Paroxysmal nocturnal haemoglobinuria [10] In this rare acquired disease, there is intravascular, complement-mediated haemolysis. The defect is due to mutation of the PIG-A gene on chromosome X which results in deficient biosynthesis of the glycosylphos- phatidylinositol (GPI) anchor. This leads to an absence of certain proteins on the red cell surface. The cells are sen- sitive to lysis when the pH of the blood becomes more acid during sleep. During an episode of haemolysis the urine passed in the morning may be brown or reddish- brown due to haemoglobinuria. Acutely, the patients show a dusky, reddish jaundice and the liver enlarges. Aspartate transaminase may be increased (due to haemolysis) and serum studies show iron deficiency (due to urinary loss of haemoglobin). Liver histology shows some centrizonal necrosis and siderosis. Hepatic vein thrombosis may be a complication. Bile duct changes similar to primary sclerosing cholangitis, perhaps due to ischaemia, have been reported [4]. Acquired haemolytic anaemia The haemolysis is due to extra-corpuscular causes. Spherocytosis is slight and osmotic fragility only mildly impaired. The patient is moderately jaundiced. The increased bilirubin is unconjugated, but in severe cases conjugated bilirubin increases and appears in the urine. This may be related to bilirubin overload in the presence of liver damage. Blood transfusion accentuates the jaundice, for transfused cells survive poorly. The haemolysis may be idiopathic. The increased haemolysis is then due to autoimmunization. The Coombs’ test is positive. The acquired type may complicate other diseases, espe- cially those involving the reticulo-endothelial system. These include Hodgkin’s disease, the leukaemias, reticu- losarcoma, carcinomatosis and uraemia. The anaemia of hepato-cellular jaundice is also partially haemolytic. The Coombs’ test is usually negative. Autoimmune haemolytic anaemia is a rare complica- tion of autoimmune chronic hepatitis and primary biliary cirrhosis. Wilson’s disease may present as a haemolytic crisis (Chapter 24). Haemolytic disease of the newborn See Chapter 26. Incompatible blood transfusion Chills, fever and backache are followed by jaundice. Urobilinogen is present in the urine. Liver function tests give normal results. In severe cases free haemoglobin is detected in blood and urine. Diagnostic difficulties arise when a patient suffering from a disease that may be com- plicated by hepato-cellular failure or biliary obstruction becomes jaundiced soon after a blood transfusion. References 1 Banerjee S, Owen C, Chopra S. Sickle cell hepatopathy. Hepatology 2001; 33: 1021. 2 Beutler E. G6PD: population genetics and clinical manifes- tations. Blood Rev. 1996; 10: 45. 3 Emre S, Kitibayashi K, Schwartz M et al. Liver transplanta- tion in a patient with acute liver failure due to sickle cell intrahepatic cholestasis. Transplantation 2000; 69: 675. 4 Huong DLT, Valla D, Franco D et al. Cholangitis associated with paroxysmal nocturnal haemoglobinuria: another instance of ischemic cholangiopathy? Gastroenterology 1995; 109: 1338. 5 Iolascon A, Miraglia del Giudice E, Perrotta S et al. Heredi- tary spherocytosis: from clinical to molecular defects. Haematologica 1998; 83: 240. 6 Lucarelli G, Galimberti M, Polchi P et al. Marrow transplan- tation in patients with thalassemia responsive to iron chela- tion therapy. N. Engl. J. Med. 1993; 329: 840. 7 O’Callaghan A, O’Brien SG, Ninkovic M et al. Chronic intra- hepatic cholestasis in sickle cell disease requiring exchange transfusion. Gut 1995; 37: 144. 8 Olivieri NF. Progression of iron overload in sickle cell disease. Semin. Haematol. 2001; 38 (Suppl. 1): 57. 9 Omata M, Johnson CS, Tong M et al. Pathological spectrum of liver diseases in sickle cell disease. Dig. Dis. Sci. 1986; 31: 247. 10 Rosse WF. Paroxysmal nocturnal haemoglobinuria as a molecular disease. Medicine 1997; 76: 63. 11 Stephan JL, Merpit-Gonon E, Richard O et al. Fulminant liver failure in a 12-year-old girl with sickle cell anaemia: favourable outcome after exchange transfusion. Eur. J. Pae- diatr. 1995; 154: 469. 12 Zanella A, Berzuini A, Colombo MB et al. Iron status in red cell pyruvate kinase deficiency: study of Italian cases. Br. J. Haematol. 1993; 83: 485. The liver in myelo- and lymphoproliferative disease [37] The liver contains multipotential cells that can differenti- ate into reticulo-endothelial, myeloid and lymphoid cells. These can be affected by malignant disease (leukaemia, lymphoma), usually in association with systemic disease, but rarely occur as a primary hepatic disease. Reduced haemopoietic activity in the marrow is followed by extra-medullary haemopoiesis in the liver. Reticulo-endothelial storage diseases affect the liver as well as other organs. This section outlines the involve- ment of the liver in this broad group of diseases. The liver is involved to a variable extent, usually with no functional effect, but with mildly abnormal liver 56 Chapter 4 function tests. However, liver biopsies are helpful for diagnosis. Staining of sections with monoclonal anti- bodies may be necessary to define the cell type