KeywordsGranulomas, amyloidosis, gastrointestinal disease, haematological disease, endocrine disease, multi-system disorders and the liver
Nonspecific reactive hepatitis 966
Space-occupying lesions in the liver 967
Hepatic granulomas 968
Sarcoidosis and the liver 974
The liver in protein-energy malnutrition 976
Total parenteral nutrition 976
The liver in gastrointestinal diseases 977
The liver in pancreatic diseases 980
The liver in endocrine diseases 982
The liver in pregnancy 983
The liver in haematological diseases 986
The liver in connective tissue and joint diseases 989
The liver in renal diseases 992
Chronic renal failure and renal replacement therapy 992
The liver in amyloidosis and monoclonal immunoglobulin deposition disease 993
The liver in cardiovascular diseases 995
The liver and lung disease 997
Miscellaneous liver involvement in other diseases 998
This chapter considers hepatic manifestations resulting from diseases of other organs, where liver dysfunction develops secondarily but can be of clinical or morphological significance. These diseases are considered here on a systemic basis. Conversely, nonspecific reactive hepatitis, granulomas and steatosis are commonly encountered hepatic morphological changes, and among their diverse causes, nonhepatic diseases merit particular consideration. Steatosis is discussed in Chapter 5 ; nonspecific reactive hepatitis and granulomas are reviewed here, together with an account of the diversity of morphological changes encountered related to mass lesions in the liver.
Nonspecific reactive hepatitis
This microscopically variable, patchy, nondescript inflammatory reaction is associated with parenchymal turnover in the liver. There is no specific clinical manifestation or derangement of liver function tests beyond mild increase of serum aminotransferase (transaminase) levels. ‘Nonspecific reactive hepatitis’ is a convenient descriptor rather than a diagnostic term, and its use in clinical practice presupposes that reasonable clinicopathological exclusions have been made, including appropriate serological and virological screening, such as for hepatitis C virus (HCV) RNA in serum. As first coined by Popper and Schaffner, in an era predating many such diagnostic tests, typical settings included resolving hepatitis, recent febrile illness and inflammation somewhere in the splanchnic bed. Identical changes may also be localized around focal liver injuries, such as vascular or space-occupying lesions.
Typically, small portal tracts contain lymphocytes and macrophages (including ceroid-laden macrophages), with characteristic variability between portal tracts ( Fig. 15.1 A and B ). Granulocytes and plasma cells are absent or rare; cholangitis and interface hepatitis are absent. The lobules show prominent Kupffer cells with hypertrophy, often with ceroid-laden cytoplasm and clustering, in perivenular areas and randomly distributed foci of hepatocyte cell death ( Fig. 15.1 C and D ). Hepatocyte necrosis may affect single or contiguous cells (with reticulin collapse), but without zonal predilection. Accompanying signs of increased hepatocellular turnover include occasional mitotic figures, limited regenerative plate widening and greater variability of cell and nuclear size. A major differential diagnosis is chronic HCV infection (see Chapter 6 ), requiring serum RNA determination for exclusion and possibly lacking helpful signs such as a more diffuse portal hepatitis, appreciable interface hepatitis, lymphocytic lobular inflammation or fibrosis. Resolving drug injury may similarly present only mild nonspecific changes. Autoimmune hepatitis (especially if a flare is remitting by the time a biopsy is done) can manifest with mild portal and lobular inflammation and only sparse plasma cells, and serum autoantibodies may only appear later. Numerous infections, including those caused by bacteria, spirochaetes, protozoa and nonhepatotropic viruses, can appear as nonspecific reactive hepatitis if more characteristic features such as granulomas or microabscesses fail to be sampled. Eosinophilia merits consideration of a parasite, from which pigments (e.g. haemozoin) or parts may be evident on further scrutiny. Viral infection in other organs, such as influenza, can be accompanied by a ‘collateral’ T cell-mediated hepatitis without viral antigen directly present in liver. A nonspecific reactive hepatitis is common in human immunodeficiency virus (HIV) infection and is associated with chronic inflammatory disorders of other organs or systems (e.g. coeliac disease) (see Chapter 7 ). Finally, lymphoproliferative disease can mimic hepatitis, in the form of an atypical granulomatous portal infiltrate or an atypical sinusoidal lymphocytosis.
Space-occupying lesions in the liver
Mass lesions produce obstructive and pressure effects on surrounding liver, which although accompanied by nonspecific reactive changes, can be distinctive when encountered in biopsies targeting the lesion. Small portal tracts in particular show changes presumably reflecting local interference with bile flow, comprising oedema and neutrophil infiltrates around interlobular ducts, together with periportal ductular reaction with neutrophil cholangiolitis ( Fig. 15.2 A and B ). Likewise, pressure haemodynamic effects may explain the typical sinusoidal dilation that is usually most striking in perivenular areas, but not usually accompanied by hepatocyte atrophy or hepatic vein abnormality ( Fig. 15.2 C ).
Some primary or metastatic neoplasms in liver provoke localized hyperplastic change within the surrounding parenchyma, termed peritumoral hyperplasia . The significance for pathologists is misinterpretation as liver cell adenoma or focal nodular hyperplasia when a targeted biopsy has missed the index neoplasm. The hyperplastic changes extend a few to several millimetres deep, over part of or the entire lesion, and comprise broadened plates and rosettes of hepatocytes showing glutamine synthetase immunopositivity, with capillarization of adjacent sinusoids (CD34 immunopositive). The outer margin is delimited by atrophy and congestion in surrounding parenchyma. The hyperplasia is thought to be a local response to ‘spillover’ perfusion with arterial-enriched blood from tumour-associated arteries, with a possible arteriolar buffer response compensating for upstream neoplastic occlusion of portal venules.
Localized peritumoral steatosis may also occur around insulinoma metastases in liver, attributable to the effect of tumour-secreted excess insulin on the hepatocytes. In analogous fashion, distinctive subcapsular steatosis may occur in patients receiving insulin administration through peritoneal dialysates and can be misinterpreted radiologically as infarcts. Aberrant venous drainage from gallbladder or pancreas may produce ‘pseudolesions’ of focal fatty change, or focal fatty sparing near the gallbladder bed in steatotic liver, which can be mistaken radiologically for invasive tumour. Adrenal rest tumour in liver may also mimic metastasis on imaging. Liver abscess usually originates with biliary or abdominal infection, including after surgical intervention, and is facilitated by immunosuppressive states. Some lesions occur after trauma or secondary infection of a pre-existing mass lesion such as metastasis or cyst.
Mass lesions can cause more widespread changes from compression of major vascular or biliary structures. Diffuse infiltration of liver parenchyma by carcinoma or non-Hodgkin lymphoma can cause acute liver failure in previously asymptomatic patients. Imaging may resemble cirrhosis, and massive hepatomegaly can be a clue, but prospective diagnosis often requires transjugular liver biopsy. Paraneoplastic hepatic manifestations of malignancy include vanishing bile duct syndrome in Hodgkin lymphoma (see Chapter 9 ). Chemotherapy or other modalities of treatment can induce changes in the nontumourous liver parenchyma, including steatohepatitis, nodular regenerative hyperplasia and sinusoidal obstruction syndrome (see Chapter 12 ). These microvascular injuries may facilitate subsequent development of focal hyperplastic lesions. Transarterial chemoembolization (TACE) for liver malignancy can be complicated by hepatic artery branch rupture or thrombosis ( Fig. 15.3 ) and subsequent ischaemic cholangitis or liver abscess. Liver resections for malignancy can show atrophy of the nontumourous liver caused by planned preoperative portal vein branch embolization (using methods including injected coils, particles or glues). This is done to stimulate growth of the future liver remnant to a size sufficient to permit safe resection. Table 15.1 summarizes the potential liver changes secondary to space-occupying lesions with or without iatrogenic intervention.
|Changes attributable to chemotherapy, local ablation therapy or embolization|
Liver granulomas may arise as part of primary liver disease or multisystem granulomatous disease or may be a nonspecific response to extrahepatic disease. Granulomas are organized clusters of mature macrophages that develop in response to persistent stimuli, which are required to maintain them. Granulomas can be considered according to the turnover rate of constituent macrophages as ‘high’ or ‘low’, relating to the toxicity of the inciting agent. Most foreign body granulomas are low turnover, although exceptions include beryllium (see Chapter 12 ), whereas infectious granulomas tend to be high turnover. Table 15.2 summarizes different histological appearances of granulomas and their correlations. So-called microgranulomas—loose lobular clusters of a few to several macrophages—are extremely nonspecific.
|Epithelioid granuloma||Discrete with distinct edges, with or without necrosis (fibrinoid, caseous, eosinophilic) |
Presence of eosinophils suggests drug, parasites, but common in primary biliary cirrhosis
Fibrosis formation in sarcoid; reticulin preservation not specific for sarcoid
|Infectious: tuberculosis, brucellosis, Mycobacterium avium, listeriosis, tuberculoid leprosy, tertiary syphilis, schistosomiasis, fungal infection, viral infection |
Noninfectious: drug reaction, foreign body, sarcoidosis, primary biliary cholangitis, Hodgkin lymphoma, chronic granulomatous disease
|Microgranuloma||Small aggregates of histiocytes and lymphocytes with apoptotic debris, often seen as part of nonspecific reactive hepatitis||Listeriosis, typhoid fever, any of the above|
|Suppurative||Stellate microabscess or mixed suppurative-granulomatous inflammation||Cat-scratch disease ( Bartonella ), yersiniosis, tularaemia (typically stellate microabscess), listeriosis, melioidosis, actinomycosis, fungi|
|Fibrin-ring granuloma||Fat vacuole within the granuloma and surrounding ring of fibrin||Q fever, toxoplasmosis, salmonellosis, CMV, EBV, leishmaniasis, non infectious (drug, lupus), Hodgkin lymphoma|
|Lipogranuloma||Granulomas containing lipid||Steatohepatitis, mineral oil in food|
|Foamy macrophages||Aggregates of foamy macrophages||Mycobacterium avium-intracellulare (immunocompromised), Whipple disease, lepromatous leprosy|
Lipogranulomas associated with liver steatosis represent a macrophage reaction to fat spilled from injured or necrotic lipid-containing hepatocytes. They comprise loose clusters of macrophages with extracellular and intracellular lipid, associated with scattered small lymphocytes in areas of hepatocyte steatosis ( Fig. 15.4 A ). Multinucleate giant cells are rare. Mineral oil lipogranulomas in nonfatty liver occur in portal tracts more often than parenchyma, where they are usually perivenular. They appear as a cluster of variably sized extracellular lipid droplets (sometimes larger than a hepatocyte), surrounded by a light infiltrate of lymphocytes and macrophages, sometimes with focal fibrosis ( Fig. 15.4 B ). Spleen and lymph nodes may also be involved. The lipid may come from processed food. Gold granules have been identified in lipogranulomas of patients with rheumatoid arthritis, the lipid component being attributed to oily vehicle for the gold. These lesions are generally of little consequence and are often incidental findings. However, Keen et al. described two patients in whom extensive mineral oil lipogranulomatosis led to venous outflow obstruction. Disseminated mineral oil granulomatosis has also followed cosmetic self-administration of mineral oil injections. In contrast, lipopeliosis refers to accumulation of coalescent lipid droplets within sinusoids and the space of Disse, related to profuse release from necrotic fatty liver. This phenomenon is well described because of preservation injury at transplantation ( Fig. 15.5 ) (see Chapter 14 ), but as early as 1929 it was shown to cause fatal hepatogenic fat embolism to lung after self-poisoning with carbon tetrachloride, by an alcoholic patient with fatty liver. Hepatogenic pulmonary fat embolism is also reported after other nontraumatic injuries to very fatty liver, such as systemic hypotension or fulminant acute hepatitis.
Fibrin-ring (or ‘doughnut’) granulomas are a distinctive but nonspecific response to injury, first noted in association with Q fever. There is a shell of circumferential fibrin within or at the margin of the granulomas and sometimes a central fat vacuole ( Fig. 15.4 C ). Fibrin-ring granulomas are documented in many conditions, including boutonneuse fever, allopurinol hypersensitivity, cytomegalovirus (CMV) infection, leishmaniasis, hepatitis A, staphylococcal infection, Epstein–Barr virus (EBV) infection, systemic lupus erythematosus (SLE) and giant cell arteritis.
The following discussion focuses on epithelioid granulomas . These are characterized by clustered macrophages that have undergone phenotypic modulation to a proinflammatory microbicidal and secretory state. The macrophages show abundant pale eosinophilic cytoplasm and may fuse to form multinucleate giant cells. The periodic acid-Schiff (PAS) stain highlights the distribution and density of parenchymal granulomas. Kupffer cells can slowly redistribute to form granulomas if directly involved (e.g. by intracellular infection), but newly recruited macrophages otherwise come from circulating bone marrow-derived monocytes. Activated antigen-specific CD4 T cells are central to the complete ‘epithelioid’ phenotypic transformation of macrophages, which is effected in tuberculosis by tumour necrosis factor (TNF) and other T-helper cell type 1 (Th1) inflammatory cytokines, interferon (IFN)-γ, interleukin-1 (IL-1) and IL-12. The granulomatous Th2 response to schistosome eggs is promoted by Th2 cytokines such as IL-4 and IL-13. T lymphocytes traffic continuously within the granuloma, including areas of necrosis. Other inflammatory cells populating granulomas include dendritic cells, B lymphocytes, granulocytes and innate lymphoid cells.
