Thalassemia Macroscopic Image

Fig. 9. Histology of hepatic adenoma arranged in plates that are two to three cells thick, separated by sinusoids

Fig. 10. Macroscopic aspect of liver adenoma with large intra-lesional hemorrhage

Dysplastic Focus

Dysplastic focus is defined as congeries of hepato-cytes, measuring less than 1 mm in diameter, which show dysplasia but no histological signs of malignancy. Dysplastic foci generally occur in cirrhosis of any origin and are extremely rare in non-cirrhotic livers. In addition, patients suffering from a-1-antitrypsin deficiency, tyrosinemia or chronic viral hepatitis B or C demonstrate a comparatively high prevalence of dysplastic foci. Usually, serum a-fetoprotein is normal or minimally increased. However, in patients with tyrosinemia, high levels of serum a-fetoprotein can be found even before nodules are macroscopically visible [12,181].

Dysplastic Nodule, High-grade

High-grade dysplastic nodules are lesions with at least a moderate degree of atypia insufficient for the diagnosis of malignancy. However, this type of lesion can be considered a precursor to HCC and thus resection should be considered. These lesions may be of any size within the grossly visible range (Fig. 11), however, as the size of the lesion increases, so too does the likelihood that high-grade or malignant lesions are present: benign lesions are usually not greater than 20 mm in diameter. Necrosis and hemorrhage are not usually seen in high-grade dysplastic nodules.

Dysplastic Nodule

A dysplastic nodule is defined as a nodular region of hepatocytes, measuring at least 1 mm in diameter showing signs of dysplasia but no definite his-tological signs of malignancy. These nodules are usually found in cirrhotic livers. Dysplastic nodules may be differentiated into two subgroups on the basis of the degree of cellular dysplasia [59, 165].

Dysplastic Nodule, Low-grade

A low-grade dysplastic nodule is a lesion with a mild degree of atypia.

Fig. 11. Cross section of a large high-grade dysplastic nodule in a cirrhotic liver, which can only be differentiated microscopically from a HCC

Hepatocellular Carcinoma (HCC)

In Europe and North America the incidence of HCC is generally below 3/100,000 inhabitants, while in parts of Asia and Africa it is about thirty times higher. The endemic occurrence of chronic hepatitis B and exposure to Aflatoxin B1 seem to be primary reasons for this [8]. In Europe and Japan the leading cause of HCC is chronic hepatitis C with consecutive cirrhosis [53].

Patients with chronic hepatitis or hemochromatosis have the highest risk of developing HCC. On the other hand, alcohol-induced cirrhosis, autoimmune hepatitis and a-1-antitrypsin-deficien-cy do not seem to increase the risk significantly. Similarly, primary biliary cirrhosis and Wilson's disease do not predispose subjects to an increased incidence of HCC [135].

Generally, the prognosis for patients with HCC is poor, and is largely dependent upon the extent of surgical intervention, the size of tumor growth, the functionality of the remaining liver parenchyma and the possibility of infiltration of the portal vein [199] (Fig. 12).

Whereas the ultimate procedure for the potential cure of patients with HCC remains liver transplantation [153], possibilities for palliative treatment include intraarterial injection of 131Iod-Lipi-odol or alcohol [55].

The macropathological division of HCC, which dates from the beginning of the 20th century, correlates relatively well with imaging findings. Three main types can be distinguished:

• the multinodular type with multiple, sharply-demarcated tumor nodules,

• the massive type with one single tumor node and smaller satellite nodules,

• the diffuse type with tumor areas interspersed throughout the liver.

Additionally, an encapsulated tumor type can be distinguished, which seems to be an early phase of the other histological types. Unfortunately, there doesn't seem to be a correlation between these morphological criteria and epidemiological findings or prognosis. The new World Health Organisation (WHO) classification presents a more differentiated set of criteria for HCC characterization [81].

Apart from the above-mentioned pathologies, it is evident that almost any chronic liver disease leading to cirrhosis may be complicated by HCC. Neoplastic development in the liver can be seen as a multi-step process that is triggered by a variety of events. Normal liver is mitotically inactive, but when cells are stimulated to divide as occurs in a variety of conditions, including liver cirrhosis, the liver becomes sensitive to carcinogenesis. However, HCC also occurs in the absence of cirrhosis in a

Fig. 12. Cut surface of a hepatocellular carcinoma without a capsule, infiltrating the liver parenchyma

small but significant (about 7%) proportion of cases [100].

A proposal as to how the multi-step development of HCC can be interpreted is presented in Table 1. However, it is important to realize that reliable differentiation between pre-cancerous developments, such as high-grade dysplastic nodules, and well-differentiated HCC is not always possible [58,142].

Microscopically, HCC has several patterns. HCC is composed of malignant hepatocytes that differentiate into normal liver structures and mimic normal hepatocyte growth, but do not form normal hepatic acini (Fig. 13). Cells in well-differentiated HCC are difficult to distinguish from normal hepatocytes or hepatocellular adenoma cells. Malignant hepatocytes may even produce bile (Fig. 14). In other cases, there are microscopic variations, with HCC containing fat (Fig. 15), tumoral secretions (large amounts of watery material), fi-brosis, necrosis and amorphous calcifications (Figs. 16, 17). This variable microscopic presentation gives rise to different appearances according to the imaging techniques employed.

Table 1. HCC development and liver cirrhosis Macro-regenerative nodule

Low-grade dysplastic nodule

High-grade dysplastic nodule

Well-differentiated HCC

Undifferentiated HCC

Spindle Cells Trabeculae Liver
Fig. 13. Grade 1 HCC consisting of small liver-like tumor cells arranged in thin trabecular layers, which may be difficult to distinguish from liver-cell adenomas and atypical hyperplastic nodules
Mosaic Pattern Hcc
Fig. 14. Histological aspect of a well-differentiated HCC showing bile production (arrows)
Fig. 15. HCC with fatty metamorphosis
Airplane Crash Bodies
Fig. 16. Cut section of a HCC with a mosaic pattern containing Fig.17. Cut section of a HCC with mosaic pattern, note the fatty fat, solid nodules, necroses, fibrosis and cystic areas and fibrous areas
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Fig. 18. Cut section of a HCC with a nodular pattern and fibrous capsule
Mosaic Pattern Hcc

Fig. 19. Histology of a fibrolamellar carcinoma demonstrating tumor cells separated by characteristic parallel lamellae of coarse, ropy collagen

Macroscopically, there are also several patterns of growth. HCC is referred to as single or massive when there is either a solitary small or a large mass, with or without a capsule (Fig. 18). Multifo-cal HCC, the second most common pattern, is characterized by multiple separate nodules. The least common pattern of diffuse or cirrhoto-mimetic growth consists of multiple small tumoral foci distributed throughout the liver, mimicking the nodules of cirrhosis. HCC is said to be encapsulated when it is completely surrounded by a fibrous capsule. Patients with encapsulated HCC have a better prognosis due to the increased possibilities for resection. However, vascular invasion of intrahepatic vessels (portal hepatic vein branches) and perihepatic vessels (inferior vena cava and portal vein) is common.