or disease. Involvement may be focal, so that serial sections should be cut. If scanning shows a focal lesion, guided biopsy is worthwhile. Rarely, fulminant liver failure complicates the primary disease, due to replacement of hepatocytes with malig- nant cells. This is reported in acute lymphoblastic leukaemia [33] and non-Hodgkin’s lymphoma [40]. It is important to differentiate these from liver failure due to viral or drug hepatitis, since liver transplantation is con- traindicated when there is underlying haematological malignancy [40]. Acute and chronic abnormalities of liver function tests may be due to treatment. Drugs given should be reviewed. More aggressive chemotherapy has increased hepato-toxic drug reactions. Multiple blood transfusions are a frequent cause of viral hepatitis, particularly hepati- tis C and non-A, non-B, non-C, and to a lesser extent type B. This is usually mild in the immunocompromised host. Hepatitis B may be reactivated during cytotoxic or immunosuppressive therapy, and there may be a fulmi- nant hepatitis-like episode following withdrawal of treatment. This is thought to be due to a rebound effect with the return of immunity, and clearance of a large number of hepatocytes containing the virus [2, 17]. Gastrointestinal haemorrhage may complicate myelo- proliferative diseases, leukaemia or lymphoma. In some this is caused by peptic ulceration or erosions. There may be portal hypertension due to hepatic, portal or splenic vein thrombosis related to a hypercoagulable state. Evidence for a myeloproliferative disorder was found in 14 of 33 patients with non-tumour-related portal vein thrombosis [35]. Occasionally the portal hypertension is pre-sinusoidal and seems to be secondary to infiltrative lesions in the portal zones and sinusoids. In others, increased blood flow due to splenomegaly may be important. Portal and central zone fibrosis can be related to cytotoxic therapy. Leukaemia Myeloid [37] The enlarged liver is smooth and firm, and the cut section shows small, pale nodules. Microscopically both portal tracts and sinusoids are infiltrated with immature and mature cells of the myeloid series. The immature cells lie outside the sinu- soidal wall. The portal tracts are enlarged with myelocytes and polymorphs, both neutrophil and eosinophil; round cells are also conspicuous. The liver cell cords are compressed by the leukaemic deposits. Lymphoid Macroscopically, the liver is moderately enlarged, with pale areas on section. Microscopically, the leukaemic infiltration involves only the portal tracts — the normal site of lymphoid tissue in the liver. The portal areas are enlarged and contain both mature and immature cells of the lymphatic series. The sinusoids are not affected. The liver cells are normal. Hairy cell leukaemia The liver is usually involved although specific clini- cal and biochemical features are rare. Sinusoidal and portal infiltration with mononuclear ‘clear’ cells is seen with sinusoidal congestion and beading. Angiomatous lesions, usually peri-portal, consist of blood spaces lined by hairy cells. Bone marrow transplantation Liver abnormalities occur at some time in the majority of patients within 12 months of bone marrow transplanta- tion [10]. The changes range from abnormal liver func- tion tests alone, to coagulation abnormalities, ascites and hepato-renal failure. There are many possible causes (table 4.3); more than one may be responsible at any one time. Pre-existing liver disease increases the risk. In the first 15 weeks, the most common causes of liver abnormality are acute graft-versus-host disease (GVHD), intra-hepatic veno-occlusive disease, drug- induced reactions and infection. Jaundice and abnormal liver enzyme tests accompany the systemic manifestations of acute GVHD — rash and diarrhoea. This usually begins 3–8 weeks’ post- transplant. The hepatic changes may persist to give cholestatic chronic GVHD with intra-hepatic bile duct damage. Chronic GVHD may also develop de novo. The development of jaundice, painful hepatomegaly, weight gain and ascites in the first weeks after bone marrow transplantation suggests a diagnosis of veno- occlusive disease. This is due to high-dose cytoreductive therapy given 5–10 days before the marrow infusion. The incidence varies from one report to another, ranging from less than 5% to over 60%, probably reflecting differ- ent patient groups, conditioning regimens and diagnos- tic criteria. Mortality in severely affected individuals is high, around 50%. There is controversy whether histo- logical evidence of venular occlusion is needed for diagnosis. Routine percutaneous liver biopsy is often contraindicated by a low platelet count, prolonged coag- ulation tests and ascites. Transjugular liver biopsy over- comes these problems, although bleeding complications may still occur [31]. This route also allows the wedged The Haematology of Liver Disease 57 hepatic venous pressure to be measured [31]. Four histo- logical abnormalities correlate with the clinical severity of disease: occluded hepatic venules, eccentric luminal narrowing/phlebosclerosis, hepatocyte necrosis and