The prevalence and causes of liver granulomas depend heavily on case-mix, geographical location and reporting era, but are reported in 2% to >10% of native liver biopsies. Most of the many causes are uncommon ( Tables 15.3 and 15.4 ). Few show distinguishing morphological features. Liver function tests (LFTs) are usually cholestatic, including increased alkaline phosphatase (ALP) level. In practical terms, the cause may be evident from the histopathology, may be known but not evident on biopsy, may be suspected only, or may remain unknown after full clinicopathological evaluation with appropriate skin or IFN-γ release assay and microbiological, serological, molecular and biochemical screening. Long-term follow-up is important and reveals a cause in an additional minority of cases, but failure to establish a cause in 25% or more patients is well documented. In broad terms, most established causes can be grouped within the categories of ‘infection’, ‘immune disorder’, ‘drug-related’ or ‘reaction to neoplasia’. In an early study of >6000 biopsies, 74% were associated with generalized granulomatous disease, 4% with primary hepatic disease, and the remaining 22% were indeterminate for cause. Gaya et al. found that 63 of 1662 consecutive liver biopsies showed hepatic granulomas; the most common underlying diagnoses were primary biliary cirrhosis (23.8%), sarcoidosis (11.1%), drugs (9.5%), HCV (9.5%), autoimmune overlap syndrome (6.3%) and Hodgkin lymphoma (6.3%). Drebber et al. had similar findings, with 48% of 442 biopsies of granulomatous hepatitis related to primary biliary cirrhosis/cholangitis (PBC), 8% to sarcoidosis and 2% to drugs. Polymerase chain reaction (PCR) identified pathogens in 15 biopsy samples ( Bartonella henselae, Listeria, Mycobacterium tuberculosis, Yersinia pseudotuberculosis , CMV, EBV). PBC and sarcoid were likewise the two most common causes in the 35 (1.3%) of 2662 liver biopsies with granulomas in a recent Turkish study.
|Infectious cause||Route/pathogenesis (geographical distribution)||Morphology||Staining/test|
|Actinomycosis||Spread from caecum, appendix||Abscess, granuloma basophilic bacilli in grains||Gram, Grocott|
|Nocardiosis||Immunocompromised||Abscess granuloma basophilic bacilli in grains||Similar to Actinomyces, but also weakly acid-fast positive; Wade-Fite|
|Bartonellosis||Cat scratch, skin and local lymphadenopathy||Stellate microabscess, granulomatous edge||Warthin-Starry|
|Borrelliosis (Lyme disease)||Tick-borne, relapsing fever||Granuloma, Kupffer cell hyperplasia, hepatocyte necrosis/mitosis||Warthin-Starry or Dieterle (10–20 µm) in sinusoids|
|Brucellosis||Ruminants, dairy products |
|Micro/epithelioid cell granuloma, ± necrosis||Serology|
Neonatal septicaemia (transplacental). Immunocompromised
|Microabscess, necrotic granuloma||Gram-positive rods|
|Melioidosis||Soil, water (India, South-east Asia)||Abscess, necrotic granuloma||Gram, Giemsa-positive rods|
|Staphylococcus||Chronic granulomatous disease||Portal macrophages, parenchymal necrotizing granuloma||Gram-positive cocci|
|Syphilis||Sexual/vertical||Granuloma in secondary, gumma in tertiary||Warthin-Starry|
|Tularaemia||Tick bite, mosquitoes, mammalian reservoir. Ulceroglandular at site of entry (Northern Hemisphere: North America, Russia, Scandinavia)||Liver involvement in bacteraemic phase (can replicate in hepatocytes)||Gram-negative|
|Typhoid||Faecal-oral transmission||Non-necrotizing granuloma, becoming necrotic in fastigium phase||Gram-negative|
|Whipple disease||Rare; possibly abnormal response to the bacterium (North America, Western Europe)||Noncaseating epithelioid granulomas |
|PAS/PASd-positive macrophages |
|Yersiniosis ( Yersinia enterocolitica )||Contaminated food (pork) |
Paediatric (North America, Europe)
|Suppurative granuloma |
Requires iron to survive (siderosis)
|Tuberculosis||Pulmonary/intestinal entry||Granuloma with/without necrosis depending on reactive or anergic state||Ziehl-Neelsen|
|Atypical mycobacteria (e.g. M. avium intracellulare )||Immunocompromised host||Granuloma||Ziehl-Neelsen, foamy macrophages stuffed with mycobacteria|
|BCG immunization and immunotherapy||Immunization/immunotherapy||Granuloma||Ziehl-Neelsen|
|Leprosy (lepromatous and tuberculoid)||Nasal oral secretion. Skin and peripheral nervous system involvement (Tropic/subtropic)||Tuberculoid granuloma with no AFB; lepromatous foamy cells with AFB; amyloid||Wade-Fite|
|Boutonneuse fever||Tick-borne (Mediterraneum, Africa, India)||Granuloma or focal hepatocyte necrosis||Immunohistochemistry|
|Q fever||Inhalation; pneumonia, hepatitis, fever NOS (North America typically)||Fibrin-ring granuloma, but other types can occur||Serology/PCR on peripheral blood|
|Rickettsia conorii infection||Tick-borne (America)||Granuloma NOS, vasculitis||IHC|
|Lymphopathia venereum||Sexual transmission (tropics)||Granuloma, perihepatitis||Cell culture, direct immunofluorescence, PCR|
|Psittacosis||Airborne||Microgranuloma||Serology, direct immunofluorescence, PCR|
Hyphae invading vessels
|Blastomycosis||Inhalation of conidia (North and South American)||Abscess/granuloma||Grocott, PASd|
|Paracoccidioidomycosis||Spread from lungs (South American blastomycosis)||Abscess/granuloma||Steering wheel-like yeasts|
|Coccidioidomycosis||Inhalation of dust with arthrospore (America)||Abscess/granuloma||Grocott, PASd|
|Cryptococcosis||Opportunistic||Sometimes epithelioid granuloma||Grocott, PASd, mucicarmine|
|Histoplasmosis||Inhalation; opportunistic (worldwide/Africa depending on organism)||Kupffer cells, granuloma, histoplasmoma, abscess||Grocott|
|Mucormycosis (zygomycosis)||Opportunistic||Abscess, vascular invasion||Grocott, PASd|
|Cytomegalovirus infection||Immunocompromised||Mononucleosis-like, epithelioid granuloma||In immunocompetent: no inclusions |
|Epstein Barr virus – infectious mononucleosis||Adolescence||Sinusoidal lymphocytosis, atypical; epithelioid granuloma||IHC; in situ hybridization |
|Hepatitis A||See Chapter 6||Fibrin-ring granuloma||See Chapter 6|
|Hepatitis B||See Chapter 6||~1.5% of HBV shows granuloma||See Chapter 6|
|Hepatitis C||See Chapter 6||~1.3% of HCV infection shows granuloma; relationship with interferon questionable||See Chapter 6|
|Herpes zoster||Chickenpox/shingles (reactivation); liver involvement in immunocompromised host||Similar to herpes|
|Ancylostomiasis||Tropics; larvae from faeces penetrate skin, spread to lung and to GI tract||Ova/parasite in stools|
|Capillariasis||Food contaminated by eggs||Granuloma, eosinophils, typical double-shelled eggs|
|Enterobiasis||Temperate zones||Granuloma around degenerate worm|
|Fascioliasis||Sheep, goat, cattle |
Worm in bile duct (Europe)
|Cholangitis; granulomas around eggs|
|Giardiasis||Faecal-oral; GI symptoms||Granuloma/abscess||Stools, serology, duodenal biopsy|
|Paragonimiasis||Raw crustaceans, upper GI tract, liver and lung (Southeast Asia, South America, Africa)||Granuloma around eggs/worms||Demonstration of ova/parasites in fluid/tissue |
|Opisthorchiasis||Freshwater fish |
Worm in biliary tract (Far East)
|Pentastomiasis||Larva stage (nymphs) of Linguatula serrata (Africa, Asia)||Calcification, granuloma|
|Schistosomiasis||Tropical worm in portal/mesenteric veins |
Eggs to liver
|Granuloma, eosinophils, eggs, haemozoin, clay pipestem fibrosis||Ova in urine, stools |
|Strongyloidiasis||Persistent, unmasked by immunosuppression (tropical-subtropical)||Associates with gram-negative sepsis; small portal veins, giant cells, eosinophils|
|Toxocariasis||Faecal-oral; dogs||Eosinophilic necrosis lined by eosinophil rich granulomas (tracks of larvae)|
|Visceral leishmaniasis (kala-azar)||Bite of sandfly (Southern Europe, Middle East, Asia, Africa)||Plasma cells, sinusoidal lymphocytosis, granuloma||Parasites in portal macrophages and Kupffer cells|
|Drugs (see Chapter 12 )||Long list of drugs may be associated with cholestatic or hepatitic pattern. Eosinophils are variably present.|
|Metals (see Chapter 12 )|
|Beryllium||Industrial exposure (metallurgy, beryllium melting)|
|Copper||Occupational (copper sulphate in vineyard spray), domestic|
|Gold||Treatment of rheumatoid arthritis|
|Common variable immunodeficiency||Defect of B-cell differentiation, hypogammaglobulinaemia, 2nd/3rd decade, autoimmune disease, lymphoid tumours|
|Chronic granulomatous disease of childhood||<1 year of age, lymphadenopathy, hepatosplenomegaly; bacterial, fungal; lipofuscin deposition|
|Polymyalgia rheumatica||Proximal muscles, over 50 years, associated with giant cell arteritis; may coexist with PBC|
|Primary biliary cholangitis||See Chapter 9|
|Primary sclerosing cholangitis||See Chapter 9|
|Rheumatic fever||Heart, joint, skin, brain involvement predominates; usually in children|
|Systemic lupus erythematosus|
|Allergic granulomatosis (Churg-Strauss syndrome)||Angitis with allergic rhinitis, asthma and peripheral eosinophilia; heart disease; hepatic infarction|
|Necrotizing angiitis in drug abuse||See reference|
|Polyarteritis nodosa||Nodular regenerative hyperplasia; bile duct damage|
|Giant cell arteritis||Large arteries, temporal, vertebral, ophthalmic|
|Wegener granulomatosis||Necrotizing granuloma of respiratory tract, necrotizing vasculitis, renal disease|
|Anthracotic pigments||See Lung disease|
|Cement and mica dust||See reference|
|Mineral oil: radiocontrast media, food additives||Portal tracts, perivenular, nonfatty liver, spleen and lymph node involvement|
|Silica||Birefringent silica particles in liver of patients with anthracosilicosis, sand blasters, dental technicians|
|Silicone rubber: renal dialysis tubing||See reference|
|Talc||Drug abusers, portal and centrilobular talc-laden macrophages|
|Thorotrast||Contrast medium (abandoned in 1955); dark-brown refractile pigment (phase contrast) (see Chapter 12 )|
|Extrahepatic malignancy||See reference|
|Hepatocellular adenoma and liver adenomatosis||See reference|
|Hodgkin lymphoma (HL)||Epithelioid granuloma in ~10% of patients, usually portal. Does not mean liver involvement by HL.|
|Non-Hodgkin lymphoma||Same as HL|
|Biliary tract obstruction: bile granulomas||See Chapter 9|
|Chronic inflammatory bowel disease|
|Jejuno-ileal bypass surgery||See Chapter 5|
|Porphyria cutanea tarda||Lobular aggregates of iron, ceroid-laden Kupffer cells and fat globules|
|Lipiodolized neocarzinostatin||Hepatocellular carcinoma|
On microscopy, granulomatous duct injury characterizes PBC but can occur with drug injury or sarcoidosis. Periductal bile granulomas may occur in large-duct obstruction, often with acute cholangitis. Poorly defined hyalinized nodules in portal tracts may mark the site of past granulomas, as in sarcoidosis. Particulate material, such as schistosome ova, may be seen on routine stains or with phase-contrast or polarizing microscopy; serial sectioning might be needed to show that the lesion is primarily vascular. Eosinophil-rich necrotizing granulomas suggest toxocariasis (visceral larva migrans). Special histochemical or immunohistochemical stains are helpful when particular infectious agents are suspected (see Chapter 7 ). In tuberculosis (TB), a nonportal distribution of granulomas is said to be characteristic, but on needle biopsy, caseation is uncommon, with acid-fast bacilli (AFB) demonstrable in <10% of proven cases (although more often in autopsy material). Instead, real-time PCR analysis is a more sensitive means of diagnosis in paraffin-embedded tissue. In miliary TB, well-formed granulomas occur infrequently, and the characteristic features are Kupffer cell hyperplasia with poorly formed macrophage ‘microgranulomas’.
Patients may be regarded as having idiopathic granulomatous hepatitis only after exhaustive investigation does not reach a specific diagnosis. The term is inaccurate in that there is seldom significant hepatocellular damage, and it has been viewed as a form of sarcoidosis confined to the liver. Some of these patients have a prolonged or recurrent pyrexial illness with weight loss, myalgia, arthralgia and vague abdominal pain. They fail to benefit from a trial of antituberculous drugs but may respond to immunosuppression. In some the condition resolves spontaneously. In other patients the granulomas are an incidental finding, appear clinically and biochemically without consequence, and follow-up may be sufficient.
Epithelioid granulomas and microgranulomas were found after liver transplantation (LT) in 42 of 563 patients (7.5%), predominantly in the early months. Most cases (71%) had a possible cause, including reaction to hepatocyte necrosis, steatosis and, in portal tracts, acute rejection or later, recurrent PBC. Subsequent studies addressed the prevalence of allograft granulomas in patients transplanted for HCV-related cirrhosis. In a review of allograft liver biopsies from 820 patients transplanted for HCV, Fiel et al. found noncaseating epithelioid granulomas in 25 biopsies (0.24%), more often in patients receiving pegylated IFN therapy. Another survey identified granulomas in liver allograft of four (8%) of 53 patients transplanted for HCV-related cirrhosis but found no prognostic significance. In 23 cases of hepatic granulomas in children, Collins et al. showed that the yield of specific diagnoses is increased when molecular approaches are included. They identified an aetiology in 87%, with Histoplasma incriminated in 65% of their cases by PCR.