Fig. 19. Histology of a fibrolamellar carcinoma demonstrating tumor cells separated by characteristic parallel lamellae of coarse, ropy collagen

Fig. 20. Cut section of a fibrolamellar carcinoma with a lobular arrangement with interconnecting fibrous septa and a central stellate scar

Fibrolamellar Carcinoma (FLC)

This type of hepatocellular carcinoma occurs both in male and female patients, typically under the age of 25 years. In contrast to HCC, underlying cirrhosis is not usually present in FLC. Pain in the right upper abdominal quadrant, nausea and weight loss are the leading symptoms, while jaundice is quite rare. Often the tumors are relatively large (> 15 cm) at the time of detection. If resected early, the five year survival rates are about 50%. Metastases from FLC are mostly located in the lymph nodes and lungs, and, in roughly half of the cases, metastatic lymph nodes are present at the time of diagnosis. Macroscopically, the tumors have a lobular appearance with fibrous septa and a central scar, which, in contrast to that in FNH, is a true scar.

FLC lesions have a distinctive microscopic pattern and are composed of eosinophilic, malignant hepatocytes containing prominent nuclei. FLCs express hepatic as well as biliary keratin. The fibrous component accounts for 50% of the tumoral mass

Fig. 20. Cut section of a fibrolamellar carcinoma with a lobular arrangement with interconnecting fibrous septa and a central stellate scar

Fig. 21. Cut section of a fibrolamellar carcinoma with a nodular appearance but with minimal demonstration of a central stellate scar

and is distributed in multilamellar strands (Fig. 19), except in larger tumors containing large central scars (Fig. 20). Satellite nodules are often present. The appearance of FLC can be similar to that of FNH as both tumors have a central scar and multiple fibrous septa (Fig. 21). In FLC, hemorrhage is rare, while necrosis and coarse calcifications are often present, especially in the central scar (in approximately 30% of cases). The origin of FLC is still to be clearly defined, although mixed FLC/HCC types seem to exist [38].

Benign and Malignant Tumors of the Biliary Tract

Bile Duct Adenoma

This tumor is found mainly by chance and its maximal size does not usually exceed 2 cm. Microscopically, small bile ducts lined by mucin-producing cells are embedded in a fibrous stroma. A malignant transformation has not yet been reported [3].

Bile Duct Cystadenoma

Hepatic cystadenoma is a very rare tumor, although analogous forms are quite common in the pancreas and ovaries. Most of the patients are women in their fifth decade of life, and the major symptoms include pain and jaundice. Infection, rupture and malignant transformation of these slowly growing tumors may occur. Surgical resection is the therapy of choice [98] (Fig. 22).

Microscopically, cystic spaces filled with viscous yellowish or reddish fluid can be seen. The most common mucinous type should be distinguished from the serous and papillary cystic types. The tumoral stroma may consist of only a thin hyaline rim, but it may also appear as a compact layer [79].

Biliary Papillomatosis

About 50 cases of multiple small papillomas of the intra- and extrahepatic bile ducts have been described. Jaundice may be the only presenting symptom, although sepsis and hemobilia with a subsequent fatal outcome may result. A temporary biliary stoma may bring about some relief, although the only curative method to date involves liver transplantation. The presence of biliary pa-pillomas seems to coincide with ulcerative colitis, Caroli's syndrome and polyposis coli [124].

Bile Duct Carcinoma (Cholangiocarcinoma, CCC)

Bile duct carcinomas are divided according to their location, into intrahepatic cholangiocarcinoma [9], hilar adenocarcinoma (Klatskin tumor) [91] and carcinoma of the extrahepatic bile ducts [5].

On cut sections, CCC is characterized by the presence of large amounts of whitish fibrous tissue (Fig. 23). Inside the tumor, especially in large examples, a variable amount of central necrosis may be present, while hemorrhage is rare. Histologically, the tumor is an adenocarcinoma with a glandular appearance and cells that resemble biliary epitheli-

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Fig. 22a, b. Biliary cystadenoma. The resected tumor (a) is well-defined and shows a thick capsule. The cut surface (b) of a biliary cys-tadenoma, in contrast to congenital simple cysts, demonstrates a multilocular appearence. Cysts may show hemorrhage and fluid-fluid levels

Fig. 22a, b. Biliary cystadenoma. The resected tumor (a) is well-defined and shows a thick capsule. The cut surface (b) of a biliary cys-tadenoma, in contrast to congenital simple cysts, demonstrates a multilocular appearence. Cysts may show hemorrhage and fluid-fluid levels

Fatty Infiltration Liver
Fig. 23. Cut section of a intrahepatic cholangiocellular carcinoma diffusely infiltrating the liver with finger-like extensions and central sclerosis

um with fibrous stroma (Fig. 24). Mucin production and calcification can sometimes be demonstrated. At autopsy there is often a layer of atypical cells surrounding the main tumor, which probably propagates relapsing tumor growth after an initial curative resection. Overall the prognosis is poor.

A large desmoplastic reaction is typical of CCC. Diagnostic studies often reveal lymph node metastases and hematogeneous spread to the lungs, bones, adrenals, spleen and pancreas. Intrahepatic carcinomas often arise in the fifth or sixth decades of life, and usually later in life than HCC. Non-specific signs such as pain and weight loss are typical, while jaundice is generally atypical. The tumor is usually hypovascular, but it may show late enhancement in cases of desmoplastic changes. Early signs of metastases include finger-like extensions along lymphatic channels and represent another reason for the poor prognosis of intrahepatic CCC (Fig. 25). Infections with Clonorchis sinensis and Opisthorchis viverrini, hepatolithiasis and congenital anomalies of the bile ducts predispose subjects to bile duct carcinoma. Other risk factors include Caroli's syndrome, sclerosing cholangitis and congenital hepatic fibrosis [18,93,94,136].

