TPN-associated hepatic disease

Infants

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.

Severe liver injury associated with longstanding total parenteral nutrition in a 13-month-old child with necrotizing enterocolitis. Prominent portal tract expansion with fibrosis, ductular reaction and mild inflammatory cell infiltration, including pigmented macrophages. A, H&E stain; B, Gordon and Sweet reticulin stain.

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 High-calorie dextrose-based TPN has been superseded by lower-calorie infusions containing fat, with a reduced incidence of hepatic dysfunction.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.

Hepatic changes on total parenteral nutrition in an adult with Crohn disease. A, Perivenular macro- and microvesicular steatosis and bilirubinostasis. B, Prominent aggregates of ceroid-containing macrophages (periodic acid-Schiff [PAS]-diastase stain.) C, Granulomatoid aggregate of foamy macrophages with some lymphocytes and plasma cells D, Portal tract inflammation with prominent macrophages, lymphocytes and occasional eosinophils. ( A, C and D, H&E stain.)

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.

Steatosis

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.

Chronic hepatitis

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.

Cirrhosis

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.

Cholangiocarcinoma

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.

Biliary intraepithelial neoplasia (BilIN) and invasive cholangiocarcinoma in primary sclerosing cholangitis associated with ulcerative colitis (H&E stain).

Other changes

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.

Coeliac disease

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

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.

Liver biopsy in patient with Whipple disease. A, Kupffer cell hyperplasia with some large intrasinusoidal cells (H&E stain). B, These cells are strongly periodic acid-Schiff positive (PAS-diastase stain).

Eosinophilic gastroenteritis

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.

Hyperthyroidism

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.

Hypothyroidism

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.

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.

Cholestasis of pregnancy. Note marked bilirubinostasis with minimal accompanying inflammation—‘bland cholestasis’. (H&E stain.)

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.

Acute fatty liver of pregnancy. A, Microvesicular steatosis involving perivenular and middle zones (H&E stain). B, At higher-power magnification, note swollen hepatocytes and microvesicular fatty accumulation (H&E stain), shown in C with an Oil Red O stain.

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.

Liver in pre-eclampsia/eclampsia. A, Area of periportal necrosis with intrasinusoidal fibrin deposition. B, Hepatic arterioles showing fibrinoid necrosis; intrasinusoidal fibrin deposition is also present. (Masson trichrome stain.)

HELLP syndrome

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

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 ).

Liver in sickle cell anaemia. Note the sickled red cells in the hepatic venule and congested sinusoids. There is also abundant haemosiderin in perivenular hepatocytes and Kupffer cells. (Martius Scarlet Blue stain.)

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.

Other anaemias

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.

Extramedullary haemopoiesis

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.

Extramedullary haemopoiesis in the liver. A, Pleomorphic intrasinusoidal infiltrate, and B, megakaryocyte (H&E stain.)

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.

Common variable immunodeficiency. A, Diffuse nodular regenerative hyperplasia. Fine micronodularity without fibrosis, most nodules being 1–2 mm in diameter and centered on portal areas. B, Same case, showing the hyperplastic periportal parenchyma with intervening atrophic regions. (H&E stain.)

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.

Hypereosinophilic syndrome

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.

Hepatic splenosis

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.

Splenosis. Hepatitis C virus (HCV)-infected cirrhotic liver removed at transplantation shows dark red-brown lesions considered to be foci of hepatocellular carcinoma clinically, but microscopically shown to correspond to splenic tissue.

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.

Secondary lymphohistocytic haemophagocytosis. Kupffer cell with erythrophagocytosis in a patient with Epstein–Barr virus (EBV)-associated lymphoproliferative disease. (H&E stain.)

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 ).

Liver in rheumatoid arthritis. A, Nodular regenerative hyperplasia in patient with Felty syndrome (Gordon and Sweet reticulin stain). B, Rheumatoid nodule (H&E stain).

(Courtesy of Dr. Carole D. Kooijman.)

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

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

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.

Catastrophic antiphospholipid syndrome. Portal vein thrombus and focal parenchymal necrosis in a patient with multiple low-opacity liver lesions. (H&E stain.)

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.

Systemic vasculitides

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.

ANCA-negative microscopic polyangiitis involving liver: transmural circumferential necrotizing arteritis (H&E stain).

Polymyalgia rheumatica

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.

Viral hepatitis

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.

Maintenance dialysis

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.