There is one report of familial granulomatous hepatitis in which two parents and three of their seven children were affected. There are also occasional reports of hepatocellular carcinoma developing in patients with chronic granulomatous hepatitis.
Sarcoidosis and the liver
Sarcoidosis is a common cause of noninfectious hepatic granulomas. Most patients are between 25 and 45 years of age, with a second peak among women over 50 years in Europe and Japan. The cause is unknown but thought to involve a genetic predisposition for exaggerated granulomatous response to pathogen-associated molecular patterns, including persistent products from killed mycobacteria or propionibacteria. Indeed, there are multiple reports of IFN-induced pulmonary and cutaneous sarcoidosis during treatment of viral hepatitis C. The development of sarcoid-like granulomatosis in liver and other organs is also reported during therapeutic TNFα blockade for various chronic inflammatory diseases, potentially reflecting interference with Th1 responses.
The liver follows lymph nodes and lung in frequency of involvement. Hepatic sarcoidosis is often asymptomatic, but about 20–30% patients have cholestatic LFTs. In one study of 837 sarcoidosis patients, 204 (24%) had abnormal liver biochemistry, among which 127 (15%) were attributed to hepatic involvement, correlating in degree with granulomatous extent and fibrosis in the minority biopsied. In some patients a diagnosis of sarcoidosis has been established on liver biopsy with no radiological evidence of pulmonary involvement. Imaging modalities such as whole-body mapping with positron emission tomography/computed tomography (PET/CT) of uptake of the glucose analogue 2-[ F]-fluoro-2-deoxy- d -glucose (FDG) help to evaluate the extent and distribution of inflammatory foci in sarcoidosis between different organs, including liver involvement. Serum angiotensin-converting enzyme (ACE) levels are not accurate for diagnosis of sarcoidosis.
The histopathology of hepatic sarcoidosis was reviewed by Ishak. Sarcoid granulomas occur more frequently in portal tracts or in the periportal area. They consist of a compact aggregate of large epithelioid macrophages, sometimes with multinucleated giant cells, and with a surrounding rim of CD4+ and CD8+ T lymphocytes and macrophages; occasionally, eosinophils may be present ( Fig. 15.6 A ). Schaumann and asteroid bodies are uncommon. Central granular eosinophilic fibrinoid necrosis may occur (liver biopsy has been rarely reported in necrotizing sarcoid ), but caseation is never found. Reticulin fibres are abundant within the granulomas, particularly in older lesions, when a surrounding cuff of fibrous tissue becomes prominent. Giant cells may persist for some time in the fibrous scars, and dense amyloid-like scars may replace the granulomas. Confluent granulomas may produce extensive irregular scarring. A nonspecific reactive hepatitis often accompanies the granulomas, and lobular hepatitis may be prominent during active clinical disease. There may be focal damage to bile ducts ( Fig. 15.6 B ), which can resemble that of PBC or primary sclerosing cholangitis (see later discussion).
Hepatic sarcoidosis infrequently progresses to clinical chronic liver disease with hepatomegaly, portal hypertension, ascites and hepatic encephalopathy. In some cases, sarcoidosis may only be recognized as the cause of liver failure on examination of the explanted liver after LT. The fibrosis can be directly related to granulomas, but extensive portal and parenchymal fibrosis unrelated to granulomas is also described as contributing to cirrhosis ( Fig. 15.6 C and D ). Signs of portal hypertension often develop in the absence of cirrhosis. Valla and Benhamou described 32 patients with sarcoidosis in whom portal hypertension was the predominant clinical feature. The portal hypertension was presinusoidal because of pressure effect by portal tract granulomas, sometimes with concurrent sinusoidal block from fibrosis. Nodular regenerative hyperplasia caused by portal venular attrition is evident in some patients. Obstruction of hepatic vein branches by sarcoid granulomas is a rare cause of Budd–Chiari syndrome, with recurrence after LT documented in one case.
Rarely, hepatic sarcoidosis manifests with a progressive ductopaenic cholestatic syndrome leading to biliary cirrhosis and thus merits consideration in the differential diagnosis of chronic cholestatic disease. Rudzki et al. reviewed 21 such cases and reported five of their own; clinically and biochemically, these patients expressed many of the features of PBC, but antimitochondrial antibody (AMA) was not found, and their five additional cases were males. Murphy et al. emphasized the progressive bile duct loss that was a feature in five patients. The similarities between sarcoidosis and PBC have been reviewed in a number of studies. In the ‘overlap’ patients the principal initial manifestations were pulmonary symptoms. In general, AMA is not present in sarcoidosis. In rare cases it remains speculative that both disorders coexist. Cutaneous and pulmonary manifestations of sarcoidosis have also occurred months after LT for PBC.
Occasional cases of cholestasis in sarcoidosis are the result of a mass effect of sarcoid nodules at the hilum of the liver with bile duct obstruction. In one patient, hepatobiliary sarcoidosis mimicked a Klatskin tumour.
Hepatic sarcoidosis does not appear to respond well to therapeutic intervention. Although frequently used, there is no evidence that corticosteroids prevent long-term hepatic disease progression in asymptomatic patients. A variety of steroid-sparing immunosuppressive agents, including methotrexate, have been used in patients with advanced liver disease. Sarcoidosis is a rare indication for LT (0.12% in a UNOS analysis). The disease can recur in the allograft and is usually mild but in about 3% patients causes graft failure.
The liver in protein-energy malnutrition
Malnutrition can contribute to or cause some liver diseases. Conversely, disturbances of nutrition that occur in liver disease can be significant factors in the accompanying clinical presentation.
Protein-energy malnutrition includes the various disease states arising from inadequate intake of protein and calories. The extreme manifestations are kwashiorkor (protein malnutrition with adequate calories) or marasmus (the childhood analogue of starvation in adults); ‘marasmic kwashiorkor’ describes states with features of both (wasting and pitting oedema). In established kwashiorkor , asymptomatic massive hepatomegaly caused by steatosis is almost invariable. The steatosis begins as small droplets in periportal hepatocytes, with subsequent large-droplet macrosteatosis that becomes panlobular. Mallory–Denk body-like material can be seen, but there is minimal hepatocyte necrosis or inflammation, and true steatohepatitis does not develop. Biochemical LFTs can show mildly raised transaminases and low albumin. Occasional cases of severe cholestasis have been described. The steatosis of kwashiorkor per se does not lead to cirrhosis; fibrosis or necroinflammation in patients with kwashiorkor is probably caused by a different disease, such as chronic hepatitis B virus (HBV) infection, malaria or TB. After refeeding, lipid first clears within days from the perivenular hepatocytes, then resolves fully.
The pathogenesis of steatosis in kwashiorkor probably includes several factors, such as increased mobilization of fat for carbohydrate synthesis, altered hepatocyte β-oxidation and deficiency of apolipoproteins mediating lipid transport from liver. In some areas, hepatotoxicity from aflatoxin ingestion might contribute.
In marasmus the hepatocytes tend to be atrophic and the sinusoids are dilated, but there is no parenchymal inflammation or fibrosis. Fatty liver is not a feature of marasmus ; steatosis, if present, is mild and focal with no particular zonal distribution. Peliosis hepatis has been reported. Marasmic kwashiorkor in developed countries can result from child abuse through neglect.
Anorexia nervosa is a common psychiatric eating disorder characterized by behaviour that maintains excessively low weight, including excessive dieting and purging. Increases of liver transaminases are common (>40% of patients ), correlating negatively with body mass index, and the severest cases can present with hypoglycaemia and acute liver failure, including ascites. Liver biopsy is infrequently required, but biopsies in 12 consecutive cases of acute liver failure attributable to anorexia nervosa, taken 1–9 days after admission, showed consistent glycogen depletion and more variable perivenular hepatocyte atrophy with mild perisinusoidal fibrosis. Despite marked alanine transaminase (ALT) elevation, there was no significant lobular inflammation, necrosis or, in many, increased apoptosis, despite >50-fold increases in transaminase values. Instead, organelle depletion and increased autophagosomes on electron microscopy suggested starvation-induced autophagy to be the primary mechanism of liver damage. Scattered single-cell hepatocyte death is also occasionally evident and probably contributes. A case report with a later liver biopsy, after 18 days of treatment, described the accumulation of glycogen in the recovering liver. Mild increases in stainable iron have occasionally been observed and speculatively linked to unused iron because of reduced haemoglobin synthesis. Liver enzyme abnormalities normally resolve during refeeding unless complicated by a refeeding syndrome, in which rising metabolic capacity depletes mineral and cofactor micronutrients, causing electrolyte and fluid shifts.
Bariatric surgery to treat severe obesity includes restrictive and malabsorptive procedures, some of which may be combined. Roux-en- Y gastric bypass is a common restrictive and malabsorptive procedure. Nutrition complications include protein malnutrition (‘secondary kwashiorkor’) and a variety of micronutrient deficiencies. A study of the effects of bariatric surgery on liver injury with biopsy at 1 and 5 years showed reduced steatosis and ballooning that correlated with improved insulin resistance, as well as a slight increase in postoperative hepatic fibrosis at 5 years, although early stage in 95% of patients. Liver failure has occurred in obese patients after jejuno-ileal bypass, a procedure that is no longer performed.
Total parenteral nutrition
Total parenteral nutrition (TPN) delivers nourishment when oral or enteral feeding is not feasible, but hepatobiliary complications have been recognized for >40 years. Patients with one of the many diseases causing a short bowel syndrome can have a prolonged need for TPN. However, patients receiving TPN may also develop hepatobiliary complications for a variety of other reasons, including sepsis, malnutrition, antibiotic use, transfusions and recent surgery. In practice, it is therefore difficult to apportion the contribution that TPN might make to liver dysfunction in individual patients. Cholestasis is the most common complication; steatosis is frequent in older children and adults but uncommon in infants. Biliary sludging, cholelithiasis and acalculous cholecystitis can complicate TPN and are predisposed conditions with ileal resection or ileal Crohn disease. Ductopenia was identified by Naini and Lassman in 25% of both infants and adults in a large review of 53 infants and 36 older children and adults receiving TPN. The authors observed that the combination in some patients of biliary periportal fibrosis with perivenular fibrosis was usefully characteristic of TPN-induced liver injury in adults and infants, compared with other causes of biliary fibrosis. Liver fibrosis of some degree develops in the great majority of infants and older patients during prolonged TPN (>6 weeks), including periportal and perivenular fibrosis. Risk factors include duration of TPN and short bowel length ; progression to severe fibrosis and cirrhosis may be more likely in infants, in particular those with short bowel syndrome. Patients with TPN-associated liver disease and intestinal failure can be evaluated for intestinal or combined liver-intestinal transplantation, for which staging of hepatic fibrosis may be required. Regression of TPN-associated native liver fibrosis can occur in those for whom isolated intestinal transplantation has allowed weaning from TPN.
TPN-associated hepatic disease
TPN-associated cholestasis in neonates is more likely with longer treatment, with younger gestational age and low birthweight. The diagnosis is one of exclusion, including differentials of ‘physiological’ cholestasis, sepsis and the numerous other causes of neonatal cholestasis (see Chapter 3 ). Morphologically, the individual changes are not specific and extremely variable. Bilirubinostasis is consistently present and may develop in days; cholestatic rosettes are often present; bile plugs may also be present in interlobular bile ducts. Steatosis is infrequent in infants. Hepatocellular ballooning is more often severe than in older children or adults. The portal tracts show a variable mixed inflammatory cell infiltrate and, with prolonged therapy, a periportal ductular reaction; progressive fibrosis can produce biliary cirrhosis ( Fig. 15.7 ). During prolonged treatment, serial liver biopsy may be needed to assess fibrosis, which is common but not usefully predicted or monitored by serum liver function tests. Fibrous progression varies widely among individuals.
The pathogenesis of TPN-associated cholestasis is uncertain. Suggestions have included altered bile composition with (in neonates) immature hepatic bile acid metabolism and transport, the lack of enteral nutrition with disturbed enterohepatic circulation of bile acids, suppression of trophic or secretion-stimulating hormones and the composition of the infusate (including nutritional deficiencies or direct epithelial toxicity).
Older children and adults
Hepatic abnormalities are common during parenteral nutrition in older children and adults, but the incidence is difficult to establish and, in most cases, biochemical evidence of dysfunction is transient. High-calorie dextrose-based TPN has been superseded by lower-calorie infusions containing fat, with a reduced incidence of hepatic dysfunction. Increases in serum bilirubin are milder and less common than in infants, but increased serum transaminases, ALP and γ-glutamyltransferase (GGT) affect 20–60% of patients, may develop after 5–20 days of treatment and persist in 15–25% of patients who receive long-term TPN. If conservative management of TPN-related liver disease fails, isolated intestinal or intestine/liver transplantation may be indicated. Changes in the liver include intrahepatic cholestasis, periportal macrovesicular steatosis and periportal fibrosis ( Fig. 15.8 ). Perivenular bilirubinostasis develops after 2–3 weeks of TPN and may be accompanied by periportal inflammation and portal fibrosis that persists after stopping TPN. Forrest et al. observed clinical improvement in a patient treated with anti-TNFα monoclonal antibody. Chronic cholestasis in TPN-associated liver disease is associated with significant secondary copper overload. The steatosis may reflect unbalanced lipid turnover; carnitine and choline deficiency have each been postulated. Steatohepatitis can occur, but the incidence of progression to cirrhosis is not clear.
The liver in gastrointestinal diseases
Hepatic involvement in diseases of the gastrointestinal (GI) tract is common. The portal vein affords direct access for toxins, microorganisms and tumour emboli to cause nonspecific reactive hepatitis, intrahepatic sepsis and intrahepatic metastases, respectively. There are also specific hepatobiliary disorders associated with chronic inflammatory bowel disease.