The most common extrahepatic locations of CCC are along the common hepatic duct and the cystic duct. In these cases, painless jaundice is the leading symptom. Associations with choledochal cysts, congenital malformations of the bile ducts and ulcerative colitis have been reported. CCC with a high cuboid epithelium located in the liver hilum is typically referred to as Klatskin tumor [91].

Klatskin Tumor
Fig. 24. Histology of the periphery of a CCC which demonstrates tumor cells in a tubular pattern in an abundant fibrous stroma entrapping normal liver cells
Fig. 25. Macroscopic distribution of diffuse hepatic metastases of a CCC

Bile Duct Cystadenocarcinoma

In contrast to bile duct carcinoma, the prognosis for patients with this tumor is somewhat better. Bile duct cystadenocarcinoma is quite rare and metastases are only seldom found. It is usually diagnosed by histologic analysis of a resected cystic mass lesion.

The majority of bile duct cystadenocarcinomas occur in middle-aged women and cause no symptoms until they are quite large in size. Since local or metastatic spread is quite rare, patients are usually referred for surgery [79,108].

Gallbladder Carcinoma

This tumor is mainly found in female patients predominantly in the sixth decade of life. The main symptoms include right upper abdominal quadrant pain, nausea and jaundice. Patients frequently have gallstones or, on occasion, a so-called "porcelain" gallbladder caused by recurrent inflammation [84].

Whereas adenocarcinoma growth usually involves just the gallbladder, squamous cell carcinoma and undifferentiated carcinoma often infiltrate neighboring structures. Local complications involving fistula, perforation or empyema may arise. Distant metastases typically occur in advanced cases [70,87].

Other quite rare tumor types in the gallbladder include sarcoma, primary malignant melanoma, carcinoid and lymphoma [111,193,198].

Benign Non-Epithelial Tumors 2.3.1

Hemangioma

The most common liver lesions are hemangiomas, which are found with a prevalence of 0.4-7.3% and only rarely cause any clinically relevant symptoms [78]. Thus, they are most often detected by chance. Small capillary hemangiomas need to be distinguished from larger cavernous hemangiomas, which are frequently categorized as benign congenital hamartomas. Macroscopically, cystic blood-filled spaces can be visualized. When detected intraoperatively, these lesions can be diagnosed as hemangiomas by simple palpation. The lining of these spaces consists of endothelial cells and thin fibrous walls. With increasing tumor size, central thrombosis with consecutive fibrosis, myx-oid changes or calcification may occur.

Therapeutic intervention should only be considered in cases of symptomatic or giant heman-gioma (larger than 10 cm) [192].

Complications such as rupture, thrombocy-topenia or disseminated intravascular coagulation (DIC), caused by stasis of blood flow in the dilated vessels, may occur on rare occasions. Multiple he-mangiomas are considered part of the syndrome of systemic hemangiomatosis. Fine needle biopsy should be avoided because of possible bleeding and because in many cases only blood is aspirated, which leads to poor diagnostic results. The diagnosis can usually be established by means of blood pool scintigraphy [166] or MRI.

Liver Fibrosis Cut Section
Fig. 26. Cut section of two large hepatic hemangiomas showing central fibrosis and hyalin changes (arrows)

On cut sections, larger hemangiomas almost always present a heterogeneous composition with areas of fibrosis, necrosis and cystic changes and intratumoral coarse calcifications (Fig. 26). In some cases abundant fibrous tissue completely replaces the lesion.

Infantile Hemangioendothelioma (IHE)

Most of these infantile mesenchymal tumors are found during the first six months of life, and there seems to be a slight female predominance [157].

Common symptoms include hepatomegaly or a palpable mass, sometimes together with diminished growth or high-output cardiac failure caused by shunting. Rupture, thrombocytopenia and hy-pofibrinogenemia may occur on rare occasions. Surgical intervention may be avoided if no life-threatening complications appear, as the tumor tends to regress gradually. Therapeutic strategies may consist of steroids, chemo- or radiotherapy, embolization or resection. Macroscopically, IHEs are usually multiple and diffuse. A solitary lesion is an uncommon variant. The nodules vary from a few millimeters to 15 cm or more in size, and are round, reddish-brown and spongy, or white-yellow with fibrotic predominance in mature cases. Microscopically, two types can be distinguished:

• Type 1 has intercommunicating vascular channels with a single-layered endothelial lining. Thrombosis and infarction in cavernous spaces is quite frequent, as is extramedullary hematopoesis.

• Type 2 demonstrates nuclear atypia and a multi-layered endothelial lining. There seems to be some resemblance to angiosarcoma, but the finding of a metastasizing IHE has not yet been reported [46].

Lymphangioma

Hepatic lymphangioma are congeries of dilated lymphatic channels containing proteinaceous fluid or blood. Lymphangiomas in the liver occur most frequently as multiple masses, although solitary lesions are found on occasions. In some cases concomitant hemangiomas can be found. When diagnosing hepatic lymphangioma, whole body cross-sectional imaging is indicated because multiple organs and tissues, (i.e. spleen, kidneys, lungs, gastrointestinal tract and skeleton), are usually involved, particularly in children. Thus, the condition is often referred to as lymphangiomatosis [72,170].

Fig. 28. Cut section of a diffuse infiltrating hepatic angiosarcoma

Angiomyolipoma

Angiomyolipomas are rare soft tissue tumors found most frequently in the kidneys and occasionally also in the liver. There is an increased incidence of these tumors in association with tuberous sclerosis [24,67,122].

Angiomyolipomas consist of blood vessels, fat and smooth muscle [66] (Fig. 27).

Fatty Infiltration Liver
Fig. 27. Macroscopic aspect of an angiomyolipoma of the liver

Malignant Non-Epithelial Tumors 2.4.1

Angiosarcoma

These tumors are the most frequent sarcomas of the liver and arise typically in the sixth and seventh decades of life, predominantly in male subjects. Exposure to thorotrast, monomers of vinyl chloride, steroids, radium and chronic arsenic intoxication is known to be associated with angiosarcoma. Liver cell hyperplasia with dilatation of the sinusoids and increased fibrosis leading to portal hypertension are typical early stages of tumor growth. Macroscopically, angiosarcomas are ill-defined sponge-like hemorrhagic tumors (Fig. 28). They are composed of malignant endothelial cells lining vascular channels of variable size, from cavernous to capillary, which attempt to form sinusoids. Metastases to lymph nodes, spleen, lung, bone and adrenals are rarely found.

