Histiocytosis X is considered to be a form of reticulosis because of the proliferation and aggregation of Langer- hans’ cells in the RES. These cells contain so-called Bir- beck granules and the neural-specific protein S-100. The involvement of the liver and spleen (which is not evident in every case) becomes visible as hepatosplenomegaly.

In most cases, there are diffuse, sinusoidal infiltrations consisting of large, mostly multinucleated, atypical his-

Fig. 38.13: Histiocytosis X: distinct portal inflammation, periduc- tal infiltration by Langhans cells simulating cholangitis ( 앖)

tiocytes (usually with hyperchromatic nuclei) and wide- spread phagocytosis of erythrocytes. (s. fig. 38.4) The Kupffer cells show hyperplasia. Periportal infiltration and cell necrosis are sometimes found. (s. fig. 38.13) Gross tumour-nodule formation in the liver and spleen is rare. (122) Mild portal fibrosis may be present. (111, 113, 118, 121) In some two-thirds of cases, periportal cho- lestasis with portal-duct proliferation can be demon- strated. (109) The clinical picture of primary sclerosing cholangitis may appear. (119) Occasionally, pronounced fibrosis with portal hypertension and oesophageal vari- ces develops. (110) Transition into cirrhosis is possible.

A suitable form of chemotherapy resulted in a 30 ⫺40%

decrease in lethality. In portal hypertension, shunt sur- gery has been applied. Liver transplantation was suc- cessfully carried out without evidence of recurrent dis- ease during a 7-year follow-up. (123)

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