Chronic inflammatory bowel disease
Inflammatory bowel disease (IBD) is thought to represent an unbalanced mucosal immune response to gut contents in genetically predisposed individuals. Hepatobiliary disease in IBD is among the most common extraintestinal manifestations. With some exceptions, the spectrum of such disease is similar between Crohn disease and ulcerative colitis (see also Chapter 9 ). Colonic Crohn disease is more often associated with hepatic dysfunction than noncolonic disease and is usually coincident with other extraintestinal systemic complications. This distinction accords with genetic association data that IBD is best categorized into three equally distinct genotype-phenotype groups, taking account of disease location: ileal Crohn disease, colonic Crohn disease and ulcerative colitis.
Abnormalities of LFTs affect approximately 50% of patients with chronic IBD. The frequency of biopsy-proven significant liver disease is considered to be lower, from 5–17% in ulcerative colitis and 10–30% in Crohn disease. If LFTs are normal, Broomé et al. found that <3% develop biopsy-proven liver disease on follow-up. Primary sclerosing cholangitis (PSC), drug hepatotoxicity, steatosis and cholelithiasis are common morbidities, and other important associations are summarized next ( Table 15.5 ). Primary biliary cirrhosis/cholangitis (PBC) is rare but appears to be more prevalent in IBD, particularly ulcerative colitis (UC), than in the general population and has a much reduced female preponderance. IBD may also occur de novo after LT; risk factors include CMV infection and immunosuppression with tacrolimus.
|Primary sclerosing cholangitis (PSC)||1–5% (especially ulcerative colitis)|
|Bile duct carcinoma||150-fold in PSC (13%)|
|Gallstones||5-10 fold (ileal Crohn disease)|
|Amyloidosis||0.5% (Crohn disease)|
|Pylephlebitis and abscess||Rare (mainly Crohn disease)|
Primary sclerosing cholangitis
The majority (~80%) of patients with PSC also have IBD at some point in their life, often preceding diagnosis of PSC. The development of PSC in IBD is thought to reflect common susceptibilities to the development of unbalanced mucosal immune responses to environmental stimuli. PSC is more prevalent in patients with UC (1–5%) than with Crohn disease (1–3%) (see Chapter 9 ), but the colitis associated with PSC often has a relatively distinct phenotype (pancolonic or predominantly right sided, but relatively quiescent with increased incidence of colonic dysplasia). PSC patients have an estimated 150-fold increased risk of cholangiocarcinoma, which affected 13% patients in one large follow-up study, was commonly apparent at or soon after diagnosis of PSC, with a subsequent incidence of about 1.5% per year, the risk being confined to those PSC patients with IBD. A detectable gallbladder mass in patients with PSC is sufficiently likely to be carcinoma to merit cholecystectomy. Small-duct PSC, in which the cholangiogram is normal, is relatively uncommon but requires liver biopsy for diagnosis and is typically associated with IBD; some patients progress to manifest large-duct PSC. Approximately 70% of children with PSC have IBD, usually UC or less often, colonic Crohn disease, the liver disease preceeding, coinciding or following IBD. The term ‘autoimmune sclerosing cholangitis’ (ASC) in children refers to the presence of cholangiopathy (as detected by cholangiography) in patients with serological and histological features of autoimmune liver disease (see Chapters 8 and 9 ). IBD is present in approximately 40–50% of patients with ASC, as opposed to about 20% of children with typical autoimmune hepatitis.
Macrovesicular steatosis is the most common histological liver abnormality in IBD, affecting about 25% of patients, although most epidemiological studies predated the recent obesity epidemic. It is asymptomatic, and the extent may be related to the severity of the bowel disease, although steatosis can persist after colectomy. Hepatomegaly is unusual. When related to IBD, the steatosis is probably a manifestation of an altered gut microbiome, malnutrition and anaemia.
A diagnosis of chronic hepatitis should not be made unless endoscopic retrograde cholangiopancreatography (ERCP) is normal; historical reported prevalence rates up to 10% were likely overestimates due to the difficulties in distinguishing autoimmune hepatitis (AIH) from PSC and an inability to account for post-transfusional chronic HCV infection. An estimate of 1–2% seems likely for UC, but there is little evidence of an association with Crohn disease.
Edwards and Truelove reported that cirrhosis was present in 2.5% of UC patients and accounted for 10% of deaths over 20 years of follow-up. The overall prevalence of cirrhosis is about 2–5%, about 12- to 50-fold more common than in controls without chronic IBD. Patients with extensive colonic disease are most at risk. Cirrhosis may develop as a sequela to PSC, where it will show a biliary pattern, or less commonly from chronic hepatitis (viral or autoimmune). Cirrhotic patients with colectomy may have variceal bleeding at the ileostomy stoma or ileorectal anastomosis. Colonic disease may be exacerbated after LT for PSC.
Approximately 8–20% of patients with cholangiocarcinoma (CC) of the proximal bile ducts have UC and are on average 20 years younger than those without IBD. The risk of CC is increased 10- to 30-fold in patients with UC, whereas in Crohn disease the association appears to be uncommon. CC develops as a complication of PSC, which is considered a premalignant condition from which carcinoma develops in 10–15% of patients. Biliary intraepithelial neoplasia (BilIN) can be seen adjacent to invasive CC ( Fig. 15.9 ). Carcinoma usually develops in patients with longstanding (≥15 years), extensive and severe UC, occasionally some years after total colectomy. Radiological discrimination from duct involvement by PSC is challenging, and CC may not be diagnosed until liver resection at transplantation or at autopsy. The prognosis is dismal, with a mean survival of approximately 6–18 months. LT is of limited value, and CC diagnosed incidentally at operation may recur in the allograft.
Patients with Crohn disease have a twofold increased incidence of gallstones, but this increases 5- to 10-fold with disease of the terminal ileum, related to the extent and duration of the ileal disease or ileal resection. This complication is thought to be caused by bile acid malabsorption and possibly changes in bile acid composition, causing cholesterol saturation in the bile. The gallbladder itself can be affected by Crohn disease.
Secondary (AA) amyloidosis affects about 0.5% IBD patients. It is more common in Crohn disease than UC and merits consideration in Crohn disease patients presenting with hepatomegaly. Regression of amyloidosis has been reported after colectomy.
Hepatic granulomas are found in approximately 5% of IBD patients, predominantly in Crohn disease, and may resolve soon after colectomy. Granulomas may also be associated with drug hepatotoxicity related to treatment of IBD, including TNFα antagonists and sulfasalazine or mesalazine. Approximately 3% of patients with granulomatous hepatitis have Crohn disease.
Pylophlebitis and pyogenic abscess are rare complications of IBD, although either can be the presenting feature, encountered mainly in Crohn disease. Abscesses are often multiple, in the right lobe, yield a positive culture, and there is often bacteraemia. Unusual differentials such as amoebic liver abscess caused by unrecognized amoebic colitis merit consideration, particularly if a patient is receiving immunosuppressive anticolitic therapy. Another differential diagnosis is of so-called aseptic abscesses, an apparently noninfectious condition that predominantly presents in patients with IBD. Typically, there are lesions in multiple organs, including usually the spleen and lymph nodes (unlike infective abscess), the liver (40% of patients) and less frequently other organs. Microscopically, there is granulomatous inflammation surrounding abundant central neutrophil infiltration. The condition usually responds to corticosteroids but may relapse. Inflammatory pseudotumour has also been reported in isolated patients with Crohn disease.
Patients with IBD have an overall threefold increased risk of venous thromboembolism, but this is much greater during disease flares, although an unique cause has not been found. Portal vein thrombosis occurs in both UC and Crohn disease. It is rare overall but is common after abdominal surgery; thrombosis affecting main or segmental branches of the portal vein affects about 40% of patients undergoing proctocolectomy, usually nonocclusive in the more proximal branches. There is a reported association with postoperative pouchitis. Mesenteric thrombosis or Budd–Chiari syndrome caused by hepatic vein thrombosis are rare complications in IBD. Nodular regenerative hyperplasia (NRH) was present in 6% of thiopurine-naive IBD patients.
TPN is often used in severe Crohn disease (see earlier and Fig. 15.8 ). Many of the therapeutic agents used in the treatment of IBD also have hepatotoxicity (see Chapter 12 ), including thiopurines (e.g. azathioprine), aminosalicylates (sulfasalazine or mesalazine), TNFα inhibitors (infliximab or adalimumab), methotrexate and corticosteroids. There is a possible association of hepatosplenic T-cell lymphoma in young patients with IBD receiving TNFα inhibitor or thiopurine therapy. Immunosuppressive treatment of IBD can reactivate chronic viral hepatitis, in particular hepatitis B. Liver dysfunction may occur as part of multiorgan failure when there is toxic megacolon.
Hepatic angiomyolipoma has been described in a patient with ulcerative colitis.
Miscellaneous bowel diseases with liver involvement
Coeliac disease can affect individuals of any age and any organ, with extraintestinal symptoms recognized as more prevalent in the clinical presentation. About 20–40% of coeliac disease patients have abnormal serum transaminases (and less often increased ALP) at diagnosis. Conversely, coeliac disease is a potential cause of increased transaminase levels of unidentified etiology or can be an unsuspected comorbidity (e.g. revealed during treatment for hepatitis C). The elevated transaminases normalize in many patients within 1 year on a gluten-free diet and are thought to be secondary to the intestinal mucosal injury and altered permeability of coeliac disease, associated with an altered or increased microbiome and microbial products draining to liver. Changes on biopsy include steatosis and nonspecific reactive hepatitis. However, coeliac disease also confers a 4- to 10-fold increased risk of specific autoimmune liver disease, before or after coeliac diagnosis, most often PBC (~6%), followed by AIH, then PSC. These conditions are not improved on a gluten-free diet, and there is an increased risk of liver fibrosis or cirrhosis (warranting consideration of coeliac disease as a comorbidity in the differential diagnosis of cryptogenic cirrhosis) and liver failure. NRH and biopsy-proven noncirrhotic portal hypertension are also reported. Rarely, hepatic T-cell lymphoma may occur.
Whipple disease ( Tropheryma whippelii infection) often shows nonintestinal involvement, which may be the only manifestation of the disease. Inappropriate immunosuppressive therapy, as for undiagnosed T whippelii arthropathy with TNF inhibitors, can trigger severe localized or disseminated forms of T. whippelii , including sepsis. Infected PAS-positive-diastase-resistant foamy macrophages characterize the intestinal involvement and may also be found in the liver ( Fig. 15.10 ). The ‘sickle-form’ bacilli seen in these macrophages have been described in Kupffer cells. Noncaseating epithelioid granulomas also occur in the liver in Whipple disease and may precede the onset of intestinal symptoms but do not contain identifiable bacilli. PCR for T. whippelii is useful to demonstrate the presence of organisms. Massive steatosis has been described in one patient.
Hepatic granulomas with a prominent eosinophil infiltrate have been reported in two patients. Two case reports document mild and intense eosinophil infiltration of portal tracts. Sclerosing cholangitis has been described in hypereosinophilic syndrome in which there was intestinal involvement.
The liver in pancreatic diseases
Cystic fibrosis is discussed in Chapter 3 .
Extrahepatic obstruction caused by an annular pancreas is rare and a diagnosis of exclusion. Acute pancreatitis is complicated by jaundice, often transient, in 15–75% of patients; this may result from inflammatory bile duct obstruction or a common cause such as alcohol excess or gallstones. Chronic pancreatitis is complicated by intrapancreatic common bile duct obstruction in 3–10% cases, which may be transient, recurrent or persistent and with or without jaundice. Transient jaundice usually manifests during acute inflammatory excacerbations; pressure from a pancreatic pseudocyst can be a contributing factor, and there is an increased risk of secondary biliary cirrhosis. Steatosis, portal tract inflammation, ductular reaction with fibrosis and cirrhosis may be seen in patients with chronic pancreatitis but probably reflect the common underlying causes of alcohol liver injury or cholelithiasis. Type I autoimmune pancreatitis (the pancreatic manifestation of IgG4-related disease) often presents with obstructive jaundice caused by concurrent IgG4-related sclerosing cholangitis, which itself can infrequently be associated with lymphoplasmacytic hilar inflammatory pseudotumours (see Chapter 9 ). Segmental or localized portal hypertension occurs in some patients with chronic hepatitis on a background of pancreatitis, most probably as a consequence of splenic vein occlusion or stenosis. Vascular complications such as hepatic artery injury and portal vein thrombosis after pancreatic surgery are relatively uncommon. Anastomotic biliodigestive stenosis and biloma can be observed as late complications after pancreatic surgery. Pancreatic pseudocysts have been described within the liver. Pancreatic malignancy presents with obstructive jaundice in about 30% of patients.
Acute pancreatitis has been found in a third of patients with panacinar liver cell necrosis. It may also occur in acute fatty liver of pregnancy and with acute hepatitis A and C.
Endocrine pancreas: diabetes mellitus
The liver has a key role in carbohydrate metabolism. The ‘hepatotropic’ effects of pancreatic hormones were first investigated by Starzl et al., and it is now clear that insulin, glucagon and insulin-like growth factors together with several other hormones and hepatic growth factors, modulate hepatic function in normal circumstances and regulate hepatic regeneration after liver injury. Only in diabetes mellitus, however, is there evidence of significant liver disease in association with islet cell dysfunction.