Thorotrast particles can be found within the malignant endothelial cells in cases of Thorotrast-induced angiosarcoma. The majority of angiosar-comas present as multiple nodules, often with areas of internal hemorrhage. When angiosarcoma appears as a single, large mass, it does not have a capsule and frequently contains large cystic areas filled with blood debris [125,152,163,194].

Malignant Epithelioid Hemangioendothelioma (EHE)

This tumor most often arises in female patients in the fifth decade of life. Patients complain of weight loss and right upper abdominal quadrant pain, sometimes in combination with jaundice. There may be an association with oral contraceptives. The tumor is most frequently located at subcapsular sites (50-65%) and macroscopically, it is a solid, fibrous mass, sometimes with calcifications and encased by vessels. In contrast to angiosarcoma, the prognosis seems to be better; increasingly patients are undergoing hepatectomy and consecutive liver transplantation. Grossly, two different types of EHE have been described: an early stage nodular type with small subcapsular lesions, which in a later stage of the disease tend to become diffuse with confluent lesions along the hepatic or portal veins. Typically, in malignant EHE a retraction of the liver surface can be noted (Fig. 29). The only other primary liver lesion in which this sign is observed is CCC. Microscopically, EHEs are com-

Liver Necrotic
Fig. 29. Cut section of a subcapsular-located malignant epith-eloid hemangioendothelioma showing a characteristic retraction of the liver surface (arrow)

posed of epithelioid and dentritic cells within a tumor matrix that may become sclerotic, hyalinized and calcified. Intratumoral necrosis and hemorrhage are common findings [54,80].

Undifferentiated (Embryonal) Sarcoma

Along with hepatoblastoma and IHE this is one of the most frequent primary malignant hepatic tumors in children, arising typically between the ages of six and ten. Increased girth and weight loss are common symptoms and a newly discovered heart murmur induced by a tumor thrombus may be present on rare occasions. Macroscopically, sarcomas have solid and cystic areas, hemorrhage or necroses, and are sometimes surrounded by a pseudocapsule. In 50% of all cases, extramedullary hematopoesis can be demonstrated. Complete tumor resection followed by chemotherapy and radiation can increase the five year survival rate to about 15% [160,173].

Rhabdomyosarcoma (Sarcoma Botryoides)

Hepatic rhabdomyosarcoma is a tumor typically found in children below the age of five. Only on very rare occasions do they arise in adults. Typically, the tumor has a grape-like appearance and grows in the lumina of larger bile ducts. Its presence leads to intermittent icteric episodes, fever and weight loss.

The prognosis and treatment modalities are similar to those of undifferentiated embryonal sarcoma [76].

Other Primary Sarcomas

Almost every type of sarcoma has been reported in the liver. They usually occur in middle and old age, in either sex, and are typically large and at an advanced stage when discovered. Although most of the tumors are slow-growing, in most cases prognosis is poor as complete excision is seldom possible due to the size and degree of advancement. Leiomyosarcomas may arise from the liga-mentum teres, the portal and hepatic veins, as well as from the liver capsule. Other rare malignant soft-tissue tumors of the liver include fibrosarco-ma, malignant fibrous histiocytoma, liposarcoma, osteosarcoma, malignant hemangiopericytoma and sarcomas with divergent cell lines (malignant mesenchymoma).

Primary Lymphoma of the Liver

Hodgkin's lymphoma, non-Hodgkin's lymphoma and leukaemia, as well as histiocytosis and masto-cytosis, may affect the liver secondarily. Nevertheless, an increasing number of primary lymphomas of the liver are being described [139, 150]. The recognition of primary hepatic lymphoma is important as treatment often has a favorable outcome. The tumor may occur at any age, from childhood to adolescence, and is around four times more likely to occur in males. Patients present with abdominal pain, hepatomegaly or a mass. Additional B-symptoms (fever, weight loss) are found in 50% of cases. On rare occasions the tumor may be associated with autoimmune disorders, chronic hepatitis, cirrhosis, infection with hepatitis B virus

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Fig. 30. Macroscopic presentation of a solid solitary primary hepatic manifestation of Hodgkin's disease

(HBV) or the human immunodeficiency virus (HIV). Although the tumors most frequently present as solitary (Fig. 30) or multiple masses, diffuse infiltration can also be found on occasions. Upon histology, most non-Hodgkin lymphomas are described as high-grade. Possible misdiagnoses include metastatic carcinoma, chronic hepatitis and inflammatory pseudotumor.

Surgical resection gives the best prognosis although multi-agent chemotherapy and/or radiation therapy are also often worthwhile [83].

Hepatoblastoma

Hepatoblastoma is typically found in young children. Up to one third of patients have concomitant anomalies such as hemihypertrophy, cleft palate, Beckwith-Wiedemann or Down's syndrome. The tumors are often palpable, while failure to thrive and weight loss, together with extremely elevated a-fetoprotein (AFP) levels, are typical symptoms. Cystic, necrotic and/or hemorrhagic areas as well as fibrosis and calcifications are common, while the tumor may also be partially encapsulated. In 20% of cases the tumors are multifocal.

Most tumors are of the epithelial, mixed or mesenchymal type. In very rare cases of teratoid or even chondroid hepatoblastoma, muscle or neuronal cells may be found. Epithelial hepatoblas-toma is composed of fetal and/or embryonal malignant hepatocytes. A mixed hepatoblastoma has both an epithelial (hepatocyte) and a mesenchymal component consisting of primitive mesenchy-mal tissue. Amorphous calcifications are seen in about 30% of cases. This histological classification has prognostic implications: the epithelial type has a better prognosis than the other forms, especially when there is a predominant hepatocyte presence. Embryonal epithelial cells are more primitive than fetal epithelial and mesenchymal cells and tumors with the former histological type carry a poorer prognosis.

Surgical resection is the primary treatment although operative mortality is high (about 25%). Accurate tumor staging is essential to determine the need for additional chemo- or radiotherapy. The long term survival rate is about 15-35%. Factors that contribute to a worse prognosis are age under one year, large tumor size, involvement of vital structures and the predominance of anaplas-tic cells [77,95,183].