sinusoidal fibrosis [30]. These findings suggest that there is extensive injury to zone 3 structures by the cytoreduc- tive therapy. Studies suggest that ursodeoxycholic acid [8], defibrotide [5] and tissue plasminogen activator [34] may be useful in the prevention or treatment of veno- occlusive disease. Opportunistic fungal and bacterial infections occur during neutropenic periods and may cause abnormal liver function; viral infections occur later. Helpful data to identify the cause of the hepatic abnor- mality include: (a) timing of the changes related to drugs, chemotherapy, radiation and bone marrow infusion; (b) the dose of cytoreductive (conditioning) therapy; (c) the source of donor marrow; (d) pre- treatment viral serology; (e) the degree of immunosup- pression; and (f) evidence of systemic disease. Bacterio- logical and virological data are important. Often more than one process is involved. In one series transvenous liver biopsy provided useful data for patient manage- ment in over 80% of cases [31]. After bone marrow transplantation, hepato-biliary scintiscanning and ultrasound commonly show abnor- malities of questionable clinical significance. Doppler ultrasonography is not reliable for the diagnosis of veno- occlusive disease [28]. Lymphoma Hepatic involvement occurs in about 70% of cases and immediately puts the patient into stage IV [14]. It may be seen as diffuse infiltrates, as focal tumour-like masses, as portal zone cellularity (fig. 4.4), as an epithelioid cell reaction or as lymphoid aggregates [14]. Rarely, lym- phomatous infiltration presents as acute liver failure [40]. In Hodgkin’s disease, typical tissue is seen spreading out from the portal tracts, with lymphocytes, large pale epithelioid cells, eosinophils, plasma cells and giant Reed–Sternberg cells (fig. 4.5). Later, fibroblasts are found in a supporting connective tissue reticulum. In patients with known extra-hepatic Hodgkin’s disease, but without obvious Reed–Sternberg cells in sections of the liver, hepatic involvement is suggested by portal infiltrates larger than 1mm in diameter, changes of acute cholangitis, portal oedema and portal infiltrates with a predominance of atypical lymphocytes. These changes should stimulate a wider search for the diagnos- tic Reed–Sternberg cell in further sections [6]. In non-Hodgkin’s lymphoma, the portal zones are usually involved. In small cell lymphocytic lymphoma, a dense, monotonous proliferation of normal-appearing lymphocytes is seen. The more aggressive lymphomas also involve portal zones and form tumour nodules. Large cell lymphoma may infiltrate sinusoids. In histiocytic medullary reticulosis, large numbers of reticulum cells fill the sinusoids and portal tracts. Occa- sionally, the deposits may be single and large. Liver granulomas with or without hepatic involvement are found with most lymphomas. Caseation without evidence of tuberculosis has been reported [15]. Paraproteinaemia and amyloidosis may be complica- tions. Diagnosis of hepatic involvement Detection of hepatic involvement can be extremely diffi- cult. It is unlikely if hepatomegaly is not found. Fever, jaundice and splenomegaly increase the likelihood. Increases in serum g-GT and transaminase values are suggestive, although often non-specific. Focal defects may be shown by ultrasound, CT and MRI scanning. Enlarged abdominal lymph nodes may also be seen. Needle liver biopsy rarely reveals Hodgkin’s tissue if the CT scan is normal. Ultrasound or CT-guided liver biopsy add to the chances of obtaining Hodgkin’s tissue. Laparoscopy with liver biopsy may establish the diagno- sis in the absence of positive CT scans [26]. Needle biopsy does not exclude hepatic involvement if only an 58 Chapter 4 Table 4.3. Hepato-biliary disease and bone marrow transplantation Problem Related to Pre-existing Fungal Granulocytopenia Viral (hepatitis type B, C) Blood products Drug Medication Biliary Stones Post-transplantation Early neutropenic phase (up to 4 weeks) acute graft-versus-host disease Donor marrow veno-occlusive disease Cytoreductive therapy nodular regenerative hyperplasia drug induced Including TPN Extra-hepatic bacterial sepsis Bacteria/endotoxin fungal biliary disease Sludge Intermediate (4–15 weeks)* Viral Cytomegalovirus Hepatitis type B, C Late (>15 weeks) chronic graft-versus-host disease Multi-organ disease chronic viral infection fungal Immunosuppression tumour recurrence *As well as continuing early problems. epithelioid histiocyte reaction is seen. Sinusoidal dilata- tion in zone 2 and 3 is found in 50% and may give a clue to the diagnosis [3]. Presentation as jaundice may provide great diagnostic difficulties (table 4.4). Lymphoma should always be con- sidered in patients with jaundice, fever and weight loss. Jaundice in lymphoma (table 4.4) Hepatic infiltrates may be massive or present as space-occupying lesions. Large intra-hepatic deposits are the commonest cause of deep jaundice. Histological evidence is essential for diagnosis. Biliary obstruction is more frequent with non- Hodgkin’s lymphoma than with Hodgkin’s disease [9]. It is usually due to hilar glands which are less