The role of type 2 diabetes mellitus in the development of nonalcoholic fatty liver disease (NAFLD) is discussed in Chapter 5 . Here we consider the liver abnormalities in insulin-dependent type 1 diabetes. The liver is central to carbohydrate and lipid metabolism. Insulin deficiency reduces the normal feedback inhibition of hepatic gluconeogenesis, increasing glucose release from the liver. Declining glucokinase levels (insulin regulated) also become rate limiting and limit hepatic trapping of glucose from sinusoidal blood. Together with reduced peripheral tissue uptake of glucose, these changes cause hyperglycaemia. Conversely, in diabetic patients taking insulin, glycogen can accumulate within the cytoplasm and nuclei of hepatocytes. The cytoplasmic glycogen appears ultrastructurally predominantly as rosettes, with nuclear glycogen as dispersed particles. Nuclear glycogenation is seen more often in periportal than perivenular hepatocytes, is very nonspecific but is considered to correlate more closely with diabetes than obesity. Abnormal hepatic glycogen loading has been attributed to high insulin dosing in patients with hyperglycaemia, which promotes glycogen storage that can accumulate with time or sometimes very acutely. Typical clinical scenarios include vigorous treatment of acutely presenting diabetes with high-dose insulin, long-term poor diabetic control involving repeated excessive insulin dosing that is then self-corrected with high-quantity glucose intake, and chronic hyperglycaemia with intermittent insulin dosing. Consequent hepatomegaly caused by glycogen loading of the liver in type 1 diabetic patients taking insulin was described by Mauriac in 1930 as part of a childhood syndrome characterized by poor glycaemic control, growth retardation, pubertal delay and cushingoid features. However, such acquired glycogenosis can also affect adults with type 1 diabetes.
The characteristic presentation is with hepatomegaly that may be painful and increased serum transaminase levels (sometimes dramatically) in a context of poor diabetic control. The changes resolve with improved glycaemic control and are not thought to lead to chronic liver injury. The liver histology of 14 affected adults and children was reviewed in detail, for which the term ‘glycogenic hepatopathy’ was coined and has subsequently become prevalent to describe the condition ( Fig. 15.11 ). Hepatocytes are enlarged, with rarefied, pale-staining cytoplasm replete with glycogen (demonstrable with PAS), frequent nuclear glycogenation, giant mitochondria and prominent cell borders contrasting with the pale cytoplasm. Sinusoids appear compressed. Steatosis was absent or sparse in most cases, and fibrosis was mild in two cases only, one showing mild steatohepatitis with mild fibrosis. Repeat biopsy in one patient after adequate glycaemic control and resolution of signs showed normal liver. A recent series of 31 diabetic children (19 with liver biopsy) showed similar histological features of glycogenosis but more prevalent steatosis, inflammation and fibrosis.
The altered lipid metabolism in type 1 diabetes includes the mobilization of free fatty acids from adipose to be converted to triglyceride and very-low-density lipoprotein (VLDL) in liver, where they accumulate. Decreased lipoprotein lipase (insulin regulated) perpetuates this hyperlipidaemic accumulation of triglyceride and VLDL. Hepatocellular fatty acid oxidation can generate acetyl coenzyme A sufficient to saturate the oxidative enzymes and cause ketone formation. However, type 1 diabetes is not itself associated with significant hepatic steatosis, unlike type 2 diabetes, confirmed with magnetic resonance imaging (MRI) in a large comparative study and in a biopsy-based survey of 155 children with steatosis on liver biopsy.
Collagenization of the space of Disse together with deposition of basement membrane components has been reported in diabetes mellitus (termed ‘diabetic hepatosclerosis’ when present without steatosis) and is thought to represent liver involvement as part of diabetic microangiopathy. An association with cholestasis has also been suggested. However, no specific association with perisinusoidal fibrosis was found in a cross-sectional comparative study of liver biopsies from 89 diabetic patients (half insulin dependent) and matched controls. Instead, hepatic arteriolosclerosis was identified as significantly increased in hypertensive diabetic patients and again suggested a possible association with cholestatic liver biochemistry and biliary abnormalities.
Iron-induced beta-cell injury was initially proposed as the cause of diabetes in haemochromatosis, although insulin resistance appears to be involved as well. The reciprocal influence of iron and insulin and the relationship among steatohepatitis, diabetes and iron overload are complex (see Chapter 4 ). An association exists between type 1 diabetes and AIH.
Diabetic patients are at increased risk of liver neoplasms. Those with an inherited monoallelic mutation of the transcription factor 1 ( TCF1 ) gene encoding for the hepatocyte nuclear factor 1α (HNF1α) may develop maturity-onset diabetes of the young type 3 and liver adenomatosis when the second allele is inactivated in hepatocytes (see Chapter 13 ). There are case reports of NRH, xanthomatous neuropathy affecting unmyelinated nerve fibres in the hilum and in large portal tracts, intrahepatic and perihepatic abscess and PSC occurring in patients with diabetes. Liver injury attributable to drugs used in the treatment of diabetes is discussed in Chapter 12 .
The liver in endocrine diseases
Polycystic ovary syndrome is the most common endocrine abnormality in premenopausal women and is associated with insulin resistance and metabolic syndrome, including fatty liver disease (see Chapter 5 ). The hepatotoxic effects of lipid-lowering drugs, oral hypoglycaemic and other drugs used in the therapy of endocrine and metabolic syndrome-related abnormalities are discussed in Chapter 12 ; this includes the effects of gonadal steroids on the liver, which occur principally in relation to their therapeutic administration.
The liver is the principal site for conversion of tetraiodothyronine (thyroxine, T4) to triiodothyronine (T3). Liver is also the main source of the major thyroid hormone-binding proteins and for conjugation and biliary excretion of the thyroid hormones. As a result, liver disease can be associated with changes in thyroid hormone metabolism and common thyroid function test values, such as increased thyroid-binding globulin in acute hepatitis. Conversely, thyroid hormones affect hepatocyte metabolism, including synthetic activity, bilirubin and bile acid metabolism, and thyroid diseases can alter liver function.
There is a well-recognized association between autoimmune thyroid disease and PBC (see Chapter 9 ); occasional cases of Graves disease with AIH and PSC are also described. Post-infantile giant cell hepatitis has been documented in a patient with Graves disease. Increased serum transaminase levels are common in patients taking propylthiouracil for hyperthyroidism. Thyroid and liver abnormalities may be produced by some drugs, including carbamazepine, mefloquine and amiodarone. Sorafenib, used to treat hepatocellular carcinoma, can cause hypothyroidism (see Chapter 12 ).
Abnormal LFTs are reported in 15–75% of patients with hyperthyroidism and usually resolve with treatment. Increased serum ALP is the most common abnormality (including the bone isoenzyme), but there may be elevated transaminases and bilirubin. Jaundice attributable only to hyperthyroidism is uncommon, usually seen during a thyroid storm, in which canalicular and sometimes hepatocellular cholestasis with associated swelling injury on liver biopsy is described. Other changes are mild and nonspecific. Jaundice in hyperthyroidism can also be precipitated in the presence of heart failure or concurrent liver disease, including associated PBC. In such patients the role of the hyperthyroidism in causing jaundice may be overlooked.
No consistent or specific LFT abnormalities have been reported; some may have derived from muscle due to myopathy rather than from liver. High protein ascites caused by myxoedema could misdirect investigations toward a search for liver disease or Meig syndrome. Baker et al. reported concentric thickening of the walls of central venules, perivenular hepatocyte loss and perivenular fibrosis, but right-sided heart pressures were normal. Increased serum bilirubin levels are common in severe myxoedema, and there is a case report of cholestasis in hypothyroidism. Ono and Ishizaki reported a case of NRH in association with Hashimoto disease. Hypothyroidism may be a risk factor for NAFLD and for hepatocellular carcinoma in women. In congenital hypothyroidism, neonatal jaundice caused by an unexplained unconjugated hyperbilirubinaemia can persist for several weeks.
Secondary hyperaldosteronism is a feature of hepatic decompensation. Adrenocortical insufficiency is recognized in critically ill patients with cirrhosis, often with severe sepsis or septic shock, but also occurs in stable patients with cirrhosis, although the incidence and pathophysiology are unclear.
Steatosis is a frequent finding in Cushing syndrome, and fatty liver can develop after a 4-week course of corticosteroid therapy. Fatal fat embolism, of presumed fatty liver origin, has been reported in a child receiving high-dose corticosteroid treatment. Acute hepatic glycogen loading in hepatocytes, resembling adult polyglucosan body disease (mutational glycogen branching enzyme deficiency), is also described in children who developed hepatomegaly within days of receiving short-term high-dose corticosteroids. Other settings of stressed glucose metabolism that may manifest similarly (‘glycogen bodies’, ‘glycogen pseudoground glass change’) include transplant recipients receiving diabetogenic immunosuppression such as tacrolimus or mycophenolate mofetil (MMF), type 2 diabetics taking insulin, patients taking β-blockers or those receiving TPN. The pathogenesis probably involves accumulation in hepatocytes of abundant linear glycogen chains under the influence of insulin-stimulated glycogen synthase, in excess relative to glycogen branching enzyme activity. The subsequent accumulation of poorly branched glycogen manifests in hepatocytes as polyglucosan bodies, similar to those of genetic glycogen branching enzyme deficiency or Lafora bodies, which represent a relatively poor source of free glucose.
Olsson et al. reported four patients with Addison disease who presented with corticosteroid-responsive elevation of serum transaminases. Liver biopsy in one patient showed lymphocytic infiltrates in the portal tracts; there are other sporadic reports of this association, including after abrupt cessation of therapeutic corticosteroids. Phaeochromocytoma may release a variety of peptides, including IL-6 (directly, or stimulated by tumour catecholamines), which may cause a paraneoplastic inflammatory syndrome, including fever and abnormal LFTs. Both intrahepatic cholestasis and portal lymphocytic infiltration have been reported as paraneoplastic phenomena in phaeochromocytoma.
Adrenal rest tumours may be nonfunctioning clinically and enter the differential diagnosis of hypervascular fatty liver masses. Histologically, the mass is composed of pale cells resembling adrenal cortex, and immunohistochemistry for adrenal 4-binding protein and enzymes involved in the synthesis of adrenocorticosteroids may confirm the origin.
There are occasional reports of transection of the porta hepatis and hepatic artery injury after right adrenalectomy .
Growth hormone (GH) is diabetogenic (insulin resistant), lipolytic and anabolic; under the influence of GH, the liver is the primary source of insulin-like growth factor 1, the levels of which fall in patients with parenchymal liver disease. Patients with acromegaly have features resembling the metabolic syndrome and visceromegaly, including hepatomegaly, with about 50% enlargement of the liver and increased excretion capacity. Hepatic changes at biopsy or autopsy in one series were heterogeneous, with individual examples of steatosis, noncirrhotic portal hypertension, portal lymphocytes and congestion related to cardiac failure.
Deficiency of growth hormone is associated with reduced growth and muscle mass with adiposity. Normal hepatic lipid metabolism requires GH, illustrated by mice deleted for the GH receptor in liver, which develop features of metabolic syndrome, marked steatosis, steatohepatitis with fibrosis and subsequent liver cell adenomas. Indeed, the development in patients with hypopituitarism of a phenotype similar to metabolic syndrome, with central obesity, hyperlipidaemia and diabetes, has been in large part attributed to GH deficiency. Such patients manifest the full spectrum of NAFLD, including cirrhosis. Neonatal (giant cell) hepatitis and cholestasis are recorded in congenital hypopituitarism.
Peliosis has been reported in patients with pituitary adenoma.
Miscellaneous endocrine diseases
Orloff reported a syndrome of hyperparathyroidism, cirrhosis and portocaval shunt. Refractory ascites and, more recently, idiopathic portal hypertension have been reported in POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes). Cases with severe liver enzyme abnormalities are occasionally encountered in severe ovarian hyperstimulation syndrome .
Elevated serum liver enzymes are common in adults with Turner syndrome (X chromosome monosomy), associated with serum cholesterol level and, in a large adult cohort, not influenced by stopping hormone replacement. Changes described on liver biopsy include chronic cholestasis, steatosis and cirrhosis. Roulot et al. described the histopathological features in 27 patients with Turner syndrome, confirming steatosis but also highlighting frequent vascular abnormalities, including obliterative portal venopathy and/or NRH in nine, with multiple focal nodular hyperplasia in two cases and two with cirrhosis. Turner syndrome may be associated with agenesis or hypoplasia of the portal vein, complicated by hepatocellular carcinoma in a child receiving GH therapy. Noncaseating granulomas were observed in three patients with Turner syndrome, and concurrent PBC was reported in one patient.
The liver in pregnancy
The following discussion describes the changes within the liver in normal pregnancy and in the liver diseases associated with pregnancy.
In general the liver functions normally in pregnancy. There is no increase in liver size. Although total blood volume and cardiac output are increased by 50%, hepatic blood flow remains unchanged; in the third trimester this results in a relative decrease of 25–30% in the proportion of the cardiac output that passes through the liver. Consequently, drugs that are cleared by the liver in a blood-flow-dependent manner have a reduced clearance rate in pregnancy.
Conventional LFTs are altered in the course of pregnancy. The increase in ALP is predominantly the placental isoenzyme, but the hepatic isoenzyme also increases; the level may remain elevated for 4–6 weeks postpartum. The serum transaminases, GGT, 5-nucleotidase and the prothrombin time remain normal, and in suspected hepatic dysfunction during pregnancy, these are of most diagnostic help. Serum albumin decreases, but fibrinogen and some clotting factors increase toward term, resulting in a hypercoagulable state in late pregnancy and puerperium. Serum cholesterol and triglycerides increase progressively in the second half of pregnancy. The gallbladder motility is reduced, and bile is more lithogenic, with reduced enterohepatic circulation of bile acids and increased cholesterol secretion.