Tumor-like Lesions

2.6.1 Cysts

The etiology and pathogenesis of solitary liver cysts have not yet been totally clarified. Moreover, it is uncertain whether they are developmental or neoplastic in origin.

Non-Parasitic Cysts

Primary, non-parasitic liver cysts are subdivided into unilocular and multilocular varieties. Whereas unilocular cysts are more likely to be developmental in origin, multilocular cysts may be neo-plastic with an increased, but nevertheless very low potential for malignant change (Fig. 31). Primary, non-parasitic liver cysts may occur at any age although the peak incidence is between the fourth and sixth decades of life with a male to female ratio of 4-5:1. Liver cysts smaller than 8-10 cm seldom cause symptoms and are therefore most often diagnosed by chance. In cases of symptomatic cysts, patients present with an upper abdominal mass and fullness, nausea and occasional vomiting. An acute abdominal crisis may be due to torsion, strangulation, hemorrhage into the cyst or rupture [143].

Parasitic Cysts Liver
Fig. 31. Liver surface with diffuse distribution of non-parasitic uncomplicated liver cysts

Symptomatic large solitary cysts are twice as likely to be found in the right lobe as in the left. Jaundice is a frequent complication. Whereas excision has often been the treatment of choice, aspiration and injection of sclerosing agents such as alcohol, polido-canol or minocyclin chloride represent an accurate therapeutic option in many cases [52, 63].

Malignant tumors arising from either type of solitary cyst may occur on very rare occasions. Although these tumors are usually adenocarcino-mas, squamous cell carcinomas and even carci-noids have been reported [20, 167].

Mesenchymal Hamartoma

Mesenchymal hamartoma most likely represents a localized abnormality of ductal plate development that precedes birth. They occur almost exclusively in young children with an average age of 15 months and have a predominance in males to females of 2:1. Association with polycystic kidney disease, congenital hepatic fibrosis and biliary hamartoma has been described. Children typically present with progressive abdominal enlargement and imaging techniques show a cystic mass which is usually large. Microscopically, a variable mixture of liver tissue is seen. Extramedullary hematopoiesis is commonly present. Surgical excision is curative and malignant transformation has not been reported [49,161].

Biliary Hamartoma

Biliary hamartomas often occur as small lesions, found by chance on fine needle biopsy. They contain irregularly-formed dilated bile ducts in a fibrous stroma and may occur together with cystic kidneys. It is still unclear as to whether cholangio-carcinomas arise from these lesions [50].

Inflammatory Pseudotumor (IPT)

A rare differential diagnosis among solid liver tumors is the so-called IPT. This lesion may appear in almost any tissue and anatomic location and on diagnostic imaging mimics other common histologi-cal and imaging findings. Despite numerous reports, the pathogenesis of IPT remains unclear. Recent publications have explained the etiology of this lesion as either a post-inflammatory regenerative process or a primary neoplastic process [11,34,47].

The suspicion of neoplasm is based on histologic findings in which an IPT is shown to consist of myofibroblasts, fibroblasts, lymphocytes and plasma cells. In such cases the pathologist may be persuaded to diagnose a sarcoma with primary benign clinical behavior. The suspicion that the lesion is of true neoplastic origin may be reinforced by the presence of histiocytes and spindle cells and when immunohistochemical and ultrastructural examinations reveal signs of benign as well as malignant growth [36].

However, examination of IPT of the ileo-cae-cum have shown that they may be associated with infection. The histology of this lesion was shown to be comparable with that of mycobacterial pseudotumors of the lymph nodes, spleen and lung in a patient infected with HIV [101].

From this observation it was concluded that the immune system plays an important role in the pathogenesis of this kind of mass lesion. Additionally, electron microscopy may demonstrate intracellular bacilliform organisms. Molecular analysis of DNA fragments was able to identify Pseudomonas sub-populations that were not known to be infectious in humans. In this regard, pathogenic organisms such as Epstein-Barr virus, actinomyces and nocardia, especially in hepatic lesions, are suspected to contribute to the development of IPT [187].

Other Tumor-like Lesions: Peliosis Hepatis

The microscopic type is characterized by an area of absent reticulin fibers, thus resulting in a dilation of the sinusoids, which are normally lined by endothelium [196]. Two varieties have been described: the phlebectatic type, in which the blood-filled spaces are lined with endothelium and are based on aneurysmal dilatation of the central veins, and the parenchymal type, in which the blood spaces are not lined with endothelium and are usually associated with hemorrhagic parenchy-mal necrosis.

There seems to be an increased incidence of peliosis with thiopurine, anabolic steroids, vitamin A and thorotrast. The macroscopic type of peliosis shows cystic blood-filled spaces, which occur in malnutrition, leukemias, tuberculosis, some forms of vasculitis, lepra and HIV. Due to the large cystic blood-filled areas, imaging studies may lead to the misinterpretation of the lesion as hemangioma [48,149,155,195].

These lesions typically have no clinical relevance, but may cause some difficulties in the differential diagnosis of focal liver lesions.

Infectious Diseases of the Liver 2.7.1

Liver Abscess

A liver abscess generally develops by one of three different routes:

• ascending infection of the bile ducts,

• hematogeneous spread in endocarditis, pneumonia and pulmonary AV-malformations,

• purulent infections draining to the portal vein, e.g. diverticulitis.

The origins of pyogenic abscesses within the liver are usually not obvious. Contributory factors include diabetes mellitus, perforated duodenal ulcer or diverticulosis. The most common pathogenic germs are E. coli, other coliforms, and Streptococcus milleri. Anaerobes are being reported with increasing frequency. However, amebiasis and several worm infections (ascariasis, clonorchiasis, fas-cioliasis) of the biliary tree, which predispose subjects to bacterial cholangitis, should be considered as possible pathogenic agents in the differential diagnosis of pyogenic liver abscesses [68].

Infection spread via the biliary tree may be due to an acute ascending cholangitis complicating a large bile duct obstructed by stones. In addition, suppurative cholecystitis, post-operative biliary stricture, acute or chronic pancreatitis and tumors in the biliary tree and pancreas may cause focal inflammation that spreads to the liver.

Today, bacterial infection via the portal vein is less common in industrialized nations. Hepatic spread arises from inflammatory processes in the appendix, the colon (as in diverticulitis) and the pancreas, leading to septic portal thrombophlebitis and thereafter to liver abscesses. In developing countries, umbilical sepsis plays a leading role and is the source of portal pyemia which may also induce splenic vein occlusion leading to splenomegaly.