mobile than those along the common bile duct which can be pushed aside. Occasionally the obstructing glands are peri-ampullary. Primary lymphoma of the bile duct itself is reported [20]. Investigations include endoscopic or percutaneous cholangiography and brush cytology. Known lymphoma elsewhere draws attention to this as a possible cause of bile duct obstruction. Differentiation from other causes of extra-hepatic biliary obstruction is difficult, and depends on the appearances on scanning The Haematology of Liver Disease 59 Fig. 4.4. Patterns of hepatic histology in lymphoma. (a) Low power showing dense portal cellular infiltrates (arrows) (H & E). (b) Higher power of portal area showing intermediate and large mononuclear cells. (c) Immunohistochemistry showing that the cells have a B cell phenotype (stained brown with antibody to CD20). Bile ducts are not stained. (d) Sinusoidal pattern of infiltration by lymphoma cells. Occasional atypical mononuclear cells are seen within the hepatic sinusoids (arrows). (a) (c) (b) (d) Fig. 4.5. Infiltration of portal zones by Hodgkin’s cells including large Reed–Sternberg like cells (arrow) (H & E). and at cholangiography, and the results of cytology and biopsy. Rarely, an idiopathic intra-hepatic, usually cholestatic, jaundice may be seen in Hodgkin’s [12] and non- Hodgkin’s lymphoma [38]. It is unrelated to deposits in the liver or bile duct compression. Hepatic histology shows canalicular cholestasis. These changes are unre- lated to therapy. The diagnosis is difficult and is made after full investigation. Liver histology may show loss of intra-hepatic bile ducts [12]. Rarely haemolysis causes deep jaundice. It may be due to Coombs’ positive autoimmune haemolytic anaemia. Jaundice is exacerbated by bilirubin overload following blood transfusion. Chemotherapy may cause jaundice. Almost all the cytotoxic drugs can be incriminated if given in suffi- cient dose. Common culprits include methotrexate, 6- mercaptopurine, cytosine arabinoside, procarbazine and vincristine. Hepatic irradiation in a dose usually exceeding 35Gy (3500rad) may cause jaundice. Post-transfusion viral hepatitis B, C or non-A, non-B, non-C, may affect the immunocompromised patient. Opportunist infections are also encountered. Primary hepatic lymphoma [1, 41] This rare lymphoma by definition affects only the liver. There is a solitary mass in 60%, multiple masses in 35% and diffuse disease in 5% [24]. Histologically, it is a non-Hodgkin’s large cell B- or less often T-cell lym- phoma. Primary low-grade B-cell lymphoma of mucosa- associated lymphoid tissue (MALT) also occurs [19]. Presentation is mainly with pain, hepatomegaly, a palpable mass and elevated alkaline phosphatase and bilirubin. Fever, night sweats and weight loss occur in 50% of cases. There is no lymphadenopathy. Ultrasound and CT show a non-specific space-occupying lesion in the liver in the majority but there may be diffuse hepatomegaly without tumour. Diagnosis is by liver biopsy. Sometimes histology may initially be confusing suggesting carcinoma or chronic hepatitis, or showing extensive haemorrhagic necrosis suggesting Budd– Chiari syndrome. The destructiveness of the infiltrate is a helpful diagnostic feature. Primary lymphoma of the liver may be found inci- dentally or complicating acquired immune deficiency syndrome (AIDS) [27]. Patients with pre-existing cirrho- sis have a poor prognosis. Negative a-fetoprotein and carcino-embryonic antigen (CEA) with a high LDH level in a patient with a liver mass should raise the possibility of lymphoma. Treatment of hepatic involvement More aggressive combination chemotherapy has con- siderably improved the prognosis of intra-hepatic Hodgkin’s deposits causing jaundice. Treatment is the same as for other stage IV patients regardless of the jaun- dice. Similarly, those with ‘idiopathic’ cholestasis should receive the therapy appropriate for their lymphoma. If MOPP (mechlorethamine, Oncovin, procarbazine and prednisone) has failed, ABVD (Adriamycin, bleomycin, vinblastine and dacarbazine) should be tried. If jaundice is persistent, some palliation may be achieved by moderate local irradiation. Extra-hepatic biliary obstruction is treated by external radiation and, if necessary, the insertion of temporary internal stents by the endoscopic or percutaneous route. If drug toxicity is the cause, treatment may have to be changed or doses reduced. Treatment for non-Hodgkin’s lymphoma causing jaundice is the same as that for Hodgkin’s disease. Primary hepatic lymphoma is treated by chemother- apy or occasionally by lobectomy [1]. Lymphosarcoma Nodules of lymphosarcomatous tissue may be found in the liver, especially in the portal tracts. Macroscopically 60 Chapter 4 Table 4.4. Features of jaundice in lymphoma Related to lymphoma Hepatic infiltrates Scans massive Liver biopsy tumour mass Biliary obstruction Usually hilar Investigate endoscopic or percutaneous cholangiography Non-Hodgkin’s usually Intra-hepatic cholestasis Rare Liver biopsy ‘pure’ cholestasis loss of bile ducts Usually Hodgkin’s Haemolysis Autoimmune haemolytic anaemia Positive Coombs’ test