Light microscopy of the normal liver in pregnancy has shown only minor nonspecific changes. These included cellular and nuclear pleomorphism, increased numbers of binucleate cells, steatosis, increased cellular and nuclear glycogen, mild reactive Kupffer cell hyperplasia and some lymphocytic infiltration of portal tracts—features which do not constitute a ‘liver of pregnancy’. Electron microscopy shows features considered to be adaptive responses to the hormonal changes: proliferation of the smooth endoplasmic reticulum, giant mitochondria with increased crystalline inclusions and increased numbers of peroxisomes.
Liver disease in pregnancy
Up to 3% of pregnancies are estimated to be complicated by liver disease; pregnancy-related liver disorders have been estimated to account for 6% of maternal deaths. Jaundice complicates approximately 1 in 1500 pregnancies, for which acute viral hepatitis is the most common cause (40% of all cases). Various medical complications in pregnancy (10%) and large-duct obstruction (6%) also contribute significantly. The settings in which liver disease occurs in pregnancy may be grouped into (1) pre-existing liver disease, (2) new liver disease not unique to pregnancy and (3) liver disease unique to the pregnant state. Table 15.6 summarizes the main aspects.
|Disease||Trimester||Clinical presentation||Tests||Liver histology|
|Liver disease unique to pregnancy (jaundice of pregnancy)|
|Intrahepatic cholestasis||Late 2nd/3rd trimester||Family history, pruritus/jaundice||Elevated bile acids, mild AST increase, normal imaging||Normal or bland cholestasis|
|Acute fatty liver||3rd trimester/postpartum||Liver failure||High AST |
Fatty liver on imaging
|Perivenular and midzonal microvesicular steatosis|
|Pre-eclampsia/eclampsia||3rd trimester/postpartum||Proteinuria oedema hypertension ± seizures |
|Mild-high elevation of AST |
Haematoma, infarct, rupture on imaging
|Periportal fibrin thrombi, necrosis and haemorrhage|
|Liver disease coincidental with pregnancy (jaundice in pregnancy)|
|Viral hepatitis A, B, C, D, E||As in nonpregnant state; hepatitis E more severe|
|Cholelithiasis||Cholelithiasis associated with dysmotility, increased cholesterol and multiple pregnancies|
|Budd–Chiari||Budd–Chiari unmasked by prothrombotic state of pregnancy|
|Other||Ischaemic hepatitis, drug reaction, acute viral|
|Pregnancy in patients with chronic liver disease|
|Flares of autoimmune hepatitis, particularly postpartum|
The liver diseases unique to the pregnant state comprise the following:
Intrahepatic cholestasis of pregnancy (ICP)
Acute fatty liver of pregnancy
Hypertension of pregnancy-related syndromes (pre-eclampsia/eclampsia, HELLP)
A miscellaneous group (associated with hyperemesis gravidarum, haemolytic and megaloblastic anaemias of pregnancy and hydatidiform mole) and an unclassifiable group (with mild jaundice, but no specific hepatic disease identified).
Intrahepatic cholestasis of pregnancy
ICP is characterized by onset of pruritus with elevated fasting serum bile acid levels and serum transaminases, which manifests typically in the late second or third trimester and may progress to mild jaundice. The incidence was particularly high in Chile, although this has declined greatly, and also in Scandinavia. Occurrence carries a significant risk of fetal loss. Histologically, the liver shows marked ‘bland’ bilirubinostasis ( Fig. 15.12 ). The changes revert within 3 weeks after delivery (an important verification of diagnosis) but often recur during subsequent pregnancies, particularly if there is a family history. In addition to possible environmental factors, genetic factors contributing to susceptibility include transporter protein defects at the hepatocyte canalicular membrane, including in some patients, ABCB4 (MDR3 gene) mutations or variant alleles of ABCB11 (the canalicular bile salt export pump gene). These factors may explain the association of ICP with cholelithiasis. Some women with familial cases classified as ICP subsequently developed liver scarring and cirrhosis, suggesting that pregnancy unmasked a previously unrecognized liver disease. A similar cholestatic syndrome is associated with oral contraceptive use.
Acute fatty liver of pregnancy
The initial observations of the condition are attributed to Tarnier in 1857 ( graisseux du foie dans la fièvre puérperale ) and a case report of ‘acute yellow atrophy’ of the liver in pregnancy by Stander and Cadden in 1934. This rare disease affects about 1 in 16,000–20,000 pregnancies, but it is a common cause of liver failure in pregnancy, with increased maternal and foetal mortality. Acute fatty liver of pregnancy is a primary mitochondrial cytopathy (see Chapters 3 and 5 ) and is considered a consequence of homozygous or compound heterozygous mutational impairment of mitochondrial β-oxidation of fatty acids in the fetus and placenta. Long-chain fatty acids accumulate, enter the maternal circulation from the placenta and are hepatotoxic. The disease manifests in late pregnancy (usually after the 30th week), at which time the mother develops increased reliance on fatty acid metabolism, with physiological maternal increases of lipolysis and decreased β-oxidation. However, the mother’s underlying heterozygous state compromises her capacity to deal with this metabolic load.
Disease onset is manifest by fatigue, nausea, persistent vomiting and abdominal pain, followed days or weeks later by jaundice and liver failure, with frequent hypoglycaemia that may cause coma. The increase in transaminase levels is minor compared with the degree of liver failure. Low platelets, coagulopathy, leukocytosis and elevated uric acid and ammonia levels are common. Hypertension, oedema and proteinuria may mimic pre-eclampsia. The clinical differential diagnosis also includes acute hepatitis of other causes, in particular viral and drug related. Liver biopsy can be helpful to confirm the diagnosis but is not usually needed.
The disease is most common in first pregnancy and twin pregnancy, although it may recur in a subsequent pregnancy. Uncomplicated cases resolve in the days after timely delivery, which is essential. Liver transplant is rarely indicated. There is no report of progression to chronic liver disease, and subsequent uncomplicated pregnancy has been reported. The mortality rate for both mother and fetus was 80–85% in early series; despite improved supportive therapy and recognition, there remains about 11–18% maternal mortality and 23–25% fetal mortality. There are reports of intrahepatic cholestasis of pregnancy complicated by acute fatty liver of pregnancy.
Macroscopically, the liver is distinctively pale yellow and usually smaller than normal because of hepatocyte loss. Microscopically, the cardinal change is microvesicular steatosis. In 1940, Sheehan observed ‘a gross fatty change affecting the entire lobule except for a sharply defined rim of normal cells around the portal tracts. The affected cells were bloated by a fine foam of tiny white vacuoles throughout the cytoplasm so that they resembled the cells of suprarenal cortex’ ( Fig. 15.13 ). The steatosis may be diffuse without periportal sparing. Canalicular and hepatocellular bilirubinostasis is also present. There is Kupffer cell hyperplasia with conspicuous aggregates of ceroid-laden macrophages at sites of confluent hepatocyte loss, the latter being readily appreciable with a reticulin stain. Intrasinusoidal fibrin deposits have been reported, occasionally associated with microhaemorrhages. There is usually only a mild mononuclear cell infiltrate of the parenchyma and portal tracts, sometimes with admixed eosinophils and occasional plasma cells. Joske et al. noted midzonal necrosis in one case. Serial biopsies in survivors show progressive disappearance of fat from the periportal to the perivenular zone within days of parturition. Ultrastructurally, the fat is not membrane bound. There is dilation of the rough endoplasmic reticulum, and some cells show cytoplasmic degeneration with autophagic vacuoles; the mitochondria show considerable variation in size and shape.
Extrahepatic complications include GI haemorrhage, renal failure (sometimes with fatty infiltration of renal tubules), intravascular haemolysis, pancreatitis and peripancreatic bleeding and disseminated intravascular coagulation (DIC). The coagulation defect accounts for many of the complications, and it may be temporarily aggravated by delivery. Pulmonary fat embolism from fatty liver of pregnancy is also described.
Hypertension-related liver diseases
Pre-eclampsia, eclampsia and HELLP (haemolysis, elevated liver enzymes, low platelets) are syndromes related to hypertension during pregnancy. Abnormal placentation, with release from the stressed placenta of circulating factors and microparticles, is considered to be central to pathogenesis. These substances cause generalized maternal endothelial dysfunction and coagulation activation, resulting in thrombotic microangiopathy. Enhanced maternal inflammatory responses and direct hepatocyte injury by placental Fas ligand (CD95) are further aggravating factors in HELLP syndrome.
The liver in pre-eclampsia/eclampsia
Pre-eclampsia is a syndrome of new hypertension presenting with significant proteinuria after 20 weeks’ gestation. It affects about 10% of pregnancies and is the most common serious medical disorder in pregnancy. Increased transaminases occur in >30% of cases and denote severe disease. Jaundice is uncommon, but there may be right upper quadrant tenderness. Liver biopsy is not indicated, but in uncomplicated pre-eclampsia it has been normal or with mild, nonspecific reactive changes on light microscopy. Arias and Mancilla-Jimenez found sinusoidal fibrin or fibrinogen deposition by immunofluorescence. In severe and fatal cases, the distinctive liver lesion comprises fibrin thrombi in periportal sinusoids, or haemorrhage, with irregular areas of liver cell necrosis ( Fig. 15.14 A ). Nearby portal arterioles and arteries may show fibrinoid change ( Fig. 15.14 B ). Sheehan found periportal lesions in 90% of fatal cases, but Antia et al. reported them in only 5 of 15 cases. Hepatic complications include infarcts, haematoma and liver rupture. Liver disease was estimated to contribute to 17 deaths among the 102 cases reviewed by Rolfes and Ishak.
This affects an estimated 0.2-0.8% of pregnancies, and is often but not always associated with pre-eclampsia. Most cases manifest during the third trimester, although early-onset severe forms are recognized, and some cases present in the early postpartum days. Serum bilirubin is usually high and unconjugated because of the haemolysis. Expedited delivery is the definitive treatment. Liver biopsies may show only mild, nonspecific portal inflammation. However, some cases show periportal fibrin and necrosis resembling the changes of severe pre-eclampsia/eclampsia. Severe hepatic complications affect 2–3% of cases, including liver failure and intrahepatic haemorrhage that may progress to subcapsular haematoma with life-threatening rupture, on occasion necessitating transplantation. Other maternal complications include placental abruption, acute renal failure and DIC. The differential diagnosis includes acute fatty liver of pregnancy, thrombotic thrombocytopenic purpura, haemolytic uraemic syndrome, catastrophic antiphospholipid syndrome and undiagnosed Wilson disease. Recurrence of the syndrome was reported in one instance. Hypoxic hepatitis simulated HELLP in a patient requiring gastric bypass surgery for a bleeding ulcer.
Liver diseases coincidental to pregnancy
Viral hepatitis, including hepatitis (A, B, C, D and E), herpes simplex virus (HSV), cytomegalovirus and Epstein–Barr virus, causes up to 40% of cases of jaundice in pregnancy in the United States. Clinical course and histopathological changes are generally comparable to the nonpregnant state. Hepatitis E virus genotype 1 infection in pregnancy is associated with increased severity and acute liver failure compared with infection in nonpregnant women. Historical accounts of jaundice epidemics with a singularly high mortality of pregnant women are considered to be a hallmark of hepatitis E. HSV hepatitis is rare but can be severe and is an important differential diagnosis in acute liver failure of pregnancy. The prothrombotic state of pregnancy can reveal thrombophilic disease such as antiphospholipid syndrome (APLS), through Budd–Chiari syndrome in pregnancy or early postpartum. Liver adenomas may enlarge. Polycystic liver disease may be exacerbated. The risk of cholelithiasis increases because of bile stasis and increased cholesterol secretion in later pregnancy.
Pregnancy in patients with chronic liver disease
Pregnancy is a state of immune tolerance, with frequent improvement of liver tests in AIH, although the disease may still present in pregnancy. A flare often occurs in the early months after delivery. In patients with portal hypertension, there is a risk of variceal bleeding in the second trimester or during labour.
Miscellaneous liver lesions in pregnancy
Hepatic infarction during pregnancy is closely associated with underlying APLS (see later) and may herald catastrophic APLS. Many patients also show HELLP or incomplete HELLP syndrome.
Spontaneous rupture of the liver
Spontaneous rupture of the liver has now been reported in >100 cases. The clinical presentation is usually acute with profound collapse, sometimes out of proportion to the amount of blood in the peritoneal cavity. The rupture is thought to occur from subcapsular haematomas, and there may be a history of minor trauma. These haematomas may be found without peritoneal leakage, and they are usually sharply circumscribed. Haemangiomas and liver cell adenomas (in particular the inflammatory subtype) may increase in size during pregnancy and become more susceptible to rupture. Spontaneous hepatic rupture occurs most frequently in association with severe pre-eclampsia/eclampsia and in the third trimester of pregnancy. Some patients have no associated hypertension, and others may present immediately postpartum.
Elevated transaminases, sometimes extremely so, are common, but jaundice is infrequent and mild. Histological examination of the liver in a small number of cases showed nonspecific reactive changes.
Hepatic ectopic pregnancy
A number of extrauterine pregnancies with placental attachment to the liver are recorded. In one case the pregnancy went to term but with eventual maternal and fetal death.
Solitary or multiple liver abscesses caused by Listeria monocytogenes are described in immunosuppressed individuals, aging diabetic persons and neonates. Listeriosis in pregnancy is well recognized but usually mild. Lindgren et al. described a case manifesting with a solitary liver abscess during pregnancy.
The liver in haematological diseases
Haematological disorders frequently affect the liver, ranging from a primary hepatic presentation, such as hepatic vascular disease in thrombophilia, to significant hepatic comorbidity, such as in congenital haemolytic anaemias, to hepatic impact of therapies directed at haematological disease, such as after stem cell transplantation and chemotherapy. Conversely, primary liver disease may give rise to haematological complications, such as hepatitis C-associated lymphoma or post-transplant lymphoproliferative disorders.