An arterial spread of infection to the liver is common. Patients usually develop clinical symptoms before a visible abscess can be depicted. Pathogenic germs include Staphylococcus, Neisseria gonorrhoeae and Chlamydia trachomatis which may induce complicated pelvic infections. Chronic granulomatosis disease facilitates arterial septic spread to the liver [119].

On rare occasions, acute cholecystitis or liver trauma may be the cause of a liver abscess. Amebic abscesses are not very frequent in Europe. While abscesses might not have a fibrous capsule initially, they tend to form coagulative necrosis and subsequently liquefy (Figs. 32,33). Thereafter, abscesses may rupture and induce peritonitis, which usually has a bad prognosis.

Hepatic Aspergillus infection typically demonstrates multiple small hemorrhagic necrosis. Hy-phae may also obstruct vessels and lead to infarction.

Multiple portal or periportal abscesses with granuloma formation are typical of Candida. In Cryptococcus infections large abscesses are absent, but small foci of necrosis may be observed which sometimes follow the bile ducts in a manner similar to sclerosing cholangitis [10].

Patients under immunosuppression or with hematologic disease are particularly at risk of developing hepatic abscesses.

Liquidfied Necrosis

Fig. 33. Abscess formation with central liquified necrosis caused by septic emboli in a patient with AV-malformations of the pulmonary vasculature

Fig. 32. Macroscopic aspect of an early-stage intrahepatic abscess formation with the beginning of central necrosis, in a patient with immune deficiency

Fig. 33. Abscess formation with central liquified necrosis caused by septic emboli in a patient with AV-malformations of the pulmonary vasculature

Abscess Formation in Bile Ducts

Usually a cholangitis is induced by biliary obstruction caused by lithiasis or strictures, and more rarely by a malignant neoplasm. Ascension from the gastrointestinal tract is the typical route of spread.

Helminthic Infections 2.7.2.1

Nematodes (Ascariasis)

Transmission of helminths is usually by the fecal-oral route. Hepatomegaly with an eosinophilic granulomatous reaction may be present during migration of the larvae. This may lead to mechanical obstruction of the bile or pancreatic ducts and subsequent cholecystitis, hepatic abscesses and septicemia [89].

Cestodes (Echinococcus)

Echinococcus granulosus, which is the cause of the unilocular hydatosis, is found throughout Europe and is mainly transmitted by contact with dogs. The larval oncospheres reach the hepatic parenchyma via the portal vein. There they form slowly growing cysts, which may lead to compression or bacterial infection of the bile ducts. The cysts may grow to a size of 30 cm, and are typically surrounded by a fibrous rim which may calcify. Daughter cysts may also occur. A liver biopsy should be avoided because of the potential risk of peritoneal spread, anaphylactic reactions and dissemination of disease. Partial liver resection or sucking of the cysts and treatment with Albenda-zole may bring about remission.

Unlike the situation with E. granulosus infection, patients with E. multilocularis infection typically complain of jaundice and ascites. Untreated alveolar hydatidosis is frequently fatal. Cysts may rupture spontaneously. There are typically multiple irregularly formed cysts with a malignant-like tendency to invade surrounding parenchyma [2, 25] (Fig. 34).

Trematodes (Schistosomiasis)

Worldwide, schistosomiasis is the leading cause of portal hypertension. Typically, there is a latency between infection and the phase when trematodes

Symmer Pipestem Fibrosis
Fig. 34. Cut section of a hepatic infection with Echinococcus alveolaris. Congeries of small hepatic cysts are present which infiltrate the liver parenchyma

(S. mansoni, S. japonicum, S. mekongi) are found in the portal vein, where the female schistosoma begins egg-laying. This may lead to the so-called Katayama fever and transient hepato-splenomegaly. In advanced schistosomiasis, microscopic examination reveals a periportal fibrosis (Symmers' clay-pipe stem fibrosis), which follows the periportal tracts. Concomitant granulomatous inflammation occurs with scarring. This leads to the typical portal hypertension of the presinu-soidal type. The length and intensity of infection correlates positively with the degree of portal hypertension [42,171].

Parenchymal Disease 2.8.1

Hemochromatosis

In hemochromatosis there is typically an increased uptake of iron in the small intestine despite already adequate iron storage. This leads to iron deposition in the liver, pancreas, joints, myocardium and hypophysis. There is both an inherited and a transfusion-induced type of hemochromatosis. Typical symptoms include diabetes, arthralgias, cardiac insufficiency and hypogonadism. To avoid permanent organic deficiency it is important to diagnose the inherited type. Whereas blood examination is able to hint at the possibility of he-mochromatosis, a liver biopsy with increased iron storage in hepatocytes establishes the diagnosis [56,144] (Fig. 35).

In MRI the increased iron content can be demonstrated by calculation of the T2 relaxation time. This allows diagnosis as well as follow-up un-

Iron Liver Tabel
Fig. 35. Histology of hepatic parenchyma affected by hemochromatosis. Hemosiderin is predominantly accumulated in periportal parenchymal cells, which is in contrast to siderosis of the liver in which iron is stored predominantly in Kupffer cells

Table 2. Causes of steatosis hepatis

Diabetes mellitus

Obesity

Kwashiorkor

Alcohol- or drug-induced liver injury Chronic inflammatory bowel disease Hepatitis C Malaria

Immotile cilia syndrome Fatty liver in pregnancy Reye's syndrome Heat-stroke SIDS

Insect bites

Chronic hepatitis B and C in transplanted livers

Wolman's disease

Chemotherapy der therapy to be assessed. Patients suffering from untreated hemochromatosis typically develop liver cirrhosis and are at high risk of HCC development. Consequently, regular imaging studies should be initiated.

Transfusional Iron Overload (Hemosiderosis)

In some aplastic or hemolytic anemias frequent transfusions are necessary, which lead to increased iron storage in the spleen, liver, lymph nodes and bone marrow. This induces fibrosis of the hepatic parenchyma. If there is additional iron uptake in the intestine, such as in thalassemia, there is the possibility of liver cirrhosis even in young patients [99].

Fatty Liver

Pathologically there are two types of fatty liver: the macrovesicular type in which there are large fat deposits, and the microvesicular type. Imaging is unable to distinguish between the two types. Focal fatty liver on histology typically shows macrovesicular fat deposits. Generally, these lesions do not cause any symptoms and may be solitary or multiple. A general disposition to steatosis (see Table 2) or a localized hypoxia may be the cause, although focal fatty infiltration of the liver may also occur in patients after chemotherapy.