Related to therapy Chemotherapy High dose can cause fulminant liver failure (Chapter 20) Hepatic irradiation More than 35Gy(3500 rad) (Chapter 20) Post-transfusion (Chapter 18) (hepatitis C) Hepatitis B reactivation (Chapter 17) Opportunist infections (Chapter 29) they resemble metastatic carcinoma. The liver may also be involved in giant follicular lymphoma. Multiple myeloma The liver may be involved in plasma cell myeloma, the portal tracts and sinusoids being filled with plasma cells. Associated amyloidosis may involve the hepatic arterioles. Angio-immunoblastic lymphadenopathy This resembles Hodgkin’s disease. The liver shows a pleomorphic portal zone infiltrate (lymphocytes, plasma cells and blast cells) without histiocytes or Reed– Sternberg cells. Extra-medullary haemopoiesis The primitive reticulum cells of hepatic sinusoids and portal tracts possess the capacity to mature into adult erythrocytes, leucocytes or platelets. If the stimulus for blood regeneration is sufficiently strong, this function can be resumed. This is rare in the adult although myeloid metaplasia in the liver of the anaemic infant is not unusual. In the adult, it occurs with bone marrow replacement or infiltration, and especially in association with secondary carcinoma of bone, myelofibrosis, myelosclerosis, multiple myeloma and the marble bone disease of Albers-Schoenberg. It complicates all condi- tions associated with a leucoerythroblastic anaemia. The condition is well exemplified by myelofibrosis and myelosclerosis, where the liver is enlarged, with a smooth firm edge. The spleen is enormous, and its removal results in even greater enlargement of the liver with increased liver enzymes. The mortality after splenectomy is 10–20%, some caused by hepatic dysfunction due to the increase in extra-medullary haemopoiesis. Ascites occurs in a low percentage of patients with extra-medullary haemopoiesis, and may be due to portal hypertension, or, after splenectomy, peritoneal deposits of extra-medullary haemopoiesis. Microscopic features The conspicuous abnormality is a great increase in the cellular content, both in the portal tracts and in the dis- tended sinusoids (fig. 4.6). The cells are of all types and varying maturity. The distribution of cells may reflect the type of underlying sinusoidal endothelial cell [4]. There are many reticulum cells and these may be con- verted into giant cells. The haemopoietic tissue may form discrete foci in the sinusoids. Rarely, larger foci may be seen on CT or MRI scanning [39]. Electron microscopy shows haematological cells in the sinusoids with transformation of peri-sinusoidal cells into fibroblasts and myofibroblast-like cells. Portal hypertension. This may be due to portal vein thrombosis or sinusoidal infiltration with haemopoietic cells. Disse’s space fibrosis contributes. Nodular regen- erative hyperplasia may also cause portal hypertension (Chapter 10). Systemic mastocytosis This is a disease of mast cell hyperplasia that may affect several organ systems. It can present with hepatomegaly as well as lymphadenopathy and skin lesions. Liver biopsy, stained with haematoxylin and eosin, shows polygonal cells with eosinophilic granules predomi- nantly in portal tracts, with fewer in the sinusoids [11]. On staining with Giemsa and toluidine blue, the typical metachromatic cytoplasmic granules may be identified. Mast cell infiltration is a common finding, but severe liver disease is unusual except in those with haematolog- ical involvement or aggressive mastocytosis. Nodular regenerative hyperplasia, portal venopathy and veno- occlusive disease are reported [21] and may be respon- sible for portal hypertension and ascites. The latter carries a poor prognosis. Cirrhosis occurs in up to 5% of patients [11]. Langerhans’ cell histiocytosis (histiocytosis X) The underlying pathology of this rare condition is proliferation and aggregation of Langerhans’ cells in the reticulo-endothelial system. Electron microscopy shows trilamellar rod-shaped structures (Birbeck granules) within the cells which also contain the neural-specific The Haematology of Liver Disease 61 Fig. 4.6. Extra-medullary haemopoiesis — megakaryocytes (arrows), erythroblasts, normoblasts and polymorphs are seen in the hepatic sinusoids (H & E). protein S-100. Langerhans’ cell histiocytosis comprises several entities (which overlap) including eosinophilic granuloma (bone lesions), Hand–Schüller–Christian disease (endocrine lesions; skin) and Letterer–Siwe disease (disseminated type; lungs, bone marrow, skin, lymph nodes, spleen, liver). The mechanism of liver injury is not known. Cholestasis is due to sclerosing cholangitis affecting intra-hepatic ducts or proliferating histiocytic cells in peri-portal areas [13]. Liver disease is present in one-third of patients. Portal hypertension and variceal haemorrhage may develop. Liver failure due to biliary cirrhosis is unusual. Transplantation has been successful with no evidence of recurrent disease up to 7 years later [42]. Lipid storage diseases The lipidoses are disorders in which abnormal amounts of lipids are stored in the cells of the reticulo-endothelial