Liver infiltration by haematological malignancy can occur, although primary hepatic lymphoma is rare; lymphoreticular neoplasms are covered in Chapter 13 . Liver involvement in Langerhans cell histiocytosis and in inherited or acquired haemophagocytic syndromes is discussed in Chapter 3 . The role of thrombophilic diseases and myeloproliferative disorders in hepatic vascular disease, including portal venopathy and portal and hepatic vein thrombosis, is discussed in Chapter 11 . Liver involvement by AL amyloid and monoclonal immunoglobulin deposition disease is discussed separately in this chapter.
Sickle cell disease
The heritable point mutation in the gene encoding β-globin causes polymerization of deoxygenated haemoglobin, deforming red blood cells (RBCs), which impairs blood flow and traumatizes endothelium. In sickle cell disease, predominantly unconjugated hyperbilirubinaemia is universal because of haemolysis; hepatomegaly is common. Transient LFT abnormalities are common during extrahepatic crises. Liver involvement in sickle cell disease often has multiple causes, including direct injury from sickling, cholelithiasis (including bilirubin pigment gallstones, which affects children and most adults), transfusional (including iron overload and historically, viral hepatitis) and cardiac failure. Chronic liver disease arising from these injuries has become more prevalent, and autopsy studies have shown cirrhosis in >10% of patients dying from sickle cell disease. Direct liver injury from sickling arises from repeated episodes of vascular obstruction, hypoxia, necrosis and repair. Crescent-shaped RBCs can be identified in the sinusoids and within Kupffer cells, which also contain haemosiderin and ceroid pigment ( Fig. 15.15 ).
About 10% patients develop an acute sickle hepatic crisis with tender hepatomegaly and jaundice. On histological evaluation, perivenular sinusoids are distended with aggregated sickled RBC thrombi, associated with congestion that may be panlobular and with pronounced Kupffer cell erythrophagocytosis of sickled cells. Patients with acute severe widespread liver involvement develop marked jaundice (termed sickle cell intrahepatic cholestasis ). Additional morphological changes include hepatocyte ballooning, focal necrosis and canalicular cholestasis. Hepatic vein thrombosis may occur. The increased risk of haemorrhage is a relative contraindication to liver biopsy, which is therefore transjugular if attempted. Self-limited sequestration of sickled RBCs occasionally occurs in the liver, accompanied with a dramatic fall in haemoglobin concentration, rapid increase in liver size but minimal alteration of LFTs. Focal nodular hyperplasia, possibly related to local ischaemia, has been reported in children, and there is a report of hepatic biloma.
Paroxysmal nocturnal haemoglobinuria (PNH)
PNH is a rare acquired clonal haemopoietic stem cell disease, characterized by haemolytic anaemia, pancytopenia and thrombosis. Thrombosis often affects the inferior vena cava and the hepatic and splanchnic veins. PNH causes up to 10% of Budd–Chiari syndrome cases.
Fatty liver often accompanies anaemia of any cause. Iron overload is common in the haemolytic and refractory anaemias; iron overload in β-thalassaemia and sideroblastic anaemias is considered in Chapter 4 . The increased incidence of cholelithiasis in haemolytic syndromes predisposes to biliary obstruction. Spherocytes in congenital spherocytosis and acanthocytes in abetalipoproteinaemia may be recognized within sinusoids on light microscopy (see Chapter 3 ). Dehydrated hereditary stomatocytosis, an inherited haemolytic anaemia with increased RBC membrane permeability to Na + and K + , often presents with self-limiting perinatal ascites and hepatitis. Spur cell anaemia is a haemolytic anaemia complicating end-stage chronic liver disease, characterized by acanthocytes in peripheral blood.
Miscellaneous haematological conditions with liver involvement
This is normal in postnatal liver up to 5 weeks after birth and is predominantly erythropoietic. Extramedullary haemopoiesis may persist in the presence of neonatal hepatitis or anaemia, particularly in thalassaemic patients. In adults it may occur in sepsis, aplastic anaemia and so-called marrow replacement syndromes, including tumour metastases, myelomatosis and osteopetrosis ( Fig. 15.16 ). Extramedullary haemopoiesis is present in >90% of patients with myelofibrosis and may form hypervascular masses simulating hepatocellular neoplasms. It is frequently observed in livers of patients with Down syndrome (see Chapter 3 ). Foci of extramedullary haemopoiesis of all lineages may populate livers removed at transplantation for massive hepatic necrosis. They are also often found in hepatocellular adenoma and vascular tumours, including infantile haemangioendothelioma and angiosarcoma.
Thrombocytopenic purpura (TTP)
TTP is a thrombotic microangiopathy caused by mutational or acquired deficiency of von Willebrand factor cleaving protein ( ADAMTS13 ). Patients develop thrombocytopenia, and a microangiopathic (schistocytic) haemolytic anaemia that may cause jaundice; fever, renal impairment and fluctuating neurological signs is characteristic. The clinical settings include acute autoimmune (‘idiopathic’, the most common), pregnancy-, drug-, transplant-, malignancy- or HIV-associated and congenital (neonatal jaundice). Patients with homozygous or compound heterozygous mutation may present in adulthood (e.g. in pregnancy). Predominant phagocytosis of platelets by Kupffer cells was demonstrated in autoimmune TTP that did not respond to splenectomy. Perisinusoidal fibrosis was also reported in 10 patients undergoing splenectomy for TTP, in eight of whom the disease was idiopathic. Platelet-derived growth factor and activated macrophages were suggested as causal factors, analogous to the similar changes in myelofibrosis. Cases have been reported in patients with biopsy-proven PBC, after LT and in a transplant recipient of a cadaveric liver from a donor with a history of thrombocytic purpura. Acute fatal hepatic veno-occlusive disease was described as a complication in one patient.
Common variable immunodeficiency (CVID)
CVID is the most common severe primary antibody deficiency and involves defective B-cell maturation with T-cell dysregulation, characterized by low serum immunoglobulins G, A and/or M. Typical onset is early adulthood. In most patients the cause is unknown, and different phenotypic groups are recognized. Historically, there has been increased risk of chronic viral hepatitis acquired from contaminated therapeutic intravenous immune globulin (IVIG). Mild clinical manifestations of liver disease are common, including mild cholestasis or elevated transaminases, hepatomegaly or splenomegaly. Approximately 10–20% of patients develop multisystem granulomas, predominantly pulmonary but often with hepatic involvement that responds poorly to immunosuppression. Diffuse NRH affected 5% of 261 patients in one study and is associated with portal hypertension that progresses in some patients ( Fig. 15.17 ). Inflammatory changes are also typically encountered, including sinusoidal lymphocytosis, nonspecific reactive hepatitis and occasional cases with more severe, AIH-like injury and severe liver dysfunction. Daniels et al. observed that the low-grade portal and lobular inflammation without plasma cells or progressive fibrosis in their series of patients was similar to that encountered with coeliac disease, related to intestinal inflammation, and went on to identify concurrent intestinal inflammation in five of seven biopsied individuals.
Autoimmune lymphoproliferative syndrome (ALPS)
ALPS is caused by a germline mutational defect in a gene of the Fas (CD95) pathway of apoptosis, most often FAS itself, or the genes encoding caspase 10 or Fas ligand. Patients develop generalized lymphadenopathy, splenomegaly, cytopaenias and autoimmune phenomena, including autoimmune cytopenias; there is polyclonal elevation of serum IgG levels, and hepatomegaly is common. A minority of patients develop glomerulonephritis and/or seronegative AIH. Liver biopsy descriptions include portal lymphocytic infiltration and in one case, chronic hepatitis with fibrosis.
This is characterized by persistent eosinophilia without conventional cause, in blood or peripheral tissues, combined with organ dysfunction. Fauci et al. noted mild hepatomegaly and/or minor disturbances of LFTs in 30% of patients. Hepatic involvement may manifest radiologically with mass lesions; lobar, segmental and subsegmental lesions have been described. Portal and lobular, mixed mononuclear and eosinophil infiltrates are reported, including involvement of portal venules, focal necrosis and deposition of major basic protein in areas of hepatocellular injury. Biliary damage has been observed, and some patients present with cholestasis. There are reports of sclerosing cholangitis associated with the hypereosinophilic syndrome.
Congenital fibrinogen deficiencies
These are counted among the so-called rare bleeding deficiencies, including quantitative deficiency (hypo- or afibrinogenaemia) and dysfunctional fibrinogen (dysfibrinogenaemia). In addition to bleeding episodes, some patients have increased risk of paradoxical venous thrombosis. Patients with hypofibrinogenaemia may have hepatic fibrinogen storage, manifesting on biopsy as eosinophilic inclusions in hepatocytes, although similar inclusions have been shown in two patients without known fibrinogen storage disease (see Chapter 3 ). Some develop cirrhosis, and although high risk, LT provides a form of cure.
Reactive lymphoid hyperplasia of the liver (‘pseudolymphoma’, ‘nodular lymphoid lesion’)
More than 50 patients are described as having liver masses, often asymptomatic, which on imaging resemble hepatocellular carcinoma but histologically represent polyclonal lymphoid tissue, often with secondary follicles. The pathogenesis remains uncertain. Some coexist with tumours or immunological disorders, including Sjögren syndrome, autoimmune thyroiditis and PBC.
Most patients with heterotopic splenic tissue have a history of splenectomy caused by splenic trauma, sometimes decades earlier. Splenosis is well recognized in both the abdominal and the thoracic cavity as multiple nodules that may also affect solid organs. Discrimination from hepatic neoplasia can be made with technetium-99m-labelled heat-denatured RBC scintigraphy and superparamagnetic iron oxide-enhanced MRI, if suspected from the history and subcapsular location ( Fig. 15.18 ). Immunohistochemical demonstration that the cells lining splenotic sinusoids have a similar immunophenotype to those of normal spleen (CD8+ CD31+ CD34−) supports the diagnosis.
Haemophagocytic lymphohistiocytoses and macrophage activation syndrome
Haemophagocytic lymphohistiocytoses (HLHs) are a heterogeneous group of genetic or acquired hyperinflammatory disorders. HLHs have common clinical manifestations related to abnormal prolonged activation of T lymphocytes and macrophages with an excess of proinflammatory cytokines (‘cytokine storm’); about 60% of patients show prominent macrophage haemophagocytosis, especially in bone marrow or lymph nodes. The mortality of patients with symptomatic episodes is high. Primary HLH is related to autosomal recessive genetic defects compromising the cytotoxic function of natural killer (NK) and CD8+ T cells (see Chapter 3 ). Secondary (acquired, reactive) HLH is usually triggered by infection (often EBV or CMV, but also other infections, including TB) or malignancy (especially lymphoma in elderly patients). However, other settings of immune dysfunction are well described, including after immunosuppressive or biological therapy, SLE and HIV infection. Some patients with secondary HLH also carry genetic susceptibilities such as compound heterozygosity.
The term macrophage activation syndrome describes secondary HLH complicating a rheumatic disease, most often systemic-onset juvenile idiopathic arthritis (see next section). Clinical manifestations include fever, splenomegaly, multiple cytopaenias, increased serum ferritin, hypertriglyceridaemia and/or hypofibrinogenaemia and sometimes morphological evidence of haemophagocytosis. On liver biopsy, Kupffer cell hypertrophy and hyperplasia with erythrophagocytosis are characteristic ( Fig. 15.19 ). Prendki et al. found these changes in 1.3% of 5194 successive adult medical liver biopsies and observed that these features were distinctive and not part of the common chronic liver diseases. In particular, they noted that whereas only 36% of the patients whose biopsies showed the changes also met complete criteria for secondary HLH, the other 64% showed the same underlying disease associations (HIV infection, haematological neoplasia, autoimmune disease, other infections such as TB, EBV and CMV). Therefore the finding on liver biopsy of changes suggesting HLH, in the context of only incomplete clinical and laboratory evidence for secondary HLH, should nevertheless prompt a similar clinical workup for potential causes.
The liver in connective tissue and joint diseases
Although LFT abnormalities are common, clinically significant direct liver involvement is rare in the connective tissue diseases. More common are hepatic injuries from drug treatment or independent concurrent liver disease that in some instances, such as chronic viral hepatitis, is itself also affected by the drug treatment.
Rheumatoid arthritis (RA)
Up to 80% of patients with RA have abnormal LFTs, most often elevated serum ALP levels (predominantly liver isoenzyme) which correlate with arthritic activity. Hypoalbuminaemia can be multifactorial and extrahepatic in origin. Mild (nonamyloid) hepatomegaly may be found in 10–20% of patients, but other clinical signs of chronic liver disease are usually lacking. Liver biopsy and autopsy studies have not identified any consistent or specific finding. The main changes are steatosis, nonspecific reactive hepatitis and minimal periportal fibrosis ; chronic hepatitis and sinusoidal dilation have been reported. Ruderman et al. found unexplained fibrosis in 8% of 188 autopsy cases, but it was severe in only 1%.
Rheumatoid vasculitis has features of a variable vessel vasculitis and is most often cutaneous leukocytoclastic or neuopathic polyangiitis-like with mononeuritis multiplex. Infrequently, rheumatoid vasculitis manifests in liver as a polyarteritis nodosa-like segmental necrotizing arteritis similar to hepatic arteritis in some other collagen vascular diseases. The focality of involvement and relatively large calibre of the artery targeted (>100 µm) are a challenge to sampling at autopsy and not likely to be sampled at needle biopsy. The arteritis can produce infarction and haematoma with catastrophic spontaneous rupture of the liver. Diffuse NRH ( Fig. 15.20 A ) in RA can be associated with Felty syndrome (see next section). Amyloid AA may complicate longstanding disease and is considered later. There is a case report of rheumatoid nodules in the liver ( Fig. 15.20 B ).