There is a distinct disease entity called non-alcohol induced steatohepatitis (NASH) which

Table 3. Causes of non-alcohol induced steatohepatitis (NASH)

• Morbid obesity

Gastroplasty, gastro-intestinal bypass

• Diabetes mellitus type II

• Drug-induced liver injury

• Parenteral nutrition

• Weber-Christian disease

• Abetalipoproteinemia demonstrates the transition from steatosis to hepatitis and cirrhosis. This was first described in adipose patients after gastrointestinal bypass (see Table 3) [7].

Wilson's Disease

Wilson's disease is an inherited autosomal-reces-sive disease typically associated with increased intestinal uptake of copper and subsequent deposition in the liver, basal ganglia and other organs. There may be an acute or even fulminant hepatitis, chronic inflammation or cirrhosis. In contrast to hemochromatosis, these patients do not demonstrate an increased risk of developing HCC.

Wilson's disease should be considered when a low level of coeruloplasmin (less than 1.3 mmol/l) and an increased quantity of copper is present in the liver (greater than 250 mg/g dry weight) [159].

Clinical symptoms of patients suffering from Wilson's disease seem to be directly related to the accumulation of copper in the brain, cornea, liver and kidneys. Liver cirrhosis induced by Wilson's disease is normally macronodular. However, a mixed type or a micronodular type can also be observed. Histology reveals nodules of variable size separated by fibrous septa with minimal cholan-giocellular proliferation and varying signs of inflammation [109].

However, the distribution of copper deposition does not correlate with the pattern of nodules [162].

The current treatment of choice is D-Penicil-lamin, which chelates unbound copper for urinary excretion [146].

However, liver transplantation can also be considered as an ultimate therapeutic option [129].

Primary Sclerosing Cholangitis

An unspecific inflammatory fibrosis of the intermediate and large bile ducts leads to irregular stenosis and ectasia of the intra- and extrahepatic bile ducts. This often remains completely asymptomatic and is only diagnosed because of increased levels of alkaline phosphatase (AP), although chronic fatigue, stomach pain and intermittent jaundice may also result [104,179,189].

Typically, primary sclerosing cholangitis predominates among male patients in their fifth decade of life [188].

The clinical course can be variable, with many patients dying due to progressive hepatic insufficiency. The only curative treatment is liver trans-plantation.About 10% of all patients with primary sclerosing cholangitis subsequently develop cholangiocarcinoma or HCC [32].

An association with chronic inflammatory bowel disease (such as Colitis ulcerosa) has also been reported. Primary sclerosing cholangitis has to be distinguished from secondary types of scle-rosing cholangitis, such as those induced by surgical intervention, cholelithiasis and even cholangio-carcinoma [128].

2.8.6 Cirrhosis

Hepatic cirrhosis is the endpoint of different toxic, autoimmune, congenital or infectious diseases (see Table 4). Typically it is a diffuse process involving fibrosis and nodule formation [13].

Macropathologically, there are micronodular (nodules < 3 mm),macronodular (nodules > 3 mm) and mixed types of cirrhosis. In micronodular cirrhosis the liver normally displays no irregularity of shape and there is an increased fibrotic reaction compared to the macronodular type (Fig. 36). Al-

Liver Drinker
Fig. 36. Cut section of liver affected by macronodular cirrhosis with a marked variation in size and shape. This is accentuated by the intervening fibrous stroma which varies from broad scars to thin delicate bands of fibrotic tissue
Uterine Window
Fig. 37. Large nodules in a macronodular cirrhosis on the capsular surface of the liver

though hepatomegaly is frequently seen in the early stages, the size of the liver subsequently decreases. The macronodular type typically displays an irregular surface (Fig. 37) and large fibrotic bands.A transition from the micro- to the macronodular type of cirrhosis sometimes occurs in patients under treatment or after alcohol abstinence [ 14].

Although many definitions of cirrhosis can be found in the literature, the most appropriate and concise of these states that cirrhosis is "a diffuse process characterized by fibrosis and a conversion of normal architecture into structurally abnormal nodules". Essential for the diagnosis of cirrhosis is the presence of both fibrosis and nodules throughout the entire liver. However, regeneration should not be present and this must be taken into account when evaluating histopathologic specimens from needle biopsies. For this reason, liver cirrhosis is a diagnosis that should only be assigned by the pathologist; cross-sectional imaging indicates only the diffuse nature of the process.

Table 4. Different pathologies leading to hepatic cirrhosis

Alcohol

Isoniazid

Amiodarone

Methotrexate Methyldopa

• Infections

Hepatitis B and C

Schistosomiasis

• Autoimmune

Chronic active hepatitis

Primary biliary cirrhosis

Wilson's disease a-1-antitrypsin-deficiency Glycogen storage disease Diseases of urea cycle

Hemochromatosis Galactosemia Tyrosinemia Abetalipoproteinemia

• Biliary obstruction

Atresia Cholelithiasis Sclerosing cholangitis

Cystic fibrosis Strictures

Budd-Chiari syndrome Chronic cardiac insufficiency

Veno-occlusive disease

Hereditary hemorrhagic teleangiectasia with AV-shunts

Neonatal hepatitis-syndrome Intestinal bypass

Indian childhood cirrhosis Sarcoidosis

Fibrosis is an integral part of cirrhosis and differentiates it from nodular regenerative hyperpla-sia. Structurally abnormal nodules may often occur but sometimes they can only be identified by means of subtle architectural changes, such as a disordered or compressed cell plate pattern. Although abnormalities in vasculature and blood flow are very important, they are not included in the definition since these changes are a consequence of the other pathologic features rather than primary abnormalities. Equally, true regenerative nodules can be a late occurrence in cirrhosis and therefore regeneration is also excluded from the definition. Although regeneration is not essential for the diagnosis of cirrhosis, it is important to point out that regeneration is a critical factor influencing the evolution of cirrhosis [13,147].

Primary Biliary Cirrhosis

This disease, whose etiology remains obscure, typically affects small hepatic ducts which become surrounded by chronic inflammatory infiltrations and are eventually destroyed. Microscopic examination frequently reveals portal tracts without bile ducts. Women in the fourth and fifth decades of life are most commonly affected and there seems to be an association with autoimmune disorders such as Sjogren's syndrome, Sicca complex, CREST syndrome and vasculitis. Typical symptoms include cholestasis, progredient fibrosis and cirrhosis [39,86,133].