system. They may be classified according to the lipid stored: xanthomatosis, cholesterol; Gaucher’s disease, cerebroside; or Niemann–Pick disease, sphingomyelin. Primary and secondary xanthomatosis Cholesterol is stored mainly in the skin, tendon sheaths, bone and blood vessels. The liver is rarely involved but there may be isolated nests of cholesterol-containing foamy histiocytes in the liver. Investigation of the liver is of little diagnostic value. Cholesteryl ester storage disease [7] This rare, autosomal recessive, relatively benign disease is due to a deficiency of lysosomal acid lipase/choles- teryl ester hydrolase. It presents with symptomless hepatomegaly. The liver is orange in colour and hepato- cytes contain excess cholesteryl ester and triglyceride. A septate fibrosis may lead to cirrhosis and patients may have early vascular disease. Complete enzyme defi- ciency (Wolman’s disease) results in death in early infancy due to involvement of the liver, adrenals and histiocytes. Gaucher’s disease [22] This rare, autosomal recessive disease was first described in 1882. It is the commonest lysosomal storage disorder. It is due to a deficiency of lysosomal acid b- glucosidase so that glucosylceramide, derived from membrane glycosphingolipids of time-expired white and red blood cells, accumulates in the reticulo- endothelial system throughout the body, particularly in the liver, bone marrow and spleen. Three types are recognized: • Type 1 (adult, chronic, non-neuronopathic) is the mildest and most common form of Gaucher’s disease. It occurs rarely in all ethnic groups (non-Jewish: 1 in 40000) but is most common in Ashkenazi Jews (1 in 850). The central nervous system is spared. • Type 2 (infantile, acute, neuronopathic) is rare. In addition to the visceral involvement there is massive fatal neurological involvement, with death in infancy. • Type 3 (juvenile, sub-acute, neuronopathic) is also rare. There is gradual and heterogeneous neurological involvement. The various forms represent different mutations in the structural gene for acid b-glucosidase on chromosome 1, although there is a variability in severity of disease within a specific genotype [23]. Four mutations account for over 95% of disease alleles in Ashkenazi patients, but only 75% of non-Jewish patients. Patients homozygous for the L444P mutation are at high risk of neurological disease, whereas the presence of at least one allele with N370S precludes this form of disease [22]. Variation in tissue damage within each genotype is probably due to individual differences in the macrophage response to glucosylceramide accumulation, but the mechanisms are unknown. The characteristic Gaucher cell is approximately 70– 80mm in diameter, oval or polygonal in shape and with pale cytoplasm. It contains two or more peripherally placed hyperchromatic nuclei between which fibrils pass parallel to each other (fig. 4.7). It is quite different from the foamy cell of xanthomatosis or Niemann–Pick disease. Electron microscopy. The accumulated glycolipid formed from degraded cell membranes precipitates within the lysosomes and forms long (20–40nm) rod-like tubules. These are seen by light microscopy. Asomewhat similar cell is seen in chronic myeloid leukaemia and in 62 Chapter 4 Fig. 4.7. Gaucher’s disease. Smears of sternal bone marrow show large pale Gaucher cells with fibrillary cytoplasm and eccentric hyperchromatic nuclei. (Coutesy of Dr Atul Mehta.) multiple myeloma due to increased turnover of b- glucocerebroside. Chronic adult form (type 1) This is the most common type. It is of variable severity and age of onset but usually commences insidiously before the age of 30 years. It is chronic and may be recog- nized in quite old people. The mode of presentation is variable, with unex- plained hepato-splenomegaly (especially in children), spontaneous bone fractures, or bone pain with fever. Alternatively there may be a bleeding diathesis, with non-specific anaemia. The clinical features include pigmentation which may be generalized or a patchy, brownish tan. The lower legs may have a symmetrical pigmentation, leaden grey in colour and containing melanin. The eyes show yellow pingueculae. The spleen is enormous and the liver is moderately enlarged, smooth and firm. Superficial lymph glands are not usually involved. Hepatic involvement is often associated with fibrosis and abnormal liver function tests. Serum alkaline phos- phatase is usually increased, sometimes with a rise in transaminase. Cirrhosis may develop but life-threaten- ing liver disease affects only a small minority. Ascites and portal hypertension with variceal bleeding are associated with large areas of confluent fibrosis with a characteristic MRI appearance [16]. Bone X-rays. The long bones, especially the lower ends of the femora, are expanded, so that the waist normally seen above the condyles disappears. The appearance has been likened to that of an Erlenmeyer flask or hock bottle. Sternal marrow shows the diagnostic Gaucher cells (fig. 4.7). Aspiration liver biopsy should be performed if sternal puncture has yielded negative results. The liver