Drug-induced liver injury or the effects of disease-modifying agents on other concurrent liver disease such as chronic viral hepatitis are important considerations in patients with RA. Common disease-modifying agents causing hepatic injury include methotrexate, sulfasalazine, gold, salicylates, T-cell co-stimulatory blockade and particularly TNF blockers (see Chapter 12 ). Lipogranulomas may be seen containing gold pigment from previous therapy.
Felty syndrome is an uncommon severe form of RA, originally characterized by splenomegaly and neutropaenia, but also manifesting anaemia, thrombocytopaenia, lymphadenopathy and skin ulcers. Patients often have hepatomegaly and develop portal hypertension associated with diffuse nodular regenerative hyperplasia (NRH) (see Chapter 11 ). The pathogenesis of NRH in RA and Felty syndrome has been suggested to be microscopic angiitis causing loss of terminal arterioles and obliteration of portal venules. Marked sinusoidal lymphocytosis is also described.
Systemic-onset juvenile idiopathic arthritis and adult-onset Still disease
Juvenile idiopathic arthritis (JIA) describes all forms of chronic arthritis arising before age 16. The systemic-onset type of JIA (previously Still disease) is a systemic autoinflammatory disorder of uncertain pathogenesis. Minor LFT abnormalities have been noted in affected patients, but in the small number of liver biopsies examined, only nonspecific reactive changes were found. Patients have significant morbidity and mortality from macrophage activation syndrome and AA amyloidosis, although the incidence of amyloid has declined with current therapies. There are reports of portal inflammation and hepatitis related to disease-modifying therapies, including methotrexate and TNFα blockade.
Adult-onset Still disease shows similar but more frequent signs of liver dysfunction, with hepatomegaly and usually mildly increased transaminases affecting up to 76% of patients. Infrequently, hepatic failure can develop, which may respond to prompt immunosuppression, although one report describes a patient with intractable acute liver failure in macrophage activation syndrome who required LT. There is a report of portal vein thrombosis and of ground-glass hepatocellular inclusions. Hepatotoxicity from disease-modifying agents is also reported.
Sjögren syndrome arises from immune-mediated destruction of exocrine glands, primarily targeting salivary and lacrimal glands. There is an increased incidence of other autoimmune diseases, including PBC, AIH, sarcoid and antiphospholipid syndrome. The occurrence of other autoimmune connective tissue disease such as RA or SLE defines secondary Sjögren syndrome. Viral infection including hepatitis C has been suggested as a potential trigger. Hepatomegaly and abnormal LFTs are common, but as with RA, there is no consistent histological change in liver biopsies, which in the absence of other concurrent primary liver disease such as hepatitis C, often show nonspecific reactive hepatitis. The clinicopathological overlap in disease spectra of Sjögren syndrome and PBC suggests common or parallel pathogenetic elements. Indeed, a majority of PBC patients report sicca symptoms, and on salivary gland biopsy, some show changes consistent with Sjögren syndrome. Primary hepatic lymphoma has been described in Sjögren syndrome.
Systemic lupus erythematosus (SLE)
Determination of the frequency of direct liver involvement with SLE is confounded by the common occurrence of one or more comorbidities, including drug injury, viral hepatitis and metabolic syndrome. Macrovesicular steatosis is common but likely often attributable to corticosteroid therapy. Chowdhary et al. reported that severe chronic liver disease in patients with SLE was usually caused by concurrent conditions such as viral or autoimmune hepatitis or fatty liver disease. However, otherwise unexplained increases in serum transaminase levels have been observed in 8–23% patients, often correlating with metrics of disease activity and diminishing with increased immunosuppression. Hepatic inflammatory changes most often include mild portal or periportal mixed mononuclear cell inflammation, without dominant plasma cells or lymphoid follicles. In a review of Japanese autopsy registry data for 1468 SLE patients, Matsumoto et al. noted a history of chronic hepatitis in 2.5% and cirrhosis in 1.1%.
It is rare for patients meeting the diagnostic criteria for SLE also to have autoimmune hepatitis (AIH). The two diseases typically differ in HLA associations and serological profile, including antibody to Smith antigen or ribosomal P antibodies (SLE), smooth muscle antibody and anti-LKM antibody (AIH). Both diseases, however, are associated with antinuclear antibodies (ANAs), although antibody to double-stranded DNA is not infrequently detectable in ANA-positive type I AIH, as well as SLE. The highly active interface and lobular hepatitis, plasma cell predominance, lymphoid follicles, hepatocyte rosetting and emperipolesis that characterize AIH are not features of SLE.
Occasional cases with coexisting SLE and PBC are described.
Hepatic vascular disease is well described in SLE, including diffuse NRH, for which the pathogenesis is unclear but may relate to thrombophilic tendency or possibly immune capillaritis. Peliosis hepatis was found in six (12%) of the 52 SLE cases reported by Matsumoto et al. Arteritis affected 18% of their patients, manifesting as a polyarteritis nodosa-like necrotizing arteritis at various stages of activity (mostly healed), affecting predominantly vessels of 100–400 µm diameter. Hepatic arteritis in SLE can be complicated by infarction and spontaneous rupture.
Hepatic granulomas have been described in several cases, as has opportunistic infection such as Cryptococcus or Candida, and rare cases of malakoplakia. Secondary haemophagocytic lymphohistiocytosis is a significant complication in some patients (see previous discussion). AA amyloidosis is a rare complication of longstanding SLE that can be encountered on liver biopsy.
The drug-induced variant of SLE is typically associated with procainamide or hydralazine, but also quinidine, minocycline, chlorpromazine, carbamazepine, interferon alfa and TNFα blockers; rare occurrences are associated with statin use (see Chapter 12 ). Neonatal lupus erythematosus (NLE) is caused by damage to fetal tissue by maternal anti-Ro and anti-La antibodies crossing the placenta (see Chapter 3 ).
Antiphospholipid syndrome (APLS)
APLS is an arterial and venous thrombophilic disorder associated with high-titre antiphospholipid autoantibodies, including anti-β 2 -glycoprotein I or anticardiolipin antibodies. About 40% of patients also have SLE; rheumatologic disease may develop after a diagnosis of primary APLS. Hepatic manifestations include Budd–Chiari syndrome (which may be the first manifestation), arterial thrombosis after LT and focal hepatic infarction ( Fig. 15.21 ). There may be an association with diffuse NRH.
Systemic sclerosis (systemic scleroderma)
Systemic sclerosis is categorized into diffuse and limited forms, discriminated clinically by the extent of skin involvement and serologically by associations with anti-topoisomerase I and anti-RNA polymerase III antibodies (diffuse disease) or anticentromeric antibodies (limited disease). Diffuse disease shows earlier and more rapidly progressive involvement of heart, lung and kidney. CREST syndrome (calcinosis, Raynaud phenomenon, oesophageal dysfunction, sclerodactyly and telangiectasis) is the limited form of the disease; up to 25% of such patients also have AMAs, although the histological changes of PBC are present in only 2–3%. PBC associated with scleroderma progresses more slowly than PBC alone.
In both a study of 727 patients and a review of 58 matched autopsy cases, liver involvement in systemic sclerosis was rare and without specific features. Morris et al. reported four systemic sclerosis patients with portal hypertension: one had cirrhosis, two had chronic hepatitis and in the fourth patient the liver showed only some granulomas. There are isolated reports of diffuse NRH, hepatic infarction, extrahepatic biliary disease with gallbladder fibrosis and large-duct obstruction caused by vasculitis and ulceration. Concurrent PSC or AIH occurs but is rare.
Mixed connective tissue disease
This syndrome is characterized by overlapping clinical features of SLE, systemic sclerosis and polymyositis, with high-titre autoantibody to the uridine-rich small nuclear ribonucleoprotein (anti-U1 RNP) fraction of extractable nuclear antigens, which may be a pathogenic target. Liver disease is uncommon, usually nonspecific reactive hepatitis, AIH or unclassified chronic hepatitis.
Liver involvement in the systemic vasculitides is also discussed in Chapter 11 . Of the large-vessel arteritides, giant cell arteritis is frequently associated with elevated serum ALP and focal defects on isotope liver scans, likely attributable to hepatic arteritis that has occasionally been proven histologically. Half of patients with giant cell arteritis develop polymyalgia rheumatica before, with or after clinical vasculitis (see next section). Abnormal liver biochemistry in Takayasu arteritis may be secondary to ischaemia. Polyarteritis nodosa affects the liver in >40% of cases, often producing infarction ; in one case, NRH and biliary changes were attributed to ischaemic cholangitis. Behçet disease is characterized by a variable vessel vasculitis and thromboangiitis ; hepatic vein thrombosis with or without portal vein thrombosis is a common major complication, and NRH may develop. Significant liver involvement in microscopic polyangiitis ( Fig. 15.22 ) or granulomatosis with polyangiitis ( Wegener) is uncommon, but in one prolonged example led to liver failure. Focal hepatic infarction was described in a case of Churg–Strauss syndrome.
Polymyalgia rheumatica is a periarticular inflammatory syndrome of subacute bilateral shoulder (or hip) pain and stiffness in patients over age 50. Increased serum ALP levels affect up to 30% of patients and improve with corticosteroid treatment of the condition. One-third of patients show abnormal fluorodeoxyglucose uptake in large vessels, suggesting subclinical vasculitis, and 20% of patients represent a polymyalgic presentation of giant cell arteritis, which can involve liver directly. Other cases show no consistent specific findings on liver needle biopsy, which may be normal; changes reported in case reports include nonspecific reactive hepatitis, portal hepatitis with mild fibrosis, diffuse NRH and granulomas.
Segmental arterial mediolysis is an apparently noninflammatory arteriopathy characterized by medial degeneration with aneurysm and dissection. This can affect coeliac axis vessels, including two reports of hepatic artery rupture with intra-abdominal haemorrhage.
The liver in renal diseases
Specific hepatic complications of individual renal diseases are extremely uncommon, although both organs can be significantly affected in several multisystem diseases. Renal and liver involvement with polycystic disease is discussed in Chapter 3 .
Chronic renal failure and renal replacement therapy
Patients with chronic kidney disease have a severely increased cardiovascular risk, including metabolic syndrome and associated fatty liver disease. Moreover, drugs typically used to treat patients with chronic renal disease have significant hepatotoxicity, including antibiotics, lipid-lowering drugs, antihypertensives and oral hypoglycaemic agents. The hepatotoxicity of immunosuppressive therapy in allograft recipients is discussed in Chapter 14 , but various hepatic microvascular changes reported in renal allograft recipients may partly be attributable to azathioprine hepatotoxicity, including peliosis hepatis, diffuse NRH (some with portal hypertension), veno-occlusive disease and perisinusoidal fibrosis with portal hypertension. The calcineurin inhibitors contribute strongly to post-transplant diabetes, dyslipidaemia and hypertension.
Patients on maintenance dialysis are at increased risk of chronic viral hepatitis. Improved infection control and vaccination have reduced the prevalence of hepatitis B infection to 0–7% among dialysis patients in developed countries, although outbreaks occur, and chronic infection remains more prevalent in developing countries. The short life expectancy for other reasons of patients on dialysis and the availability of antiviral treatments limit detailed understanding of the natural history of dialysis-acquired viral hepatitis B. Clinical outcomes are generally comparable, although histological progression of chronic hepatitis may be accelerated. HBV-infected kidney allograft recipients have reduced graft and patient survival compared with uninfected patients, but this improves with antiviral treatment. There is more rapid progression of chronic hepatitis B after renal transplantation, and occasional cases of fibrosing cholestatic hepatitis B have been described in renal allograft recipients, including one after allograft failure and removal but with the patient maintained on corticosteroids.
Hepatitis C infection is relatively prevalent in long-term haemodialysis patients, especially in developing countries. Nosocomial transmission is predominantly responsible where haemopoietic growth factors have replaced the need for blood transfusion, and with effective blood product screening. Maintenance haemodialysis patients with hepatitis C have increased mortality compared with uninfected patients and gain a clear survival benefit from renal transplantation compared with remaining on dialysis. Graft and patient survival after renal transplantation, however, is still reduced compared with uninfected recipients because of cirrhosis and hepatocellular carcinoma. Rapidly progressive HCV infection may develop after renal transplant, resembling the fibrosing cholestatic hepatitis of HBV. Delladetsima et al. suggested that this manifestation was more likely if HCV infection was acquired about the time of transplantation.
Chronic progressive viral hepatitis E can develop in renal allograft recipients just as in other chronically immunosuppressed patients; serum testing for viraemia with PCR is necessary because seroconversion can be delayed. Cytomegalovirus acute infection or reactivation may occur in >50% of patients undergoing renal transplantation, in the absence of prophylaxis strategies, and is one of the increased medical complications of participating in ‘transplant tourism’. Herpes simplex hepatitis after primary infection or reactivation typically manifests early after renal transplantation but is rare (0.3% of transplants without prophylaxis). Disseminated varicella-zoster infection after primary infection or reactivation is also rare.
Hepatic iron overload is well described in long-term haemodialysis patients receiving transfusions before the availability of erythropoietin. Some developed hepatic dysfunction and cirrhosis, among whom HFE mutations are likely to have increased the susceptibility to pathological iron overload. Patients with chronic kidney disease are prone to vascular calcification. Extensive calcification of necrotic hepatocytes, attributed to dystrophic calcification and altered calcium/phosphate homeostasis, has been reported in dialysis patients after shock-related ischaemic liver injury. Silicone particles from dialysis tubing can provoke a granulomatous reaction and scarring. Numerous aluminium-containing epithelioid cell granulomas were found in the liver, spleen and lymph nodes of two patients after long-term haemodialysis. Acquired dialysis-related β 2 -microglobulin amyloid has been identified in hepatic vessels in a few cases. Extensive subcapsular steatosis is described in patients receiving insulin administration through peritoneal dialysates.