Secondary Biliary Cirrhosis

This type of cirrhosis is induced by obstruction of the extrahepatic bile ducts. Choledocholithiasis as well as benign strictures or malignant neoplasms may be the cause. Since regenerative nodules are typically absent, the condition is more a diffuse regenerative process than a true cirrhosis. Portal hypertension without typical morphological signs of liver cirrhosis is frequently observed [137,151,185].

Reye's Syndrome

Reye's syndrome is an acute fatty degeneration of the liver occurring together with encephalopathy. It typically affects children with viral infections (influenza B or varicella) who have been treated with acetylic salicylic acid. There is only limited hepatomegaly and the steatosis seems to be intermittent. Hence, the only decisive finding for prognosis is the extent of the neurological symptoms [31,132].

Caroli's Syndrome

This cystic ectasia of small intrahepatic ducts is typically found diffusely, although cases of segmental occurrence may also be observed. Cholelithiasis leads to an intermittent obstructive jaundice with pain and fever and concomitant cholangitis. Possible complications are similar to those of choledochal cysts. In cases of segmental occurrence, a partial hepatic resection is curative. There is an association with congenital hepatic fibrosis and Potter's sequence [28,113].

Patients with Caroli's syndrome have an increased risk of intrahepatic cholangiocellular carcinoma, and thus regular imaging studies should be performed (Fig. 38).

Meconium Staining

Fig. 38. Macroscopic aspect of a liver affected by Caroli's disease. The parenchyma shows yellowish changes due to cystically dilated bile-ducts and congestion of bile

Liver Disease in Patients with Cystic Kidneys

Cystic Liver Disease in Combination with Cystic Kidney Disease

Liver cysts are associated with the autosomal dominant as well as the recessive type of renal cysts. In the dominant type there are hepatic cysts at birth of up to 10 cm in size, which usually become symptomatic in the fifth decade of life. The most common symptoms are hepatomegaly, pain, and fever in cases of infection. Women seem to be affected more frequently than men, and there is a correlation with the number of pregnancies. Di-verticles of the colon, a vitium cordis, ovarian cysts, inguinal herniation or intracranial aneurysms may occur concomitantly. Von Meyenburg complexes, which involve irregularly-dilated bile ducts, seem to be associated with the development of liver cysts in autosomal dominant cystic kidney disease [112,130].

In the autosomal recessive type of disease the degree of hepatic involvement may vary. Infants with the perinatal type typically do not live long because of pulmonary complications.

In the neonatal and infantile type there is a tendency to portal fibrosis and cystic dilation of bile ducts in combination with renal insufficiency. The juvenile type presents with portal hypertension. Microscopically, there is an increased number of bile ducts in the portal tracts, which are irregularly formed and linked together [21].

Congenital Hepatic Fibrosis and Cystic Kidneys

Congenital hepatic fibrosis together with cystic kidneys is a distinct entity. Symptoms of cholangi-tis and portal hypertension are relevant findings. Patients typically present late with esophageal variceal bleeding. Macroscopically, the liver seems to be enlarged and tough, and cysts are not visible. Concomitant congenital malformations may be found [64,96] (see Table 5).

Fig. 38. Macroscopic aspect of a liver affected by Caroli's disease. The parenchyma shows yellowish changes due to cystically dilated bile-ducts and congestion of bile

Table 5. Pathologies and syndromes with concomitant hepatic cirrhosis

Langerhans Cell Histiocytosis

Liver involvement in histiocytosis is found in 2971% of all cases. The leading symptoms are scle-rosing cholangitis with cholestasis, progressive decrease of intrahepatic bile ducts and fibrosis with portal hypertension. Systemic chemotherapy may lead to an improvement, but in severe pediatric cases transplantation may be the only curative treatment [69,120].

Table 6. Overview of glycogen storage diseases

Storage Diseases

Glycogen Storage Disease

The different forms of glycogen storage disease are all autosomal recessive inherited diseases. Glyco-gen storage disease should always be considered in children with hepatomegaly, hypoglycemia, growth retardation, an unproportional distribution of body fat and increased transaminases [117, 140] (Table 6).

2.8.13.2 Galactosemia

Galactosemia is an inherited autosomal-recessive condition that manifests primarily through the first exposure to galactose via lactose in fed milk. The cause and effect of this disease are mostly due to a defect in the enzyme galactose-1-phosphate uridyl transferase [82].

Children with this disease typically present shortly after birth with growth retardation, nausea, vomiting, diarrhea and jaundice. If untreated, a cirrhosis may develop by the age of six months [156].

Table 6. Overview of glycogen storage diseases

Type

Hepatic manifestation

Other manifestations

• Ia (von Gierke)

Hepatomegaly, HCC, hepatic adenoma

Growth retardation, seizures, hypoglycemia, osteoporosis, gout, glomerulonephritis, amyloidosis

• Ib

Hepatomegaly, HCC, hepatic adenoma

Growth retardation, seizures, hypoglycemia, osteoporosis, gout, glomerulonephritis, amyloidosis, neutropenia and frequent infections

• II (Pompé)

Microscopic changes, hepatomegaly

Hypotonia, respiratory and cardiac insufficiency (infantile type)

• III (Forbes)

Hepatomegaly, cirrhosis, hepatic adenoma

Hypoglycemia, muscle weakness, growth retardation

• IV (Anderson)

Hepatomegaly, cirrhosis, focal fatty areas

Growth retardation, cardiac insufficiency

• VI & IX

Hepatomegaly

Growth retardation, mild hypoglycemia, hyperlipidemia

• Congenital hepatic fibrosis

• Familial congenital heart disease

• Pulmonary arterivenous fistula

Gastric ulcers

• Protein-losing enteropathies syndrome

• Laurence-Moon-Biedl-syndrome

• Similar changes

• Meckel's syndrome

• Ivemark's syndrome

• Ellis-van-Crefeld syndrome

• Nephronophthisis - congenital hepatic fibrosis

• Jeune syndrome

• Vaginal atresia syndrome

• Tuberous sclerosis

• Medullary cystic disease

Hereditary Intolerance of Fructose

This inherited disorder of fructose metabolism is either caused by a deficiency of fructose-1-phosphate aldolase or is due to a dysfunction of the enzyme fructose-1,6-biphosphatase [15,62].

P

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