is dif- fusely involved (fig. 4.8) Peripheral blood changes. With diffuse bone marrow involvement, a leucoerythroblastic picture may be seen. Alternatively leucopenia and thrombocytopenia with prolonged bleeding time may be associated with only a moderate hypochromic microcytic anaemia [29]. Diagnosis may be made by measuring acid b- glucosidase activity in leukocytes. Blood biochemical changes. Serum alkaline phosphatase is usually increased, sometimes with a rise in transamin- ase. Serum cholesterol is normal. Treatment Enzyme replacement therapy is now available. The acid b-glucosidase was first prepared from pooled human placentae, though most patients now receive enzyme made by recombinant technology. It is given by intra- venous infusion. Several treatment regimens have been shown to be effective. After endogenous enzymatic de- glycosylation, exogenous enzyme is taken up by mannose receptors on macrophages, in the liver, spleen and skeleton, where it is highly effective in reversing the haematological and visceral (liver, spleen) features. Skeletal disease is slow to respond. Splenectomy, partial or total, has been done for the very large spleen causing abdominal discomfort, and occasionally for thrombocytopenia or an acquired haemolytic anaemia. Total splenectomy is followed by more aggressive bone disease and pre-planned enzyme therapy is needed to prevent this. Liver transplantation for decompensated cirrhosis has been done [32]. This does not correct the metabolic defect, and enzyme replacement therapy remains neces- sary. Bone marrow transplantation has been done, but the risks are considered prohibitive in comparison with enzyme replacement therapy. Acute infantile Gaucher’s disease (type 2) This acute form of the disease presents within the first 6 months of life and is usually fatal before 2 years. The child appears normal at birth. There is cerebral involve- ment, progressive cachexia and mental deterioration. The liver and spleen are enlarged and superficial lymph nodes may also be palpable. Autopsy shows Gaucher cells throughout the reticulo- endothelial system. They are, however, not found in the brain and the pathogenesis of the cerebral disease is not understood. Niemann–Pick disease This rare, familial disease, inherited as autosomal The Haematology of Liver Disease 63 Fig. 4.8. Gaucher’s disease. Liver section showing large pink- staining Gaucher cells (arrowed) between the pale liver cells. (Periodic acid–Schiff after diastase digestion (DPAS) stain.). recessive, mainly affects the Jewish race. The deficiency is in the enzyme sphingomyelinase, in the lysosomes of the reticulo-endothelial system. This results in the lyso- somal storage of sphingomyelin. The liver and spleen are predominantly involved. The characteristic cell is pale, ovoid or round, 20– 40mm in diameter. In the unfixed state it is loaded with granules; when fixed in fat solvents the granules are dissolved, giving a vacuolated and foamy appearance. There are usually only one or two nuclei. Electron microscopy shows lysosomes as laminated myelin-like figures. These contain the abnormal lipid. Niemann–Pick disease type A (acute, neuronopathic form) occurs in infants, who die before the age of 2 years. The condition starts in the first 3 months, with anorexia, weight loss and retardation of growth. The liver and spleen enlarge, the skin becomes waxy and acquires a yellowish-brown coloration on exposed parts. The superficial lymph nodes are enlarged. There are pul- monary infiltrates. The patient is blind, deaf and men- tally retarded. The fundus may show a cherry-red spot due to retinal degeneration at the macula. The peripheral blood shows a microcytic anaemia and in the later stages the foamy Niemann–Pick cell may be found. The disease may present as neonatal cholestatic jaundice which remits. Progressive neurological deterioration appears in late childhood. A further type B (chronic, non-neuronopathic form) is associated with neonatal cholestasis which resolves. Cirrhosis develops slowly and may lead to portal hyper- tension, ascites and liver failure [25]. Liver transplanta- tion for hepatic failure has been successful [32]. Although hepatic lipid accumulation was not seen at 10 months, longer follow-up is needed to assess the meta- bolic outcome. Diagnosis is made by marrow puncture, which reveals characteristic Niemann–Pick cells, or by finding a low level of sphingomyelinase in leucocytes. Bone marrow transplant has been done for patients with early severe liver disease [36]. Preliminary reports were promising with reduction of sphingomyelin from liver, spleen and bone marrow, but longer follow-up is needed. Sea-blue histiocyte syndrome This rare condition is characterized by histiocytes stain- ing a sea-blue colour with Wright or Giemsa stain in bone marrow and in reticulo-endothelial cells of the liver. The cells contain deposits of phosphosphingolipid and glucosphingolipid. Clinically the liver and spleen are enlarged. The prognosis is usually good although thrombocytopenia and hepatic cirrhosis have been reported. It probably represents adult Niemann–Pick disease [18]. References 1 Anthony PP, Sarsfield P, Clarke T. Primary lymphoma of the liver: clinical and pathological features of 10 patients. J. Clin. Pathol. 1990; 43: 1007. 2 Bird GLA, Smith H, Portmann B et al. Acute liver decom- pensation on withdrawal of cytotoxic chemotherapy and immunosuppressive therapy in hepatitis B carriers. Q. J. 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The Haematology of Liver Disease 65 [...]... especially the hypothenar and thenar eminences and pulps of the fingers (fig 6. 12) Islets of erythema may be found at the bases of the fingers The soles of the feet may be similarly affected The mottling blanches on pressure and the colour rapidly returns When a glass slide is pressed on the palm it flushes synchronously with the Hepato-cellular Failure 89 Mechanism of skin changes Fig 6. 12 Palmar erythema ( liver. .. occur especially on the front of the chest and the abdomen The venous star is found with elevation of venous pressure It usually overlies the main tributary to a vein of large size It is 2 3 cm in diameter and is not obliterated by pressure Venous stars are seen on the dorsum of the foot, legs, back and on the lower border of the ribs Palmar erythema (liver palms) The hands are warm and the palms bright... 1999; 13: 529 16 Macdonald GA, Peduto AJ Magnetic resonance imaging (MRI) and diseases of the liver and biliary tract Part 1 Basic principles, MRI in the assessment of diffuse and focal hepatic disease J Gastroenterol Hepatol 20 00; 15: 980 17 Macdonald GA, Peduto AJ Magnetic resonanace imaging and diseases of the liver and biliary tract Part 2 Magnetic resonance cholangiography and angiography and conclusions... in liver disease Gut 19 82; 23 : 3 62 2 Rudman D, Di Fulco TJ, Galambos JT et al Maximal rates of excretion and synthesis of urea in normal and cirrhotic subjects J Clin Invest 1973; 52: 22 41 3 Walshe JM Disturbances of amino-acid metabolism following liver injury Q J Med 1953; 22 : 483 Skin changes An older Miss Muffett Decided to rough it And lived upon whisky and gin Red hands and a spider Developed... Note the elevated centre and radiating branches scattered in random fashion through the skin, usually on the upper arms These resemble the silk threads in American dollar bills and the condition is called paper money skin A further association is the appearance of white spots on the arms and buttocks on cooling the skin [3] Examination with a lens shows that the centre of each spot represents the beginnings... production of cytokines: tumour necrosis factor (TNF), interleukin-1 (IL1) and IL6 RE, reticuloendothelial shows a reduction in factors such as fibronectin, opsonins and chemo-attractants, including members of the complement cascade Systemic toxaemia of intestinal origin results in deterioration of the scavenger functions of the reticulo-endothelial system and also to renal damage (fig 6.9) [6] These factors... analysis Scand J Gastroenterol 19 92; 27 : 355 5 Bennett HS, Baggenstoss AH, Butt HR The testis, breast and prostate of men who die of cirrhosis of the liver Am J Clin Pathol 1950; 20 : 814 6 Cavanaugh J, Niewoehner CB, Nuttall FQ Gynecomastia and cirrhosis of the liver Arch Intern Med 1990; 150: 563 7 Cornely CM, Schade RR, Van Thiel DH et al Chronic advanced liver disease and impotence: cause and effect?... followed by MRI and/ or MRCP scanning to help in the diagnosis and to show the extent of disease For the diagnosis of gallbladder stones, US is the primary method of choice Tc-IDA scanning provides an alternative non-invasive method to US for diagnosing acute cholestasis, and is used to demonstrate post-operative biliary patency and 78 Chapter 5 Table 5.1 Non-invasive imaging for hepato -biliary disease... Matsunaga N MR imaging of the liver: techniques and clinical applications Eur J Radiol 1999; 32: 2 11 Khan MA, Combs CS, Brunt EM et al Positron emission tomography in the evaluation of hepatocellular carcinoma J Hepatol 20 00; 32: 7 92 12 Killi RM Doppler sonography of the native liver Eur J Radiol 1999; 32: 21 13 Kreeftenberg HG, Mooyaart EL, Huizenga JR et al Quantification of liver iron concentration... [2] , hepatic artery thrombosis (after liver transplantation) and portal vein thrombosis In portal hypertension the direction of portal flow and the patency of porto- 70 Chapter 5 Fig 5.5 Ultrasound scan in cirrhosis showing irregular edge of liver (arrowed) together with coarse echo pattern systemic shunts can be seen Flattening of the Doppler waveform from the hepatic veins suggests the presence of . Jewish race. The deficiency is in the enzyme sphingomyelinase, in the lysosomes of the reticulo-endothelial system. This results in the lyso- somal storage of sphingomyelin. The liver and spleen are. liver. Reticulo-endothelial storage diseases affect the liver as well as other organs. This section outlines the involve- ment of the liver in this broad group of diseases. The liver is involved to a variable. in bone marrow and in reticulo-endothelial cells of the liver. The cells contain deposits of phosphosphingolipid and glucosphingolipid. Clinically the liver and spleen are enlarged. The prognosis